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  • 651.
    Yakymovych, Ihor
    et al.
    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.
    Grimsby, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Heldin, Carl-Henrik
    Uppsala University.
    Souchelnytskyi, Serhiy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Inhibition of transforming growth factor-beta signaling by low molecular weight compounds interfering with ATP- or substrate-binding sites of the TGF beta type I receptor kinase2002In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 41, no 36, p. 11000-11007Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor-beta (TGFbeta) is a potent regulator of cell proliferation, differentiation, apoptosis, and migration. TGF-beta type I receptor (TbetaR-I), which has intrinsic serine/threonine kinase activity, is a key component in activation of intracellular TGFbeta signaling. We studied two different classes of TbetaR-I inhibitors, i.e., compounds interfering with the ATP-binding site of the kinase and substrate-mimicking peptides. We found that pyridinylimidazole compounds inhibited TbetaR-I kinase at micromolar concentration. A representative compound, SB203580, inhibited in vivo Smad2 phosphorylation by TbetaR-I and affected TGFbeta-dependent transcriptional activation. Peptides mimicking the TbetaR-I phosphorylation sites at the C-terminus of Smad2 also inhibited the autophosphorylation of TbetaR-I and phosphorylation of Smad2 by TbetaR-I in vitro and in vivo, whereas a similar peptide from Smad5 was without effect. The substrate-mimicking peptide, fused to penetratin, inhibited a TGFbeta1-dependent transcriptional response in a luciferase reporter assay and ligand-dependent growth inhibition of Mv1Lu cells. Thus, the substrate-mimetic peptide is a new type of specific inhibitor of the TGFbeta signaling in vivo.

  • 652.
    Yakymovych, Ihor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Hamidi, Anahita
    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.
    Landstöm, Marene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Heldin, Carl-Heldin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Mechanism of regulation of Src kinase by transforming growth factor ßManuscript (preprint) (Other academic)
  • 653.
    Yakymovych, Ihor
    et al.
    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.
    Souchelnytskyi, Serhiy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Smad2 phosphorylation by type I receptor: contribution of arginine 462 and cysteine 463 In the C terminus of Smad2 for specificity2004In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 279, no 34, p. 35781-35787Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor-beta (TGFbeta) is a potent regulator of cell proliferation, differentiation, motility, and apoptosis. TGFbeta binds to and activates serine/threonine kinase receptors that phosphorylate Smad2 and Smad3 intracellular signal transducers at two C-terminal serine residues. Here we show that substitutions of Arg-462 and Cys-463 residues, which are in proximity of the C-terminal serine residues, inhibited TGFbeta type I receptor-dependent phosphorylation of the C-terminal Smad2 peptides and full-length GST-Smad2 proteins in vitro. In vivo, mutation of Arg-462 and Cys-463 inhibited TGFbeta1-stimulated phosphorylation of the C-terminal serine residues in Smad2. Moreover, Smad2 with mutated Arg-462 and Cys-463 was less efficient in activation of the Smad2-responsive activin-responsive element-containing luciferase reporter ARE-luc, as compared with the wild-type protein. Thus, Arg-462 and Cys-463, which are in proximity of the C-terminal serine residues, contribute to recognition and phosphorylation of the C terminus of Smad2 by type I TGFbeta receptor.

  • 654.
    Yakymovych, Ihor
    et al.
    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.
    Regulation of smad function by phosphorylation2006In: Smad Signal Transduction: Smads in Proliferation, Diffrentiation and Disease / [ed] Peter ten Dijke, Carl-Henrik Heldin, Dordrecht: Springer, 2006, p. 235-252Chapter in book (Other (popular science, discussion, etc.))
    Abstract [en]

    The importance of TGF-β signaling in the suppression of tumorigenesis is supported by the presence of frequent mutations in genes encoding both TGF-β receptors and intermediates in this signaling pathway in cancer. In epithelial cancers sporadic mutations have been found in the genes encoding both the receptor-activated Smad2 (MADH2) and the common intermediate, Smad4 (MADH4). Germline mutations in MADH4 and in BMPR1 (BMP type 1 receptor gene) are the most common mutations in the familial cancer syndrome, Familial Juvenile Polyposis, FJP. More recent studies have revealed epigenetic mechanisms that also play important roles in subverting the function of this pathway. In this chapter, we discuss some of these mechanisms, and provide insight into novel ways in which Smad signaling contributes to the maintenance of tissue homeostasis and ultimately to the suppression of cancer

  • 655.
    Yakymovych, Ihor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    ten Dijke, Peter
    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.
    Souchelnytskyi, Serhiy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Regulation of Smad signaling by protein kinase C2001In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 15, no 3, p. 553-555Article in journal (Refereed)
    Abstract [en]

