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  • 1. Arsura, Marcello
    et al.
    Panta, Ganesh R.
    Bilyeu, Jennifer D.
    Cavin, Lakita G.
    Sovak, Mika A.
    Oliver, Aundrea A.
    Factor, Valentina
    Heuchel, Rainer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Mercurio, Frank
    Thorgeirsson, Snorri S.
    Sonenshein, Gail E.
    Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation.2003In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 22, no 3, 412-425 p.Article in journal (Refereed)
    Abstract [en]

    NF-kappaB has been implicated in the regulation of apoptosis, a key mechanism of normal and malignant growth control. Previously, we demonstrated that inhibition of NF-kappaB activity by TGF-beta1 leads directly to induction of apoptosis of murine B-cell lymphomas and hepatocytes. Thus, we were surprised to determine that NF-kappaB is transiently activated in response to TGF-beta1 treatment. Here we elucidate the mechanism of TGF-beta1-mediated regulation of NF-kappaB and induction of apoptosis in epithelial cells. We report that TGF-beta1 activates IKK kinase, which mediates IkappaB-alpha phosphorylation. In turn, the activation of IKK following TGF-beta1 treatment is mediated by the TAK1 kinase. As a result of NF-kappaB activation, IkappaB-alpha mRNA and protein levels are increased leading to postrepression of NF-kappaB and induction of cell death. Inhibition of NF-kappaB following TGF-beta1 treatment increased AP-1 complex transcriptional activity through sustained c-Jun phosphorylation, thereby potentiating AP-1/SMADs-mediated cell killing. Furthermore, TGF-beta1-mediated upregulation of Smad7 appeared independent of NF-kappaB. In hepatocellular carcinomas of TGF-beta1 or TGF-alpha/c-myc transgenic mice, we observed constitutive activation of NF-kappaB that led to inhibition of JNK signaling. Overall, our data illustrate an autocrine mechanism based on the ability of IKK/NF-kappaB/IkappaB-alpha signaling to negatively regulate NF-kappaB levels thereby permitting TGF-beta1-induced apoptosis through AP-1 activity.

  • 2.
    Chen, X.
    et al.
    Karolinska Inst, Dept Cell & Mol Biol, Berzelius Vag 35, S-17177 Stockholm, Sweden..
    Kamranvar, Siamak A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Karolinska Inst, Dept Cell & Mol Biol, Berzelius Vag 35, S-17177 Stockholm, Sweden.
    Masucci, M. G.
    Karolinska Inst, Dept Cell & Mol Biol, Berzelius Vag 35, S-17177 Stockholm, Sweden..
    Oxidative stress enables Epstein-Barr virus-induced B-cell transformation by posttranscriptional regulation of viral and cellular growth-promoting factors2016In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 35, no 29, 3807-3816 p.Article in journal (Refereed)
    Abstract [en]

    Infection of human B lymphocytes by Epstein-Barr virus (EBV) leads to the establishment of immortalized lymphoblastoid cell lines (LCLs) that are widely used as a model of viral oncogenesis. An early consequence of infection is the induction of DNA damage and activation of the DNA damage response, which limits the efficiency of growth transformation. The cause of the DNA damage remains poorly understood. We have addressed this question by comparing the response of B lymphocytes infected with EBV or stimulated with a potent B-cell mitogen. We found that although the two stimuli induce comparable proliferation during the first 10 days of culture, the EBV-infected blasts showed significantly higher levels of DNA damage, which correlated with stronger and sustained accumulation of reactive oxygen species (ROS). Treatment with ROS scavengers decreased DNA damage in both mitogen-stimulated and EBV-infected cells. However, while mitogen-induced proliferation was slightly improved, the proliferation of EBV-infected cells and the establishment of LCLs were severely impaired. Quenching of ROS did not affect the kinetics and magnitude of viral gene expression but was associated with selective downregulation of the viral LMP1 and phosphorylated cellular transcription factor STAT3 that have key roles in transformation. Analysis of the mechanism by which high levels of ROS support LMP1 expression revealed selective inhibition of viral microRNAs that target the LMP1 transcript. Our study provides novel insights into the role of EBV-induced oxidative stress in promoting B-cell immortalization and malignant transformation.

  • 3.
    Dubrovska, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Kanamoto, Takashi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Lomnytska, Marta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Volodko, Natalya
    Souchelnytskyi, Serhiy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    TGFbeta1/Smad3 counteracts BRCA1-dependent repair of DNA damage2005In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 24, no 14, 2289-2297 p.Article in journal (Refereed)
    Abstract [en]

    Inactivation of the BRCA1 gene has been found to confer susceptibility to early-onset familial breast and ovarian cancers. BRCA1 regulates DNA repair, chromatin remodeling and affects gene transcription. Transforming growth factor-beta (TGFbeta) is a potent regulator of growth, apoptosis and invasiveness of tumor cells, including breast cancer cells. Here we show that Smad3 which is a component of the TGFbeta signaling pathway, forms a complex with BRCA1 in vitro and in vivo. The interaction is mediated by the MH1 domain of Smad3 and the C-terminal part of BRCA1. We observed a co-localization of Smad3 and BRCA1 in nuclear complexes. We also found that TGFbeta1/Smad3 counteracted BRCA1-dependent repair of DNA double-strand breaks in human breast epithelial cells, as evaluated by BRCA1 nuclear foci formation, single-cell gel electrophoresis and cell survival assays. Thus, TGFbeta1/Smad3 suppresses BRCA1-dependent DNA repair in response to a DNA damaging agent.

  • 4.
    Ekman, Simon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Kallin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Engström, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Rönnstrand, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    SHP-2 is involved in heterodimer specific loss of phosphorylation of Tyr771 in the PDGF β-receptor2002In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 21, no 12, 1870-1875 p.Article in journal (Refereed)
    Abstract [en]

    We have previously shown that the binding site for GTPase activating protein of Ras (RasGAP) in the PDGF beta-receptor, Tyr771, is phosphorylated to a much lower extent in the heterodimeric configuration of PDGF alpha- and beta-receptors, compared to the PDGF beta-receptor homodimer. The decreased recruitment of the RasGAP to the receptor leads to prolonged activation of the Ras/MAP kinase pathway, which could explain the increase in mitogenicity seen upon induction of heterodimers. The molecular mechanism underlying these differences was investigated. We could show that the loss of phosphorylation of Tyr771 was dependent on presence of intact binding sites for the protein tyrosine phosphatase SHP-2 on the PDGF beta-receptor. Thus, in PDGF receptor mutants in which binding of SHP-2 was lost, a higher degree of phosphorylation of Tyr771 was seen, while other phosphorylation sites in the receptor remained virtually unaffected. Thus, SHP-2 appears to play an important role in modulating phosphorylation of Y771, thereby controlling RasGAP recruitment and Ras/MAP kinase signaling in the heterodimeric configuration of the PDGF receptors.