    Cross talk between transforming growth factor beta(TGF-beta) serine/threonine kinase receptor signaling and tyrosine kinase receptor signaling modulates cell responsiveness to polypeptide growth factors regulating cell proliferation, differentiation, and apoptosis. Here we provide a mechanism through which Smad-dependent TGF-beta signaling is modulated by protein kinase C (PKC). PKC, for example, is activated downstream of tyrosine kinase receptors. We show that PKC directly phosphorylates receptor-regulated Smad proteins. This phosphorylation abrogates the ability of Smad3 to bind directly to DNA, which leads to subsequent inability to mediate transcriptional responses dependent on the direct binding of Smad3 to DNA. Interference with PKC regulation of Smad functions increased cell sensitivity to transformation by the tumor promoter phorbol 12-myristate 13-acetate (PMA). PKC-dependent phosphorylation of Smad3 was found also to be a key event in the PMA-dependent inactivation of TGF-beta-stimulated cell death. Thus, PKC-dependent phosphorylation of Smad3 leads to down-regulation of the growth inhibitory and apoptotic action of TGF-beta.

  • 656.
    Yakymovych, Ihor
    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.
    Yakymovych, Mariya
    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.
    Zang, Guangxiang
    Mu, Yabing
    Bergh, Anders
    Landström, Marene
    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, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    CIN85 modulates TGF beta signaling by promoting the presentation of TGF beta receptors on the cell surface2015In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 210, no 2, p. 319-332Article in journal (Refereed)
    Abstract [en]

    Members of the transforming growth factor beta (TGF beta) family initiate cellular responses by binding to TGF beta receptor type II (Tf3R11) and type I (TpRI) serine/threonine kinases, whereby Srnad2 and Smad3 are phosphorylated and activated, promoting their association with Smadzi. We report here that T beta RI interacts with the SH3 domains of the adaptor protein CIN85 in response to TGF beta stimulation in a TRAF6-dependent manner. Small interfering RNA mediated knockdown of CIN85 resulted in accumulation of T beta RI in intracellular compartments and diminished TGF beta-stimulated Sniad2 phosphorylation. Overexpression of CIN85 instead increased the amount of T beta RI at the cell surface. This effect was inhibited by a dominant-negative mutant of Rab11, suggesting that CIN85 promoted recycling of TGF beta receptors. CIN85 enhanced TGF beta-stimulated Smad2 phosphorylation, transcriptional responses, and cell migration. CIN85 expression correlated with the degree of malignancy of prostate cancers. Collectively, our results reveal that CIN85 promotes recycling of TGF beta receptors and thereby positively regulates TGF beta signaling.

  • 657. Yenamandra, Surya Pavan
    et al.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Kempkes, Bettina
    Darekar, Suhas Deoram
    Petermann, Sabine
    Sculley, Tom
    Klein, George
    Kashuba, Elena
    Epstein-Barr virus encoded EBNA-3 binds to vitamin D receptor and blocks activation of its target genes2010In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 67, no 24, p. 4249-4256Article in journal (Refereed)
    Abstract [en]

    Epstein-Barr virus (EBV) is a human gamma herpes virus that infects B cells and induces their transformation into immortalized lymphoblasts that can grow as cell lines (LCLs) in vitro. EBNA-3 is a member of the EBNA-3-protein family that can regulate transcription of cellular and viral genes. The identification of EBNA-3 cellular partners and a study of its influence on cellular pathways are important for understanding the transforming action of the virus. In this work, we have identified the vitamin D receptor (VDR) protein as a binding partner of EBNA-3. We found that EBNA3 blocks the activation of VDR-dependent genes and protects LCLs against vitamin-D3-induced growth arrest and/or apoptosis. The presented data shed some light on the anti-apoptotic EBV program and the role of the EBNA-3-VDR interaction in the viral strategy.

  • 658.
    Yin, Beatrice W T
    et al.
    Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
    Kiyamova, Ramziya
    The Laboratory of Cell Growth Regulation, Department of Cell Signaling, Institute of Molecular Biology and Genetics, Kyiv, Ukraine.
    Chua, Ramon
    Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
    Caballero, Otavia L
    Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
    Gout, Ivan
    Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom.
    Gryshkova, Vitalina
    The Laboratory of Cell Growth Regulation, Department of Cell Signaling, Institute of Molecular Biology and Genetics, Kyiv, Ukraine.
    Bhaskaran, Nimesh
    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.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Filonenko, Valeriy
    The Laboratory of Cell Growth Regulation, Department of Cell Signaling, Institute of Molecular Biology and Genetics, Kyiv, Ukraine.
    Jungbluth, Achim A.
    Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
    Odunsi, Kunle
    Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.
    Lloyd, Kenneth O
    Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
    Old, Lloyd J
    Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
    Ritter, Gerd
    Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
    Monoclonal antibody MX35 detects the membrane transporter NaPi2b (SLC34A2) in human carcinomas2008In: Cancer Immunity, ISSN 1424-9634, E-ISSN 1424-9634, Vol. 8, p. 3-Article in journal (Refereed)
    Abstract [en]