  • 5. Franklin, Gary C.
    et al.
    Adam, Gail I.R.
    Miller, Stephen J.
    Moncrieff, Colin L.
    Ullerås, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
    Ohlsson, Rolf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
    An Inr-containing sequence flanking the TATA box of the human c-sis (PDGF-B) proto-oncogene promoter functions in cis as a co-activator for its intronic enhancer1995In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 11, no 9, 1873-1884 p.Article in journal (Other academic)
    Abstract [en]

    High-level activity of the human PDGF-B promoter in choriocarcinoma cell lines depends upon an atypical, intronic enhancer-like element which does not function with heterologous promoters tested. An extensive series of mutant PDGF-B promoter-driven constructs identified a sequence flanking the TATA box which is required specifically for enhancer-mediated transcription in human choriocarcinoma cell lines. This element, which we here term an enhancer-dependent cis co-activator (EDC) contains an Inr (initiator) consensus sequence upstream of the TATA box which is required, but not sufficient for its function. Requirement for the EDC is cell type-specific, since it was dispensable for enhancer-mediated transcription in a human breast cancer cell line. Although it lies within the region defined, the TATA box itself is not required for EDC function, or for basal promoter function which may derive from a second Inr-like sequence situated at the transcriptional start site. These observations indicate that interactions between some promoter and enhancer elements may be more complex than that generally described for 'classical' enhancer systems and may suggest an additional function for the initiator motif.

  • 6.
    Gal, Annamaria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Fedorova, L.
    Microbiology and Tumour Biology Center, Karolinska Institute, Stockholm, Sweden.
    Imreh, S.
    Microbiology and Tumour Biology Center, Karolinska Institute, Stockholm, Sweden.
    Beug, Hartmut
    Research Institute of Molecular Pathology, Vienna, Austria.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Sustained TGF beta exposure suppresses Smad and non-Smad signalling in mammary epithelial cells, leading to EMT and inhibition of growth arrest and apoptosis2008In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 27, no 9, 1218-1230 p.Article in journal (Refereed)
    Abstract [en]

    To better understand the dual, tumour-suppressive and tumour-promoting function of transforming growth factor-beta (TGFbeta), we analysed mammary epithelial NMuMG cells in response to short and long-term TGFbeta exposure. NMuMG cells became proliferation-arrested and apoptotic after exposure to TGFbeta for 2-5 days, whereas surviving cells underwent epithelial-mesenchymal transition (EMT). After chronic TGFbeta exposure (2-3 weeks), however, NMuMG cells became resistant to proliferation arrest and apoptosis, showing sustained EMT instead (TD cells). EMT was fully reversed by a pharmacologic TGFbeta-receptor-I kinase inhibitor or withdrawal of TGFbeta for 6-12 days. Interestingly, both cell cycle arresting/proapoptotic (Smads, p38 kinase) and antiapoptotic, proliferation and EMT-promoting signalling pathways (PI3K-PKB/Akt, ERK) were co-suppressed to low, but significant levels. Except for PI3K-Akt, TGFbeta-dependent downregulation of these signalling pathways in transdifferentiated (TD) cells was fully reversed upon TGFbeta withdrawal, together with partial re-induction of proliferation arrest and apoptosis. Co-injection of non-tumorigenic NMuMG cells with tumour-forming CHO cells oversecreting exogenous TGFbeta1 (CHO-TGFbeta1) allowed outgrowth of epithelioid cells in CHO-TGFbeta1 cell-induced tumours. These epithelial islands enhanced CHO-TGFbeta1 tumour cell proliferation, possibly due to chemokines (for example, JE/MCP-1) secreted by NMuMG/TD cells. We conclude that suppression of antiproliferative, proapoptotic TGFbeta signalling in TD cells may permit TGFbeta-dependent proliferation, survival and EMT-enhancing signalling pathways to act at low levels. Thus, TGFbeta may modulate its own signalling to facilitate switching from tumour suppression to tumour progression.

  • 7.
    Hawinkels, L J A C
    et al.
    Department of Gastroenterology-Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.
    Paauwe, M
    Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
    Verspaget, H W
    Department of Gastroenterology-Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.
    Wiercinska, E
    Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
    van der Zon, J M
    Department of Gastroenterology-Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.
    van der Ploeg, K
    Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
    Koelink, P J
    Department of Gastroenterology-Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.
    Lindeman, J H N
    Department of Vascular Surgery, Leiden University Medical Centre, Leiden, The Netherlands.
    Mesker, W
    Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands.
    ten Dijke, P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
    Sier, C F M
    Department of Gastroenterology-Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.
    Interaction with colon cancer cells hyperactivates TGF-β signaling in cancer-associated fibroblasts2014In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 33, no 1, 97-107 p.Article in journal (Refereed)
    Abstract [en]

    The interaction between epithelial cancer cells and cancer-associated fibroblasts (CAFs) has a major role in cancer progression and eventually in metastasis. In colorectal cancer (CRC), CAFs are present in high abundance, but their origin and functional interaction with epithelial tumor cells has not been elucidated. In this study we observed strong activation of the transforming growth factor-β (TGF-β)/Smad signaling pathway in CRC CAFs, accompanied by decreased signaling in epithelial tumor cells. We evaluated the TGF-β1 response and the expression of target genes including matrix metalloproteinases (MMPs) and plasminogen activator inhibitor (PAI)-1 of various epithelial CRC cell lines and primary CAFs in vitro. TGF-β1 stimulation caused high upregulation of MMPs, PAI-1 and TGF-β1 itself. Next we showed that incubation of CAFs with conditioned medium (CM) from epithelial cancer cells led to hyperactivation of the TGF-β signaling pathway, enhanced expression of target genes like PAI-1, and the expression of α-smooth muscle actin (α-SMA). We propose that the interaction of tumor cells with resident fibroblasts results in hyperactivated TGF-β1 signaling and subsequent transdifferentiation of the fibroblasts into α-SMA-positive CAFs. In turn this leads to cumulative production of TGF-β and proteinases within the tumor microenvironment, creating a cancer-promoting feedback loop.

  • 8.
    Hede, Sanna-Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Savov, Vasil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Weishaupt, Holger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Sangfelt, O.
    Swartling, Fredrik Johansson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Oncoprotein stabilization in brain tumors2014In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 33, no 39, 4709-4721 p.Article, review/survey (Refereed)
    Abstract [en]

    Proteins involved in promoting cell proliferation and viability need to be timely expressed and carefully controlled for the proper development of the brain but also efficiently degraded in order to prevent cells from becoming brain cancer cells. A major pathway for targeted protein degradation in cells is the ubiquitin-proteasome system (UPS). Oncoproteins that drive tumor development and tumor maintenance are often deregulated and stabilized in malignant cells. This can occur when oncoproteins escape degradation by the UPS because of mutations in either the oncoprotein itself or in the UPS components responsible for recognition and ubiquitylation of the oncoprotein. As the pathogenic accumulation of an oncoprotein can lead to effectively sustained cell growth, viability and tumor progression, it is an indisputable target for cancer treatment. The most common types of malignant brain tumors in children and adults are medulloblastoma and glioma, respectively. Here, we review different ways of how deregulated proteolysis of oncoproteins involved in major signaling cancer pathways contributes to medulloblastoma and glioma development. We also describe means of targeting relevant oncoproteins in brain tumors with treatments affecting their stability or therapeutic strategies directed against the UPS itself.

  • 9. Hunter, K. E.
    et al.
    Palermo, C.
    Kester, J. C.
    Simpson, K.
    Li, Jin-ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tang, L. H.
    Klimstra, D. S.
    Vlodavsky, I.
    Joyce, J. A.
    Heparanase promotes lymphangiogenesis and tumor invasion in pancreatic neuroendocrine tumors2014In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 33, no 14, 1799-1808 p.Article in journal (Refereed)
    Abstract [en]

    Heparan sulfate proteoglycans are an important and abundant component of the extracellular matrix, which undergo substantial remodeling throughout tumorigenesis via the enzymatic activity of heparanase. Heparanase has been shown to be upregulated in many human cancers; however, its specific functions in human pancreatic neuroendocrine tumors (PanNETs) and spontaneous mouse models of cancer have not been evaluated. Here, we investigated the role of heparanase in PanNETs using patient samples and the RIP1-Tag2 (RT2) PanNET-transgenic mouse model. High heparanase expression significantly correlated with more advanced tumor stage, higher tumor grade and the presence of distant metastasis in PanNET patients. We genetically manipulated heparanase levels in the RT2 model using heparanase-transgenic mice, which constitutively overexpress heparanase, and heparanase-knockout mice. Heparanase was found to have a critical role in promoting tumor invasion, through both macrophage and cancer cell sources in the tumor microenvironment. In addition, elevated heparanase levels significantly increased peritumoral lymphangiogenesis in vivo and promoted the trans-differentiation of macrophages into lymphatic endothelial cell-like structures in culture. Conversely, we found that heparanase deletion led to increased angiogenesis and pericyte coverage. Together, these data identify important roles for heparanase in regulating several critical aspects of tumorigenesis, demonstrating that heparanase represents a potential therapeutic target for PanNET patients.

  • 10.
    Hägerstrand, Daniel
    et al.
    Department of Oncology/Pathology, Karolinska Institutet, Cancer Center Karolinska, Stockholm, Sweden.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Achterberg, Sefanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Wickenberg Bolin, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kowanetz, Marcin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Kastemar, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nistér, Monica
    Department of Oncology/Pathology, Karolinska Institutet, Cancer Center Karolinska, Stockholm, Sweden.
    Östman, Arne
    Department of Oncology/Pathology, Karolinska Institutet, Cancer Center Karolinska, Stockholm, Sweden.
    Characterization of an imatinib-sensitive subset of high-grade human glioma cultures2006In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 25, no 35, 4913-4922 p.Article in journal (Refereed)
    Abstract [en]

    High-grade gliomas, including glioblastomas, are malignant brain tumors for which improved treatment is urgently needed. Genetic studies have demonstrated the existence of biologically distinct subsets. Preliminary studies have indicated that platelet-derived growth factor (PDGF) receptor signaling contributes to the growth of some of these tumors. In this study, human high-grade glioma primary cultures were analysed for sensitivity to treatment with the PDGF receptor inhibitor imatinib/Glivec/Gleevec/STI571. Six out of 15 cultures displayed more than 40% growth inhibition after imatinib treatment, whereas seven cultures showed less than 20% growth inhibition. In the sensitive cultures, apoptosis contributed to growth inhibition. Platelet-derived growth factor receptor status correlated with imatinib sensitivity. Supervised analyses of gene expression profiles and real-time PCR analyses identified expression of the chemokine CXCL12/SDF-1 (stromal cell-derived factor 1) as a predictor of imatinib sensitivity. Exogenous addition of CXCL12 to imatinib-insensitive cultures conferred some imatinib sensitivity. Finally, coregulation of CXCL12 and PDGF alpha-receptor was observed in glioblastoma biopsies. We have thus defined the characteristics of a novel imatinib-sensitive subset of glioma cultures, and provided evidence for a functional relationship between imatinib sensitivity and chemokine signaling. These findings will assist in the design and evaluation of clinical trials exploring therapeutic effects of imatinib on malignant brain tumors.

  • 11. Ingemarsdotter, C K
    et al.
    Baird, S K
    Connell, C M
    Öberg, Daniel
    Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
    Halldén, G
    McNeish, I A
    Low-dose paclitaxel synergizes with oncolytic adenoviruses via mitotic slippage and apoptosis in ovarian cancer.2010In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 29, no 45, 6051-63 p.Article in journal (Refereed)
    Abstract [en]

    The microtubule-stabilizing drug paclitaxel has activity in relapsed ovarian cancer. dl922-947, an oncolytic adenovirus with a 24-bp deletion in E1A CR2, replicates selectively within and lyses cells with a dysregulated Rb pathway and has efficacy in ovarian cancer. In the aggressive A2780CP xenograft, combination treatment with weekly dl922-947 and paclitaxel has significantly greater efficacy than either treatment alone and can produce complete tumor eradication in some animals. We investigated the mechanisms of paclitaxel's synergy with dl922-947 in ovarian cancer. The host-cell microtubule network is grossly rearranged and stabilized following adenovirus infection, but paclitaxel does not increase this significantly. Paclitaxel does not synergize by increasing infectivity, viral protein expression or virus release. However, destabilizing the microtubule network with nocodazole reduces viral exit, revealing a novel microtubule-dependent pathway for non-lytic adenoviral exit. dl922-947 can override multiple cell cycle checkpoints but induces cell death by a non-apoptotic mechanism. In combination, dl922-947 and low-dose paclitaxel induces aberrant, multipolar mitoses, mitotic slippage and multinucleation, triggering an apoptotic cell death.

  • 12. Jandt, Enrico
    et al.
    Denner, Karsten
    Kovalenko, Marina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Östman, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Böhmer, Frank-D
    The protein-tyrosine phosphatase DEP-1 modulates growth factor-stimulated cell migration and cell-matrix adhesion2003In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 22, no 27, 4175-4185 p.Article in journal (Refereed)
    Abstract [en]

    Density-enhanced protein-tyrosine phosphatase-1 (DEP-1 also CD148) is a transmembrane molecule with a single intracellular PTP domain. It has recently been proposed to function as a tumor suppressor. We have previously shown that DEP-1 dephosphorylates the activated platelet-derived growth factor (PDGF) beta-receptor in a site-selective manner (Kovalenko et al. (2000). J. Biol. Chem. 275, 16219-16226). We analysed cell lines with inducible DEP-1 expression for cellular functions of DEP-1. Several aspects of PDGFbeta-receptor signaling were negatively affected by DEP-1 expression. These include PDGF-stimulated activation of inositol trisphosphate formation, Erk1/2, p21Ras, and Src. Activation of receptor-associated phosphoinositide-3 kinase activity and of Akt/PKB were weakly attenuated at early time points of stimulation. Inhibition of PDGF-stimulated signaling depended on DEP-1 catalytic activity. Importantly, DEP-1 inhibited PDGF-stimulated cell migration. The catalytically inactive DEP-1 C1239S variant enhanced cell migration and PDGF-stimulated Erk1/2 activation, suggesting a dominant negative interference with endogenous DEP-1. In contrast to cell migration, cell-substrate adhesion was promoted by active DEP-1 and delayed or suppressed by DEP-1 C1239S, correlating with positive effects of DEP-1 on adhesion-stimulated Src kinase. We propose that negative regulation of growth-factor stimulated cell migration and promotion of cell-matrix adhesion may be related to the function of DEP-1 as tumor suppressor.

  • 13.
    Johansson, Fredrik K
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Göransson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Expression analysis of genes involved in brain tumor progression driven by retroviral insertional mutagenesis in mice2005In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 24, 3896-3905 p.Article in journal (Refereed)
    Abstract [en]

    Retroviral tagging previously identified putative cancer-causing genes in a mouse brain tumor model where a recombinant Moloney murine leukemia virus encoding the platelet-derived growth factor B-chain (MMLV/PDGFB) was intracerebrally injected in newborn mice. In the present study, expression analysis using cDNA arrays revealed several similarities of virus-induced mouse gliomas with human brain tumors. Brain tumors with short latency contained on average 8.0 retroviral insertions and resembled human glioblastoma multiforme (GBM) whereas long-latency gliomas were of lower grade, similar to human oligodendroglioma (OD) and had 2.3 insertions per tumor. Several known and novel genes of tumor progression or cell markers were differentially expressed between OD- and GBM-like tumors. Array and quantitative real-time PCR analysis demonstrated elevated expression similar to Pdgfr of retrovirally tagged genes Abhd2, Ddr1, Fos, Ng2, Ppfibp1, Rad51b and Sulf2 in both glioma types compared to neonatal and adult normal brain. The retrovirally tagged genes Plekhb1, Prex1, Prkg2, Sox10 and 1200004M23Rik were upregulated in the tumors but had a different expression profile than Pdgfr whereas Rap1gap, Gli1, Neurl and Camk2b were downregulated in the tumors. The present study accentuates the proposed role of the retrovirally tagged genes in PDGF-driven gliomagenesis and indicates that insertional mutagenesis can promote glioma progression.