    Mouse monoclonal antibody MX35 was developed against ovarian cancer. The antibody showed homogeneous reactivity with approximately 90% of human ovarian epithelial cancers and with a limited number of normal tissues by immunohistochemistry. Although mAb MX35 has been used in a number of clinical trials in ovarian cancer, it has been difficult to define the molecular identity of MX35. We report here that mAb MX35 recognizes the sodium-dependent phosphate transport protein 2b (NaPi2b) in human cancer cells. This conclusion is based on several lines of experimental evidence, including 1) the identification of SLC34A2, the gene coding for NaPi2b, by immunoscreening an ovarian cancer cell line cDNA expression library with mAb MX35; 2) mass spectrometry sequencing of peptides obtained by fragmentation from mAb MX35 affinity-purified antigen, which show complete sequence homology to amino acid sequences in NaPi2b; 3) selective down-regulation of SLC34A2 gene expression by RNA interference and the resulting loss of mAb MX35 binding to MX35-expressing human cancer cells; and 4) the demonstration of specific mAb MX35 reactivity with recombinant fusion proteins and with synthetic peptides of the putative largest extracellular loop of NaPi2b. We further show that NaPi2b in cancer cells is expressed on the cell surface as a heavily N-glycosylated protein, with evidence of additional post-translational modifications such as palmitoylation and the formation of disulfide bridges in the major extracellular loop. Membrane transporter molecules, such as NaPi2b, represent a new family of potential cell surface targets for the immunotherapy of cancer with monoclonal antibodies.

  • 659. Yoshizaki, Lucila
    et al.
    Troncoso, María F.
    Lopes, Jose L. S.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Beltramini, Leila M.
    Wolfenstein-Todel, Carlota
    Calliandra selloi Macbride trypsin inhibitor: isolation, characterization, stability, spectroscopic analyses2007In: Phytochemistry, ISSN 0031-9422, E-ISSN 1873-3700, Vol. 68, no 21, p. 2625-2634Article in journal (Refereed)
    Abstract [en]

    A trypsin inhibitor was purified from Calliandra selloi Macbride seeds (CSTI). SDS-PAGE under non-reducing conditions showed a single band of approximately 20,000Da, while under reducing conditions two bands of 16,000 and 6000Da were observed, indicating that CSTI consists of two polypeptide chains. Molecular masses of 20,078 and 20,279 were obtained by mass spectrometry, although only one pI of 4.0 was observed and one peak was obtained by reversed phase chromatography. Amino-terminal sequence analysis showed homology to Kunitz-type inhibitors. CSTI was able to inhibit trypsin (K(i) 2.21x10(-7)M), alpha-chymotrypsin (K(i) 4.95x10(-7)M) and kallikrein (K(i) 4.20x10(-7)M) but had no effect on elastase. Trypsin inhibitory activity was stable over a wide range of pH and temperature. CSTI was particularly susceptible to DTT treatment, followed by addition of iodoacetamide. Far-UV circular dichroism measurements revealed that CSTI is a beta-II protein. Thermal unfolding showed a two-state transition with a midpoint at 68 degrees C. Far-UV CD spectra of CSTI at pH extremes showed little changes, while more pronounced differences in near-UV CD spectra were detected. Remarkably, treatment with 1mM DTT caused very slight changes in the far-UV CD spectrum, and only after carbamidomethylation was there was a marked loss observed in secondary structure.

  • 660.
    Zakharchenko, Olena
    et al.
    Department of Oncology-Pathology, Karolinska Biomics Center, Karolinska Institute, Stockholm.
    Greenwood, Christina
    Helen Rollason Research Laboratory, Anglia Ruskin University, Chelmsford, United Kingdom.
    Lewandowska, Anna
    Faculty of Biology, University of Warmia and Mazury, Olsztyn, Poland.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Alldridge, Louise
    Griffith University, School of Medicine, Gold Coast, Australia.
    Souchelnytskyi, Serhiy
    Department of Oncology-Pathology, Karolinska Biomics Center, Karolinska Institute, Stockholm.
    Meta-data analysis as a strategy to evaluate individual and common features of proteomic changes in breast cancer2011In: Cancer Genomics & Proteomics, ISSN 1109-6535, E-ISSN 1790-6245, Vol. 8, no 1, p. 1-14Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Individual differences among breast tumours in patients is a significant challenge for the treatment of breast cancer. This study reports a strategy to assess these individual differences and the common regulatory mechanisms that may underlie breast tumourigenesis. MATERIALS AND METHODS: The two-step strategy was based firstly on a full-scale proteomics analysis of individual cases, and secondly on the analysis of common features of the individual proteome-centred networks (meta-data). RESULTS: Proteomic profiling of human invasive ductal carcinoma tumours was performed and each case was analysed individually. Analysis of primary datasets for common cancer-related proteins identified keratins. Analysis of individual networks built with identified proteins predicted features and regulatory mechanisms involved in each individual case. Validation of these findings by immunohistochemistry confirmed the predicted deregulation of expression of CK2α, PDGFRα, PYK and p53 proteins. CONCLUSION: Meta-data analysis allowed efficient evaluation of both individual and common features of the breast cancer proteome.

  • 661. Zernii, Evgenii Yu
    et al.
    Tikhomirova, Natalia K.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Philippov, Pavel P.
    Senin, Ivan I.
    Annexins in bovine photoreceptors2004In: Annexins, Vol. 1, no 1, p. 44-50Article in journal (Refereed)
  • 662.
    Zhang, Fan
    et al.
    National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
    Tang, Zhongshu
    National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
    Hou, Xu
    National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Li, Yang
    National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
    Koch, Alexander W.
    Neurodegeneration Labs, Protein Chemistry, Genentech, Inc. San Francisco, CA 94080, USA.
    Scotney, Pierre
    CSL Limited, Parkville, Victoria 3052, Australia.
    Lee, Chunsik
    National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
    Arjunan, Pachiappan
    National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
    Dong, Lijin
    National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
    Kumar, Anil
    National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
    Rissanen, Tuomas T.
    Department of Biotechnology and Molecular Medicine, University of Kuopio, FIN-70211, Kuopio, Finland.
    Wang, Bin
    Department of Radiology, Medical Imaging Centre of the Affiliated Hospital, Weifang Medical University, Weifang 261042, China.
    Nagai, Nobuo
    Department of Physiology, Kinki University School of Medicine, Osaka 589-8511, Japan.
    Fons, Pierre
    Sanofi-Aventis Recherche, Cardiovascular-Thrombosis Research Department, 31036 Toulouse Cedex, France.
    Fariss, Robert
    National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
    Zhang, Yongqing
    TRIAD Technology Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
    Wawrousek, Eric
    National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
    Tansey, Ginger
    National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
    Raber, James
    National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
    Fong, Guo-Hua
    Center for Vascular Biology, University of Connecticut, Farmington, CT 06030, USA.
    Ding, Hao
    Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada MB R3E 3P5.
    Greenberg, David A.
    Buck Institute for Age Research, Novato, CA 94945, USA.
    Becker, Kevin G.
    TRIAD Technology Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
    Herbert, Jean-Marc
    Sanofi-Aventis Recherche, Cardiovascular-Thrombosis Research Department, 31036 Toulouse Cedex, France.
    Nash, Andrew
    CSL Limited, Parkville, Victoria 3052, Australia.
    Yla-Herttuala, Seppo
    Department of Biotechnology and Molecular Medicine, University of Kuopio, FIN-70211, Kuopio, Finland.
    Cao, Yihai
    Department of Microbiology, Karolinska Institute, 171 77 Stockholm, Sweden.
    Watts, Ryan J.
    Neurodegeneration Labs, Protein Chemistry, Genentech, Inc. San Francisco, CA 94080; dCSL Limited, Parkville, Victoria 3052, Australia.
    Li, Xuri
    National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
    VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 15, p. 6152-6157Article in journal (Refereed)
    Abstract [en]

    VEGF-B, a homolog of VEGF discovered a long time ago, has not been considered an important target in antiangiogenic therapy. Instead, it has received little attention from the field. In this study, using different animal models and multiple types of vascular cells, we revealed that although VEGF-B is dispensable for blood vessel growth, it is critical for their survival. Importantly, the survival effect of VEGF-B is not only on vascular endothelial cells, but also on pericytes, smooth muscle cells, and vascular stem/progenitor cells. In vivo, VEGF-B targeting inhibited both choroidal and retinal neovascularization. Mechanistically, we found that the vascular survival effect of VEGF-B is achieved by regulating the expression of many vascular prosurvival genes via both NP-1 and VEGFR-1. Our work thus indicates that the function of VEGF-B in the vascular system is to act as a "survival," rather than an "angiogenic" factor and that VEGF-B inhibition may offer new therapeutic opportunities to treat neovascular diseases.