  • 14.
    Karlsson, Torbjörn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Songyang, Z
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Landgren, E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lavergne, C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Di Fiore, P P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Anafi, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Pawson, T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Cantley, L C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Molecular interactions of the Src homology 2 domain protein Shb with phosphotyrosine residues, tyrosine kinase receptors and Src homology 3 domain proteins1995In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 10, no 8, 1475-1483 p.Article in journal (Refereed)
    Abstract [en]

    The molecular interactions of the Src homology 2 (SH2) domain and the N-terminal proline-rich sequence motifs (pro-1 to pro-5) of the SH2 protein Shb with other components were presently characterised. Using a degenerate phosphopeptide library the preferred binding site for the Shb SH2 domain was determined to pTyr-Thr/Val/Ile-X-Leu at positions +1 to +3 relative the phosphotyrosine residue. Experiments with competing peptides and platelet-derived growth factor (PDGF) beta-receptor mutants with Y to F substitutions in autophosphorylation sites revealed multiple binding sites for the Shb SH2 domain in the receptor. The Shb SH2 domain also binds to in vitro phosphorylated fibroblast growth factor receptor-1 (FGFR-1) mainly through position Y776. The receptor experiments suggest that other residues besides the +1 to +3 positions may also be of significance for Shb binding. The pro-4/pro-5 motif of Shb binds in vitro particularly well to the Src, p85 alpha PI3-kinase and Eps8 SH3 domains expressed as GST fusion proteins. However, the GST-SH3 domain fusion proteins tested bind in vitro to peptides corresponding to the pro-1 to pro-5 motifs of Shb with low affinity and selectivity, suggesting that sequences outside the core proline motif may also be important for Shb-SH3 domain interactions. In vivo association between Shb-SH3 domain proteins v-Src and Eps8 was detected by coimmunoprecipitation. PDGF treatment did not affect the association between Eps8 and Shb. The data suggest that Shb is an adaptor protein linking SH3 domain proteins to tyrosine kinases or other tyrosine phosphorylated proteins.

  • 15.
    Karlsson, Torbjörn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Apoptosis of NIH3T3 cells overexpressing the Src homology 2 domain protein Shb1996In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 13, no 5, 955-961 p.Article in journal (Refereed)
    Abstract [en]

    To understand the role of the Src homology 2 (SH2) domain protein Shb in the signal transduction of tyrosine kinase receptor, NIH3T3 cells were transfected with a DNA construct expressing the Shb cDNA (NIHSHB cells). The NIHSHB cells expressed elevated levels of proteins with the estimated molecular weights of 77, 66 and 55 kDa as determined by immunoblotting. In contrast to the control cells, the NIHSHB cells failed to increase in cell number in the presence of 1% serum. This effect was largely due to apoptosis, since staining of pyknotic nuclei was observed using the terminal transferase labeling method. The NIHSHB cells displayed similar levels of c-myc mRNA and decreased contents of the p53 protein after culture in 1% serum compared with control cells. The addition of platelet-derived growth factor (PDGF-BB) restored the growth of the NIHSHB cells, whereas insulin-like growth factor-1 (IGF-1) failed to affect the proliferation of Shb overexpressing cells in 1% serum. We conclude that Shb overexpression is associated with cell degeneration under certain conditions, and that Shb could transduce apoptotic signals from tyrosine kinase receptors.

  • 16. Knauth, K
    et al.
    Bex, C
    Jemth, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Buchberger, A
    Renal cell carcinoma risk in type 2 von Hippel-Lindau disease correlates with defects in pVHL stability and HIF-1 alpha interactions2006In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 25, no 3, 370-377 p.Article in journal (Refereed)
    Abstract [en]

    The von Hippel-Lindau (VHL) tumor suppressor protein is the substrate binding subunit of the CBC(VHL) E3 ubiquitin ligase complex. Mutations in the VHL gene cause a variety of tumors with complex genotype/phenotype correlations. Type 2A and type 2B VHL disease are characterized by a low or high risk of renal cell carcinoma, respectively. To investigate the molecular basis underlying the difference between disease types 2A and 2B, we performed a detailed biochemical analysis of the two most frequent type 2A mutations, Y98 H and Y112 H, in comparison to type 2B mutations in the same residues, Y98N and Y112N. While none of these mutations affected the assembly of CBC(VHL) complexes, the type 2A mutant proteins exhibited higher stabilities at physiological temperature. Moreover, the type 2A mutant proteins possessed higher binding affinities for the key cellular substrate, hypoxia-inducible transcription factor 1 (HIF-1alpha). Consistent with these results, type 2A but not type 2B mutant VHL proteins retained significant ubiquitin ligase activity towards HIF-1alpha in vitro. We propose that this residual ubiquitin ligase activity is sufficient to suppress renal cell carcinogenesis in vivo.

  • 17.
    Lindberg, Nanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kastemar, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Olofsson, T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Oligodendrocyte progenitor cells can act as cell of origin for experimental glioma2009In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 28, no 23, 2266-2275 p.Article in journal (Refereed)
    Abstract [en]

    Gliomas are primary brain tumors mainly affecting adults. The cellular origin is unknown. The recent identification of tumor-initiating cells in glioma, which share many similarities with normal neural stem cells, has suggested the cell of origin to be a transformed neural stem cell. In previous studies, using the RCAS/tv-a mouse model, platelet-derived growth factor B (PDGF-B)-induced gliomas have been generated from nestin or glial fibrillary acidic protein-expressing cells, markers of neural stem cells. To investigate if committed glial progenitor cells could be the cell of origin for glioma, we generated the Ctv-a mouse where tumor induction would be restricted to myelinating oligodendrocyte progenitor cells (OPCs) expressing 2',3'-cyclic nucleotide 3'-phosphodiesterase. We showed that PDGF-B transfer to OPCs could induce gliomas with an incidence of 33%. The majority of tumors resembled human WHO grade II oligodendroglioma based on close similarities in histopathology and expression of cellular markers. Thus, with the Ctv-a mouse we have showed that the cell of origin for glioma may be a committed glial progenitor cell.

  • 18.
    Morikawa, Masato
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Koinuma, D
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
    Miyazono, Kohei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genome-wide mechanisms of Smad binding2013In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 32, no 13, 1609-1615 p.Article, review/survey (Refereed)
    Abstract [en]

    A dual role of transforming growth factor β (TGF-β), to both suppress and promote tumor progression and metastasis, has been well established, but its molecular basis has remained elusive. In this review, we focus on Smad proteins, which are central mediators of the signal transduction of TGF-β family members. We describe current knowledge of cell-type-specific binding patterns of Smad proteins and mechanisms of transcriptional regulation, obtained from recent studies on genome-wide binding sites of Smad molecules. We also discuss potential application of the genome-wide analyses for cancer research, which will allow clarification of the complex mechanisms occurring during cancer progression, and the identification of potential biomarkers for future cancer diagnosis, prognosis and therapy.