  • 663.
    Zhang, Long
    et al.
    Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
    Zhou, Fangfang
    Department of Molecular Cell Biology, Cancer Genomics Centre and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
    ten Dijke, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Department of Molecular Cell Biology, Cancer Genomics Centre and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
    Signaling interplay between transforming growth factor-beta receptor and PI3K/AKT pathways in cancer2013In: TIBS -Trends in Biochemical Sciences. Regular ed., ISSN 0968-0004, E-ISSN 1362-4326, Vol. 38, no 12, p. 612-620Article, review/survey (Refereed)
    Abstract [en]

    The transforming growth factor (TGF)-beta and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathways are used in cells to control numerous responses, including proliferation, apoptosis, and migration. TGF-beta is known for its cytostatic effect's in premalignant states and its pro-oncogenic activity in advanced cancers. The pro-cell survival response exerted by growth-factor-mediated activation of PI3K/AKT has been linked to stimulation of tumor formation. Both TGF-beta receptor and PI3K/AKT pathways were initially modeled as linear signaling conduits. Although early studies suggested that these two pathways might counteract each other in balancing cell survival, emerging evidence has uncovered multiple modes of intricate signal integration and obligate collaboration in driving cancer progression. These new insights provide the rationale for exploring their dual targeting in cancer.

  • 664.
    Zhang, Shouting
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Ekman, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Thakur, Noopur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Bu, Shizhong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Davoodpour, Padideh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Grimsby, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Tagami, Seicchi
    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.
    Landström, Marene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    TGF beta 1-induced activation of ATM and p53 mediates apoptosis in a Smad7-dependent manner2006In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 5, no 23, p. 2787-2795Article in journal (Refereed)
    Abstract [en]

    ATM, a DNA-damage sensitive kinase and p53, are frequently inactivated in a variety of cancers as they together with gamma H2AX are critical guardians against DNA damage. Here, we report of a functional cross-talk between the cytokine TGF beta and p53, leading to apoptosis of epithelial cells, involving Smad7, a TGF beta target gene, p38 MAP kinase, and ATM. Using ectopic expression of p53, siRNA for Smad7, p38a(-/-) deficient cells and specific inhibitors, we show that TGF-beta induces apoptosis via ATM and p53 in epithelial cells. Intriguingly, Smad7 act as a scaffold protein to promote functional interactions between p38, ATM and p53 upon TGF beta treatment, facilitating their activation. Smad7. colocalizes with gamma H2AX in DNA damage foci and was required for proper cell cycle checkpoints to prevent genetic instability. Our data imply that Smad7 plays a crucial role upstream of ATM and p53 to protect the genome from insults evoked by extracellular stress.

  • 665.
    Zhang, Yanyu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Valsala Madhavan Unnithan, Ragaseema
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Caja, Laia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. 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.
    Saupe, Falk
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Siegbahn, Agneta
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    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.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cedervall, Jessica
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    TBK1, an NF-κB activating kinase, is required for platelet-induced EMTManuscript (preprint) (Other academic)
    Abstract [en]

    Platelets can promote several steps during the metastatic process, and hence

    contribute to malignant progression. During early stages of metastasis, platelets

    promote invasive properties of tumor cells by induction of epithelial to mesenchymal transition (EMT). In this study we show that TANK binding kinase-1 (TBK1) is a previously unknown mediator of platelet-induced EMT - a finding that suggests a possible role of TBK1 as a potential driver of metastatic disease. Using the two mammary epithelial cell lines Ep5 and MCF10A (M2), we show that co-culture with isolated platelets induced morphological as well as molecular features indicative of EMT, and that this is paralleled with activation of TBK1. Inhibiting TBK1 using siRNA suppressed platelet induced EMT in both Ep5 and MCF10A (M2) cells. Furthermore, platelet induced NF-κB signaling was suppressed after TBK1 knock down, suggesting that TBK1 is a crucial mediator of platelet-induced NF-κB signaling and subsequent EMT. Altogether, these results suggest that TBK1 contribute to tumor invasiveness and may hence be a driver of metastatic spread in mammary epithelial tumors.

  • 666.
    Zheng, Wei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Hendriks, Wiljan
    Department of Cell Biology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Hellberg, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    The LAR protein tyrosine phosphatase enables PDGF β-receptor activation through attenuation of the c-Abl kinase activity2011In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 23, no 6, p. 1050-1056Article in journal (Refereed)
    Abstract [en]

    The receptor tyrosine phosphatase (RPTP) LAR negatively regulates the activity of several receptor tyrosine kinases. To investigate if LAR affects the platelet-derived growth factor (PDGF) receptor signaling, mouse embryonic fibroblasts (MEFs) from mice where the LAR phosphatase domains were deleted (LARΔP), and wt littermates, were stimulated with 20ng/ml PDGF-BB. In LAR phosphatase deficient MEFs, the phosphorylation of the PDGF β-receptor was surprisingly reduced, an event that was rescued by re-expression of wt LAR. The decreased phosphorylation of the PDGF β-receptor was observed independent of ligand concentration and occurred on all tyrosine residues, as determined by immunoblotting analysis using site-selective phosphotyrosine antibodies. This suggests that LAR is required for full PDGF β-receptor kinase activation. Downstream of receptor activation, phosphorylation of Akt and PLCγ were decreased in LARΔP MEFs, whereas Src and Erk MAP kinase pathways were less affected. The proliferation of LARΔP MEFs in response to PDGF-BB was also reduced. The inhibitory effect on the PDGF β-receptor in LARΔP cells was exerted via increased basal activity of c-Abl, since inhibition of c-Abl, by AG957 or siRNA, restored PDGF β-receptor phosphorylation. These observations suggest that LAR reduces the basal c-Abl activity thereby allowing for PDGF β-receptor kinase activation.

  • 667.
    Zhou, Alex-Xianghua
    et al.
    Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden.
    Toylu, Asli
    Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden.
    Nallapalli, Rajesh K.
    Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden.
    Nilsson, Gisela
    Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden.
    Atabey, Nee
    Department of Medical Biology and Genetics, Dokuz Eylu¨l University, Izmir, Turkey.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Borén, Jan
    Wallenberg Laboratory, Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Sweden.
    Bergo, Martin O.
    Wallenberg Laboratory, Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Sweden.
    Akyürek, Levent M.
    Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden.
    Filamin A mediates HGF/c-MET signaling in tumor cell migration2011In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 128, no 4, p. 839-846Article in journal (Refereed)
    Abstract [en]

    Deregulated hepatocyte growth factor (HGF)/c-MET axis has been correlated with poor clinical outcome and drug resistance in may human cancers. Identification of novel regulatory mechanisms influencing HGF/c-MET signaling may therefore be necessary to develop more effective cancer therapies. In our study, we show that multiple human cancer tissues and cells express filamin A (FLNA), a large cytoskeletal actin-binding protein, and expression of c-MET is significantly reduced in human tumor cells deficient for FLNA. The FLNA-deficient tumor cells exhibited poor migrative and invasive ability in response to Kg. On the other hand, the anchorage-dependent and independent tumor cell proliferation was not altered by HGF. The FLNA-deficiency specifically attenuated the activation of the c-MET downstream signaling molecule AKT in response to HGF stimulation. Furthermore, FLNA enhanced c-MET promoter activity by its binding to SMAD2. The impact of FLNA deficiency on c-NET expression and HGF-mediated cell migration in human tumor cells was confirmed in primary mouse embryonic fibroblasts deficient for Flna. These data suggest that FLNA is one of the important regulators of c-MET signaling and HGF-induced tumor cell migration.

  • 668.
    Zi, Zhike
    et al.
    BIOSS Centre for Biological Signalling Studies and Center for Biological Systems Analysis (ZBSA), University of Freiburg, Freiburg, Germany.
    Feng, Zipei
    Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO, USA.
    Chapnick, Douglas A.
    Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO, USA.
    Dahl, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Deng, Difan
    BIOSS Centre for Biological Signalling Studies and Center for Biological Systems Analysis (ZBSA), University of Freiburg, Freiburg, Germany.
    Klipp, Edda
    Theoretical Biophysics, Institute for Biology, Humboldt-Universita¨ t zu Berlin, Berlin, Germany.
    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.
    Liu, Xuedong
    Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO, USA.
    Quantitative analysis of transient and sustained transforming growth factor-beta signaling dynamics2011In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 7, no 492Article in journal (Refereed)
    Abstract [en]

    Mammalian cells can decode the concentration of extracellular transforming growth factor-beta (TGF-beta) and transduce this cue into appropriate cell fate decisions. How variable TGF-beta ligand doses quantitatively control intracellular signaling dynamics and how continuous ligand doses are translated into discontinuous cellular fate decisions remain poorly understood. Using a combined experimental and mathematical modeling approach, we discovered that cells respond differently to continuous and pulsating TGF-beta stimulation. The TGF-beta pathway elicits a transient signaling response to a single pulse of TGF-beta stimulation, whereas it is capable of integrating repeated pulses of ligand stimulation at short time interval, resulting in sustained phospho-Smad2 and transcriptional responses. Additionally, the TGF-beta pathway displays different sensitivities to ligand doses at different time scales. While ligand-induced short-term Smad2 phosphorylation is graded, long-term Smad2 phosphorylation is switch-like to a small change in TGF-beta levels. Correspondingly, the short-term Smad7 gene expression is graded, while long-term PAI-1 gene expression is switch-like, as is the long-term growth inhibitory response. Our results suggest that long-term switch-like signaling responses in the TGF-beta pathway might be critical for cell fate determination.