  • 19. Papadimitriou, E
    et al.
    Vasilaki, Eleftheria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Vorvis, C
    Iliopoulos, D
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kardassis, D
    Stournaras, C
    Differential regulation of the two RhoA-specific GEF isoforms Net1/Net1A by TGF-β and miR-24: role in epithelial-to-mesenchymal transition2012In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Oncogene, ISSN 1476-5594, Vol. 31, no 23, 2862-2875 p.Article in journal (Refereed)
    Abstract [en]

    In the present study we analyzed the regulation of the two isoforms of the RhoA-specific guanine nucleotide exchange factor Net1 by transforming growth factor-β (TGF-β) in keratinocytes. We report that short-term TGF-β treatment selectively induced Net1 isoform2 (Net1A) but not Net1 isoform1. This led to upregulation of cytoplasmic Net1A protein levels that were necessary for TGF-β-mediated RhoA activation. Smad signaling and the MAPK/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway were involved in Net1A upregulation by TGF-β. Interestingly, long-term TGF-β treatment resulted in Net1 mRNA downregulation and Net1A protein degradation by the proteasome. Furthermore, we identified the microRNA miR-24 as a novel post-transcriptional regulator of Net1A expression. Silencing of Net1A resulted in disruption of E-cadherin- and zonula occludens-1 (ZO-1)-mediated junctions, as well as expression of the transcriptional repressor of E-cadherin, Slug and the mesenchymal markers N-cadherin, plasminogen activator inhibitor-1 (PAI-1) and fibronectin, indicating that late TGF-β-induced downregulation of Net1A is involved in epithelial-to-mesenchymal transition (EMT). Finally, miR-24 was found to be implicated in the regulation of the EMT program in response to TGF-β and was shown to be directly involved in the TGF-β-induced breast cancer cell invasiveness through Net1A regulation. Our results emphasize the importance of Net1 isoform2 in the short- and long-term TGF-β-mediated regulation of EMT.

  • 20.
    Porsch, Helena
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Bernert, Berit
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Mehić, Merima
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Theocharis, A D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Heldin, Carl-Henrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Heldin, Paraskevi
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Efficient TGF beta-induced epithelial-mesenchymal transition depends on hyaluronan synthase HAS22013In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 32, no 37, 4355-4365 p.Article in journal (Refereed)
    Abstract [en]

    Epithelial-mesenchymal transition (EMT) is a developmental program, which can be adopted by cancer cells to increase their migration and ability to form metastases. Transforming growth factor β (TGFβ) is a well-studied inducer of EMT. We demonstrate that TGFβ potently stimulates hyaluronan synthesis via upregulation of hyaluronan synthase 2 (HAS2) in NMuMG mammary epithelial cells. This stimulatory effect requires the kinase active type I TGFβ receptor and is dependent on Smad signaling and activation of the p38 mitogen-activated protein kinase. Knockdown of HAS2 inhibited the TGFβ-induced EMT by about 50%, as determined by the phase contrast microscopy and immunostaining using the EMT marker ZO-1. Furthermore, real-time PCR analysis of the EMT markers fibronectin, Snail1 and Zeb1 revealed decreased expressions upon HAS2 suppression, using specific small interfering RNA (siRNA) for HAS2. Removal of the extracellular hyaluronan by Streptomyces hyaluronidase or inhibiting the binding to its cell surface receptor CD44 by blocking antibodies, did not inhibit TGFβ-induced EMT. Interestingly, HAS2 suppression completely abolished the TGFβ-induced cell migration, whereas CD44 knockdown did not. These observations suggest that TGFβ-dependent HAS2 expression, but not extracellular hyaluronan, has an important regulatory role in TGFβ-induced EMT.

  • 21.
    Preobrazhenska, Olena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Yakymovych, Mariya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Kanamoto, Takashi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Yakymovych, Ihor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Stoika, Rostyslav
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Souchelnytskyi, Serhiy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    BRCA2 and Smad3 synergize in regulation of gene transcription2002In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 21, no 36, 5660-5664 p.Article in journal (Refereed)
    Abstract [en]

    Smad3 is an essential component in the intracellular signaling of transforming growth factor-beta (TGFbeta), which is a potent inhibitor of tumor cell proliferation. BRCA2 is a tumor suppressor involved in early onset of breast, ovarian and prostate cancer. Both Smad3 and BRCA2 possess transcription activation domains. Here, we show that Smad3 and BRCA2 interact functionally and physically. We found that BRCA2 forms a complex with Smad3 in vitro and in vivo, and that both MH1 and MH2 domains of Smad3 contribute to the interaction. TGFbeta1 stimulates interaction of endogenous Smad3 and BRCA2 in non-transfected cells. BRCA2 co-activates Smad3-dependent transcriptional activation of luciferase reporter and expression of plasminogen activator inhibitor-1 (PAI-1). Smad3 increases the transcriptional activity of BRCA2 fused to the DNA-binding domain (DBD) of Gal4, and reciprocally, BRCA2 co-activates DBD-Gal4-Smad3. Thus, our results show that BRCA2 and Smad3 form a complex and synergize in regulation of transcription.

  • 22.
    Rahman-Roblick, R.
    et al.
    Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Becker, S.
    Department of Oncology-Pathology, Karolinska Biomic Center, Karolinska Institutet, Stockholm, Sweden.
    Bader, F.G.
    Department of Surgery, University of Schleswig-Holstein, Lu¨beck, Germany.
    Auer, G.
    Department of Oncology-Pathology, Karolinska Biomic Center, Karolinska Institutet, Stockholm, Sweden.
    Wiman, K.G.
    Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
    Roblick, U.J.
    Department of Surgery, University of Schleswig-Holstein, Lu¨beck, Germany.
    Proteomic identification of p53-dependent protein phosphorylation2008In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 27, no 35, 4854-4859 p.Article in journal (Refereed)
    Abstract [en]

    The p53 tumor suppressor regulates transcription of target genes. We have previously analysed the p53-dependent proteome and identified novel protein targets. Here we have examined p53-dependent phosphorylation using two-dimensional gel electrophoresis and staining with the fluorescent phosphoprotein dye Pro-Q Diamond. We report that p53 induces phosphorylation of a subset of proteins including Nm23, DJ-1, ANXA1 and PrxII. Our identification of p53-dependent phosphorylation of specific target proteins reveals new aspects of the p53-dependent cellular response and suggests that such posttranslational modifications may contribute to p53-mediated tumor suppression.

  • 23.
    Sakurai, T.
    et al.
    Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo, Japan..
    Isogaya, K.
    Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo, Japan..
    Sakai, S.
    Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo, Japan..
    Morikawa, Masato
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Morishita, Y.
    Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo, Japan..
    Ehata, S.
    Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo, Japan..
    Miyazono, K.
    Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo, Japan..
    Koinuma, D.
    Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo, Japan..
    RNA-binding motif protein 47 inhibits Nrf2 activity to suppress tumor growth in lung adenocarcinoma2016In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 35, no 38, 5000-5009 p.Article in journal (Refereed)
    Abstract [en]

    RNA-binding proteins provide a new layer of posttranscriptional regulation of RNA during cancer progression. We identified RNA-binding motif protein 47 (RBM47) as a target gene of transforming growth factor (TGF)-beta in mammary gland epithelial cells (NMuMG cells) that have undergone the epithelial-to-mesenchymal transition. TGF-beta repressed RBM47 expression in NMuMG cells and lung cancer cell lines. Expression of RBM47 correlated with good prognosis in patients with lung, breast and gastric cancer. RBM47 suppressed the expression of cell metabolism-related genes, which were the direct targets of nuclear factor erythroid 2-related factor 2 (Nrf2; also known as NFE2L2). RBM47 bound to KEAP1 and Cullin 3 mRNAs, and knockdown of RBM47 inhibited their protein expression, which led to enhanced binding of Nrf2 to target genomic regions. Knockdown of RBM47 also enhanced the expression of some Nrf2 activators, p21/CDKN1A and MafK induced by TGF-beta. Both mitochondrial respiration rates and the side population cells in lung cancer cells increased in the absence of RBM47. Our findings, together with the enhanced tumor formation and metastasis of xenografted mice by knockdown of the RBM47 expression, suggested tumor-suppressive roles for RBM47 through the inhibition of Nrf2 activity.

  • 24.
    Savary, Katia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Caglayan, Demet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Caja, Laia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tzavlaki, Kalliopi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bin Nayeem, Sarmah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jiang, Yiwen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Forsberg-Nillson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ferletta, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Snail depletes the tumorigenic potential of glioblastoma2013In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 32, no 47, 5409-5420 p.Article in journal (Refereed)
    Abstract [en]

    Glioblastoma multiforme (GBM) is an aggressive brain malignancy characterized by high heterogeneity and invasiveness. It is increasingly accepted that the refractory feature of GBM to current therapies stems from the existence of few tumorigenic cells that sustain tumor growth and spreading, the so-called glioma-initiating cells (GICs). Previous studies showed that cytokines of the bone morphogenetic protein (BMP) family induce differentiation of the GICs, and thus act as tumor suppressors. Molecular pathways that explain this behavior of BMP cytokines remain largely elusive. Here, we show that BMP signaling induces Smad-dependent expression of the transcriptional regulator Snail in a rapid and sustained manner. Consistent with its already established promigratory function in other cell types, we report that Snail silencing decreases GBM cell migration. Consequently, overexpression of Snail increases GBM invasiveness in a mouse xenograft model. Surprisingly, we found that Snail depletes the GBM capacity to form gliomaspheres in vitro and to grow tumors in vivo, both of which are important features shared by GICs. Thus Snail, acting downstream of BMP signaling, dissociates the invasive capacity of GBM cells from their tumorigenic potential.

  • 25.
    Sayadi, Ahmed
    et al.
    Institute of Molecular and Cell Biology, Singapore, Singapore.
    Jeyakani, J
    Seet, S H
    Wei, C-L
    Bourque, G
    Bard, F A
    Jenkins, N A
    Copeland, N G
    Bard-Chapeau, E A
    Functional features of EVI1 and EVI1Δ324 isoforms of MECOM gene in genome-wide transcription regulation and oncogenicity.2015In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594Article in journal (Refereed)
    Abstract [en]

    The MDS1 and ecotropic viral integration site 1 (EVI1) complex locus (MECOM) gene encodes several transcription factor variants including MDS1-EVI1, EVI1 and EVI1Δ324. Although MDS1-EVI1 has been associated with tumor-suppressing activity, EVI1 is a known oncogene in various cancers, whose expression is associated with poor patient survival. Although EVI1Δ324 is co-transcribed with EVI1, its activity in cancer cells is not fully understood. Previous reports described that unlike EVI1, EVI1Δ324 protein cannot transform fibroblasts because of its disrupted N-terminal zinc finger (ZNF) domain. To better understand EVI1Δ324 biology and function, we obtained genome-wide binding occupancies and expression data in ovarian cancer cells. We characterized its DNA-binding sites, binding motif and target genes. Comparative analyses with previous study show that EVI1 and EVI1Δ324 share similar transcriptional activities linked to their common C-terminus ZNF domain. They bind to an E-twenty-six family (ETS)-like motif, target to a large extent the same genes and cooperate with AP1 transcription factor. EVI1Δ324-occupied genes were 70.7% similar to EVI1-bound genes. More strikingly, EVI1 and EVI1Δ324 differentially expressed genes were 99.87% identical, indicating comparable transcriptional regulatory functions. Consistently with gene ontologies linked to these target genes, EVI1Δ324 expression in HeLa cells could enhance anchorage-independent growth, such as EVI1, showing that EVI1Δ324 expression also lead to pro-oncogenic effects. The main specific feature of EVI1 variant is its N-terminus ZNF domain that binds DNA through GATA-like motif. We found that most GATA-like EVI1 chromatin immunoprecipitation sequencing peaks are far from genes and are not involved in transcriptional regulation. These genomic regions were enriched in simple sequence repeats and displayed high meiotic recombination rates. Overall, our genomics analyses uncovered common and specific features of two major MECOM isoforms. Their influence on transcription and downstream cell proliferation was comparable. However, EVI1-specific GATA-like binding sites, from its N-terminus ZNF domain, associated with high recombination rates, suggesting possible additional oncogenic potential for EVI1 in modulating genomic stability.Oncogene advance online publication, 3 August 2015; doi:10.1038/onc.2015.286.

  • 26. Sun, J.
    et al.
    Mohlin, S.
    Lundby, A.
    Kazi, J. U.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Pahlman, S.
    Olsen, J. V.
    Ronnstrand, L.
    The PI3-kinase isoform p110 delta is essential for cell transformation induced by the D816V mutant of c-Kit in a lipid-kinase-independent manner2014In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 33, no 46, 5360-5369 p.Article in journal (Refereed)
    Abstract [en]

    PI3-kinase has a crucial role in transformation mediated by the oncogenic c-Kit mutant D816V. In this study, we demonstrate that the c-Kit/D816V-mediated cell survival is dependent on an intact direct binding of PI3-kinase to c-Kit. However, mutation of this binding site had little effect on the PI3-kinase activity in the cells, suggesting that c-Kit/D816V-mediated cell survival is dependent on PI3-kinase but not its kinase activity. Furthermore, inhibition of the lipid kinase activity of PI3-kinase led only to a slight inhibition of cell survival. Knockdown of the predominant PI3-kinase isoform p110 delta in c-Kit/D816V-expressing Ba/F3 cells led to reduced cell transformation both in vitro and in vivo without affecting the overall PI3-kinase activity. This suggests that p110 delta has a lipid-kinaseindependent role in c-Kit/D816V-mediated cell transformation. We furthermore demonstrate that p110 delta is phosphorylated at residues Y524 and S1039 and that phosphorylation requires an intact binding site for PI3-kinase in c-Kit/D816V. Overexpression of p110 delta carrying the Y523F and S1038A mutations significantly reduced c-Kit/D816V-mediated cell survival and proliferation. Taken together, our results demonstrate an important lipid-kinase-independent role of p110 delta in c-Kit/D816V-mediated cell transformation. This furthermore suggests that p110 delta could be a potential diagnostic factor and selective therapeutic target for c-Kit/D816V-expressing malignancies.