  • 669.
    Zieba, Agata
    et al.
    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.
    Pardali, Katerina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. 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.
    Lindbom, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nyström, Erik
    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.
    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.
    Intercellular variation in signaling through the TGF-β pathway and its relation to cell densityand cell cycle phase2012In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 11, no 7, article id M111.013482Article in journal (Refereed)
    Abstract [en]

    Fundamental open questions in signal transduction remain concerning the sequence and distribution of molecular signaling events among individual cells. In this work we have characterized the intercellular variability of transforming growth factor β-induced Smad interactions, providing essential information about TGF-β signaling and its dependence on the density of cell populations and the cell-cycle phase. By employing the recently developed in situ proximity ligation assay, we investigated the dynamics of interactions and modifications of Smad proteins and their partners under native and physiological conditions. We analyzed the kinetics of assembly of Smad complexes and the influence of cellular environment and relation to mitosis. We report rapid kinetics of formation of Smad complexes, including native Smad2-Smad3-Smad4 trimeric complexes, in a manner influenced by the rate of proteasomal degradation of these proteins, and we found a striking cell to cell variation of signaling complexes. The single-cell analysis of TGF-β signaling in genetically unmodified cells revealed previously unknown aspects of regulation of this pathway, and it provided a basis for analysis of these signaling events to diagnose pathological perturbations in patient samples, and to evaluate their susceptibility to drug treatment.

  • 670. Zielin„ski, Rafal
    et al.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Kubinski, Konrad
    Szyszka, Ryszard
    Fip1 - an essential component of the Saccharomyces cerevisiae polyadenylation machinery is phosophorylated by protein kinase CK22006In: Molecular and Cellular Biochemistry, ISSN 0300-8177, E-ISSN 1573-4919, Vol. 286, no 1-2, p. 191-197Article in journal (Refereed)
    Abstract [en]

    Since Fip1 is phosphoprotein we investigated whether it is a substrate for protein kinase CK2. According to the amino acid sequence Fip1 harbours twenty putative CK2 phosphorylation sites. Here we have report characterization of Fip1 as a substrate for both forms of CK2. Fip1 serves as a substrate for both the recombinant CK2α ′ (K m 1.28 μM) and holoenzyme (K m 1.4 μM) but not for CK1. By MALDI-MS we identified the two serine residues at positions 73 and 77 as the possible in vitro phosphorylation sites. These data may help to elucidate the role of Fip1 in the mRNA 3'-OH polyadenylation process and the involvement of CK2 mediated phosphorylation in regulation of interactions and activity members of cleavage/polyadenylation factor (CPF) complex.

  • 671. Zielinski, Rafał
    et al.
    Pilecki, Marek
    Kubin„ski, Konrad
    Zien, Piotr
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Szyszka, Ryszard
    Inhibition of yeast ribosomal stalk phosphorylation by Cu-Zn superoxide dismutase2002In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 296, no 5, p. 1310-1316Article in journal (Refereed)
    Abstract [en]

    Reversible phosphorylation of acidic ribosomal proteins of Saccharomyces cerevisiae is an important mechanism, regulating the number of active ribosomes. The key role in regulation of this process is played by specific, second messenger-independent protein kinases. A new protein-inhibitor regulating activity of PK60S kinase has been purified from yeast extracts and characterised. Peptide mass fingerprinting (PMF) and amino-acid sequence analysis by Post Source Decay (PSD) have identified the inhibitor as a Cu-Zn superoxide dismutase (SOD). Inhibition by SOD is competitive with respect to protein substrates-P proteins and 80S ribosome-with K(i) values of 3.7 microM for P2A protein and 0.6 microM for 80S ribosomes. A close correlation was found between the state of phosphorylation of P proteins in diauxic shift and logarithmic growth yeast cells and activity of SOD. The possible mechanism of regulation of PK60S activity, and participation of SOD protein in regulation of 80S-ribosome activity in stress conditions, is discussed.

  • 672. Zolessi, Flavio R
    et al.
    Durán, Rosario
    Engström, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Cerveñansky, Carlos
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Arruti, Cristina
    Identification of the chicken MARCKS phosphorylation site specific for differentiating neurons as Ser 25 using a monoclonal antibody and mass spectrometry2004In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 3, no 1, p. 84-90Article in journal (Refereed)
    Abstract [en]

    MARCKS is an actin-modulating protein that can be phosphorylated in multiple sites by PKC and proline-directed kinases. We have previously described a phosphorylated form of this protein specific for differentiating chick neurons, detected with mAb 3C3. Here, we show that this antibody binds to MARCKS only when it is phosphorylated at Ser 25. These and previous data provide hints for a possible answer to the question of why this ubiquitous protein seems to be essential only for neural development.