  • 27.
    Sundqvist, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zieba, Agata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vasilaki, Eleftheria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Herrera Hidalgo, Carmen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Koinuma, D
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
    Miyazono, Kohei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    ten Dijke, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Molecular Cell Biology, Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
    van Dam, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Molecular Cell Biology, Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
    Specific interactions between Smad proteins and AP-1 components determine TGFβ-induced breast cancer cell invasion2013In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 32, no 31, 3606-3615 p.Article in journal (Refereed)
    Abstract [en]

    Deregulation of the transforming growth factor β (TGFβ) signal transduction cascade is functionally linked to cancer. In early phases, TGFβ acts as a tumor suppressor by inhibiting tumor cell proliferation, whereas in late phases, it can act as a tumor promoter by stimulating tumor cell invasion and metastasis. Smad transcriptional effectors mediate TGFβ responses, but relatively little is known about the Smad-containing complexes that are important for epithelial-mesenchymal transition and invasion. In this study, we have tested the hypothesis that specific members of the AP-1 transcription factor family determine TGFβ signaling specificity in breast cancer cell invasion. Using a 3D model of collagen-embedded spheroids of MCF10A-MII premalignant human breast cancer cells, we identified the AP-1 transcription factor components c-Jun, JunB, c-Fos and Fra1 as essential factors for TGFβ-induced invasion and found that various mesenchymal and invasion-associated TGFβ-induced genes are co-regulated by these proteins. In situ proximity ligation assays showed that TGFβ signaling not only induces complexes between Smad3 and Smad4 in the nucleus but also complexes between Smad2/3 and Fra1, whereas complexes between Smad3, c-Jun and JunB could already be detected before TGFβ stimulation. Finally, chromatin immunoprecipitations showed that c-Jun, JunB and Fra1, but not c-Fos, are required for TGFβ-induced binding of Smad2/3 to the mmp-10 and pai-1 promoters. Together these results suggest that in particular formation of Smad2/3-Fra1 complexes may reflect activation of the Smad/AP-1-dependent TGFβ-induced invasion program.

  • 28.
    Swartling, Fredrik J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ferletta, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kastemar, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Weiss, W. A.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Cyclic GMP-dependent protein kinase II inhibits cell proliferation, Sox9 expression and Akt phosphorylation in human glioma cell lines2009In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 28, no 35, 3121-3131 p.Article in journal (Refereed)
    Abstract [en]

    Earlier we used a glioma model to identify loci in the mouse genome, which were repeatedly targeted by platelet-derived growth factor (PDGF)-containing Moloney murine leukemia viruses. The gene Prkg2, encoding cyclic guanosine monophosphate (cGMP)-dependent protein kinase II, cGKII, was tagged by retroviral insertions in two brain tumors. The insertions were both situated upstream of the kinase domain and suggested creating a truncated form of the cGKII protein. We transfected different human glioma cell lines with Prkg2 and found an overall reduction in colony formation and cell proliferation compared with controls transfected with truncated Prkg2 (lacking the kinase domain) or empty vector. All glioma cells transfected with the cGKII phosphorylate vasodilator-stimulated phosphoprotein, VASP, after cGMP analog treatment. Glioma cell lines positive for the Sox9 transcription factor showed reduced Sox9 expression when Prkg2 was stably transfected. When cGKII was activated by cGMP analog treatment, Sox9 was phosphorylated, Sox9 protein expression was suppressed and the glioma cell lines displayed loss of cell adhesion, inhibition of Akt phosphorylation and G1 arrest. Sox9 repression by siRNA was similarly shown to reduce glioma cell proliferation. Expression analysis of stem and glial lineage cell markers also suggests that cGKII induces differentiation of glioma cell lines. These findings describe an anti-proliferative role of cGKII in human glioma biology and would further explain the retroviral tagging of the cGKII gene during brain tumor formation in PDGF-induced tumors.

  • 29.
    Tchougounova, Elena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Jiang, Yiwen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Bråsäter, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Lindberg, Nanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Kastemar, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Sox5 can suppress platelet-derived growth factor B-induced glioma development in Ink4a-deficient mice through induction of acute cellular senescence2009In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 28, no 12, 1537-1548 p.Article in journal (Refereed)
    Abstract [en]

    SOX5 is a member of the high-mobility group superfamily of architectural non-histone proteins involved in gene regulation and maintenance of chromatin structure in a wide variety of developmental processes. Sox5 was identified as a brain tumor locus in a retroviral insertional mutagenesis screen of platelet-derived growth factor B (PDGFB)-induced mouse gliomas. Here we have investigated the role of Sox5 in PDGFB-induced gliomagenesis in mice. We show that Sox5 can suppress PDGFB-induced glioma development predominantly upon Ink4a-loss. In human glioma cell lines and tissues, we found very low levels of SOX5 compared with normal brain. Overexpression of Sox5 in human glioma cells led to a reduction in clone formation and inhibition of proliferation. Combined expression of Sox5 and PDGFB in primary brain cell cultures caused decreased proliferation and an increased number of senescent cells in the Ink4a-/- cells only. Protein analyses showed a reduction in the amount and activation of Akt and increased levels of p27(Kip1) upon Sox5 expression that was dominant to PDGFB signaling and specific to Ink4a-/- cells. Upon inhibition of p27(Kip1), the effects of Sox5 on proliferation and senescence could be reversed. Our data suggest a novel pathway, where Sox5 may suppress the oncogenic effects of PDGFB signaling during glioma development by regulating p27(Kip1) in a p19(Arf)-dependent manner, leading to acute cellular senescence.

  • 30.
    Tchougounova, Elena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kastemar, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bråsäter, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Holland, E C
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Loss of Arf causes tumor progression of PDGFB-induced oligodendroglioma2007In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 26, no 43, 6289-6296 p.Article in journal (Refereed)
    Abstract [en]

    In a subset of gliomas, the platelet-derived growth factor (PDGF) signaling pathway is perturbed. This is usually an early event occurring in low-grade tumors. In high-grade gliomas, the subsequent loss of the INK4a-ARF locus is one of the most common mutations. Here, we dissected the separate roles of Ink4a and Arf in PDGFB-induced oligodendroglioma development in mice. We found that there were differential functions of the two tumor suppressor genes. In tumors induced from astrocytes, both Ink4a-loss and Arf-loss caused a significantly increased incidence compared to wild-type mice. In tumors induced from glial progenitor cells there was a slight increase in tumor incidence in Ink4a-/- mice and Ink4a-Arf-/- mice compared to wild-type mice. In both progenitor cells and astrocytes, Arf-loss caused a pronounced increase in tumor malignancy compared to Ink4a-loss. Hence, Ink4a-loss contributed to tumor initiation from astrocytes and Arf-loss caused tumor progression from both glial progenitor cells and astrocytes. Results from in vitro studies on primary brain cell cultures suggested that the PDGFB-induced activation of the mitogen-activated protein kinase pathway via extracellular signal-regulated kinase was involved in the initiation of low-grade oligodendrogliomas and that the additional loss of Arf may contribute to tumor progression through increased levels of cyclin D1 and a phosphoinositide 3-kinase-dependent activation of p70 ribosomal S6 kinase causing a strong proliferative response of tumor cells.

  • 31. Tommiska, J
    et al.
    Bartkova, J
    Heinonen, M
    Hautala, L
    Kilpivaara, O
    Eerola, H
    Aittomäki, K
    Hofstetter, B
    Lukas, J
    von Smitten, K
    Blomqvist, C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Ristimäki, A
    Heikkilä, P
    Bartek, J
    Nevanlinna, H
    The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer2008In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 27, no 17, 2501-6 p.Article in journal (Refereed)
    Abstract [en]

    The ataxia-telangiectasia-mutated (ATM) kinase is a key transducer of DNA damage signals within the genome maintenance machinery and a tumour suppressor whose germline mutations predispose to familial breast cancer. ATM signalling is constitutively activated in early stages of diverse types of human malignancies and cell culture models in response to oncogene-induced DNA damage providing a barrier against tumour progression. As BRCA1 and BRCA2 are also components of the genome maintenance network and their mutations predispose to breast cancer, we have examined the ATM expression in human breast carcinomas of BRCA1/2 mutation carriers, sporadic cases and familial non-BRCA1/2 patients. Our results show that ATM protein expression is aberrantly reduced more frequently among BRCA1 (33%; P=0.0003) and BRCA2 (30%; P=0.0009) tumours than in non-BRCA1/2 tumours (10.7%). Furthermore, the non-BRCA1/2 tumours with reduced ATM expression were more often estrogen receptor (ER) negative (P=0.0002), progesterone receptor (PR) negative (P=0.004) and were of higher grade (P=0.0004). In our series of 1013 non-BRCA1/2 cases, ATM was more commonly deficient (20%; P=0.0006) and p53 was overabundant (47%; P<0.0000000001) among the difficult-to-treat ER/PR/ERBB2-triple-negative subset of tumours compared with cases that expressed at least one of these receptors (10 and 16% of aberrant ATM and p53, respectively). We propose a model of 'conditional haploinsufficiency' for BRCA1/2 under conditions of enhanced DNA damage in precancerous lesions resulting in more robust activation and hence increased selection for inactivation or loss of ATM in tumours of BRCA1/2 mutation carriers, with implications for genomic instability and curability of diverse subsets of human breast cancer.

  • 32. Wallez, Y.
    et al.
    Cand, F.
    Cruzalegui, F.
    Wernstedt, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Souchelnytskyi, Serhiy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Vilgrain, I.
    Huber, P.
    Src kinase phosphorylates vascular endothelial-cadherin in response to vascular endothelial growth factor: identification of tyrosine 685 as the unique target site2007In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 26, no 7, 1067-1077 p.Article in journal (Refereed)
    Abstract [en]

    Src-family tyrosine kinases are regulatory proteins that play a pivotal role in the disorganization of cadherin-dependent cell-cell contacts. We previously showed that Src was associated with vascular endothelial (VE)-cadherin and that tyrosine phosphorylation level of VE-cadherin was dramatically increased in angiogenic tissues as compared to quiescent tissues. Here, we examined whether VE-cadherin was a direct substrate for Src in vascular endothelial growth factor (VEGF)-induced VE-cadherin phosphorylation, and we identified the target tyrosine sites. Co-transfections of Chinese hamster ovary cells (CHO) cells with VE-cadherin and constitutively active Src (Y530F) resulted in a robust tyrosine phosphorylation of VE-cadherin that was not detected with kinase-dead Src (K298M). In an in vitro Src assay, the VE-cadherin cytoplasmic domain is directly phosphorylated by purified Src as well as the tyrosine residue 685 (Tyr)685-containing peptide RPSLY(685)AQVQ. VE-cadherin peptide mapping from human umbilical vein endothelial cells stimulated by VEGF and VE-cadherin-CHO cells transfected with active Src revealed that Y685 was the unique phosphorylated site. The presence of PhosphoY685 was confirmed by its ability to bind to C-terminal Src kinase-SH2 domain in a pull-down assay. Finally, we found that in a VEGF-induced wound-healing assay, cadherin adhesive activity was impaired by Src kinase inhibitors. These data identify that VEGF-induced-VE-cadherin tyrosine phosphorylation is mediated by Src on Y685, a process that appears to be critical for VEGF-induced endothelial cell migration.

  • 33. Welsh, M
    et al.
    Mares, J
    Karlsson, T
    Lavergne, C
    Bréant, B
    Claesson-Welsh, L
    Shb is a ubiquitously expressed Src homology 2 protein.1994In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 9, no 1, 19-27 p.Article in journal (Refereed)
    Abstract [en]

    To identify serum-inducible genes in the insulin-producing cell line beta TC-1, a library subtraction screening procedure was performed on serum-deprived (G0) and serum-restimulated (G1) insulin-producing beta TC-1 cells. A cDNA containing a motif with strong homology to Src homology 2 (SH2) domains was found using this procedure and called Shb. The Shb cDNA contains two methionine codons in its N-terminus and thus may code for two proteins of 67 and 56 kDa, each with one SH2 domain in its C-terminus. No other structural similarity to proteins with catalytic activity could be detected, suggesting that Shb is a so called adaptor. Shb contains the proline-rich sequence PPPGPGR between the two proposed initiator methionines which resembles a sequence for binding to Src homology 3 (SH3) domains. A second proline-rich sequence was detected after the second methionine codon. The Shb cDNA hybridized to a similar or identical mRNA of 3.1 kb expressed in mouse brain, liver, kidney, heart, NIH3T3 fibroblasts and beta TC-1 cells. Western blot analysis of the same tissues using an antiserum directed against a synthetic peptide corresponding to a part of the SH2 domain of Shb, revealed reactivity with two proteins of 56 and 67 kDa. In addition, a third reactive component of 40 kDa was detected in most tissues. Transfection and transient expression of the Shb cDNA in COS-1 cells yielded increased expression of the 67, 56 and 40 kDa proteins. Transfection and stable expression of the Shb cDNA in pig aortic endothelial cells showed increased expression primarily of the 67 kDa protein. A fusion protein consisting of the SH2 domain of Shb linked to glutathione S-transferase showed increased binding to glycoproteins of cells stimulated with platelet-derived growth factor (PDGF-BB). Furthermore, the autophosphorylated PDGF beta-receptor but not the autophosphorylated epidermal growth factor (EGF) receptor bound specifically to immobilized fusion protein. It is concluded that Shb is a novel SH2-containing protein with proline-rich domains and therefore probably involved in the signal-transduction of some ligand-activated tyrosine kinase receptors.

  • 34.
    Welsh, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Songyang, Zhou
    Frantz, J Daniel
    Trub, Thomas
    Reedquist, Kris A
    Karlsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Miyazaki, Masaya
    Cantley, Lewis C
    Band, Hamid
    Shoelson, Steven E
    Stimulation through the T cell receptor leads to interactions between SHB and several signaling proteins1998In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 16, no 7, 891-901 p.Article in journal (Refereed)
    Abstract [en]

    Shb is a recently described Src homology 2 (SH2) domain-containing adaptor protein. Here we show that Shb is expressed in lymphoid tissues, and is recruited into signaling complexes upon activation of Jurkat T cells. Grb2 binds proline-rich motifs in Shb via its SH3 domains. As a result, a number of proteins detected in anti-Shb and anti-Grb2 immunoprecipitates are shared, including phosphoproteins of 22, 36/38, 55/57 and 70 kDa. Shb-association with p22, which represents the T cell receptor associated chain, occurs through the Shb SH2 domain. The central region of Shb binds p36/38. Since this interaction was inhibited by phosphotyrosine, this region of Shb is likely to contain a non-SH2 PTB (phosphotyrosine binding) domain. The Shb PTB domain was found to preferentially bind the sequence Asp-Asp-X-pTyr when incubated with a phosphopeptide library. A peptide corresponding to a phosphorylation site in 34 kDa Lnk inhibited association between Shb and p36/38. Overexpression of Shb in Jurkat cells led to increased basal phosphorylation of Shb-associated p36/38 and p70 proteins. Inactivation of the Shb SH2 domain by an R522K mutation resulted in a reduced stimulation of tyrosine phosphorylation of several proteins in response to CD3 crosslinking when expressed in Jurkat cells. Together, our results show three distinct domains of Shb all participate in the formulation of multimeric signaling complexes in activated T cells. These results indicate that the Shb protein functions in T cell receptor signaling.

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