  • 673.
    Zuberovic, Aida
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Hanrieder, Jörg
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Wetterhall, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Proteome profiling of human cerebrospinal fluid: exploring the potential of capillary electrophoresis with surface modified capillaries for analysis of complex biological samples.2008In: European journal of mass spectrometry, ISSN 1469-0667, E-ISSN 1751-6838, Vol. 14, no 4, p. 249-260Article in journal (Refereed)
    Abstract [en]

    A bottom-up proteomic approach, based on capillary electrophoresis (CE) in combination with matrix- assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-ToF/ToF MS), was used to analyze immunoaffinity depleted human cerebrospinal fluid (CSF) and compare it with a non-depleted sample. After enzymatic digestion and desalting, the tryptic peptides were separated by CE using PolyE-323 modified capillaries and fractionated off-line onto MALDI target plates for further analysis by MALDI-MS and MS/MS. The protein profile of the depleted sample was compared with non depleted CSF. Overall, 85 proteins were identified with 95% significance in both samples. The significance scores for proposed biomarkers, such as amyloid-like protein 1 precursor, could be increased up to 12 times after the depletion. Other proteins, often suggested to be related to neurodegenerative diseases, like amyloid beta A4 protein precursor, superoxide dismutase and apolipoprotein E precursor could only be found in the depleted CSF samples. The effect of a derivatization of tryptic peptides with 2- methoxy-4,5-dihydro-1H-imidazole reagent for protein identification with MS was also employed to increase the number of identified proteins and the sequence coverages. The results presented in this study illustrate the benefit of combining a sample pre-fractionation step and a label's ability to enhance the ionization efficiency with the potential of CE using PolyE-323 modified capillaries in the analysis of complex samples. The straight-forward approach that provides speed and simplicity resulting in high-resolution separations and low sample consumption represents an easily applicable separation technique that can serve as a complement to other currently existing analytical approaches needed in modern proteomic analysis of clinically relevant samples.

  • 674.
    Zuberovic, Aida
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Ullsten, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    E. Markides, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Capillary electrophoresis off-line matrix-assisted laser desorption/ionisation mass spectrometry of intact and digested proteins using cationic-coated capillaries2004In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 18, no 23, p. 2946-2952Article in journal (Refereed)
    Abstract [en]

    Capillary electrophoresis (CE) was coupled off-line with matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOFMS) for the analysis of proteins and peptides. CE fractions were collected directly on a matrix-coated MALDI target, using a sheath-flow interface. Protein adsorption during CE separations was prevented by coating the capillaries with the physically adsorbed, cationic polymer PolyE-323. The CE/MALDI-MS system was used for the analysis of model proteins and peptides at physiological pH as well as analysis of proteins in tear fluid. Moreover, tryptic on-target digestion of the collected protein fractions, with subsequent MALDI-MS and MS/MS peptide analysis, was demonstrated.

  • 675.
    Zuo, Shusheng
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Lundahl, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    On the oligomeric state of the red blood cell glucose transporter GLUT12003In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1618, no 1, p. 8-16Article in journal (Refereed)
    Abstract [en]

    We stripped human red blood cell membranes of cytoskeleton proteins at pH 12 without reductant, partially solubilized the obtained vesicles by use of octaethylene glycol n-dodecyl ether and purified the glucose transporter GLUT1 by anion-exchange chromatography followed by sulfhydryl-affinity chromatography, which removed most of the nucleoside transporter (NT) and the lipids. Eighty percent of the sulfhydryl-bound GLUT1 could be eluted with sodium dodecyl sulfate (SDS) indicating that the bound protein was multimeric. Matrix-assisted laser desorption ionization-time of flight-mass spectrometry (MALDI-ToF-MS) of the trypsinized major SDS-PAGE zone of the purified material identified GLUT1 but no other membrane protein. Transmembrane helices 1 and 8 were among the detected fragments. The reconstituted purified GLUT1 showed glucose transport activity, although only approximately 0.05 high-affinity cytochalasin B (CB) binding sites were present per GLUT1 monomer. The vesicles used as starting material for the purification showed 0.4 CB sites per GLUT1 monomer, similar to vesicles prepared in the presence of dithioerythritol. The data are consistent with the coexistence of monomeric GLUT1 with high-affinity CB-binding activity and preferentially solubilized multimeric GLUT1 with no CB-binding activity in the red blood cell membrane vesicles prepared without reductant.

  • 676.
    Åhlin, Mikaela
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Role of MKP-2 in crosstalk between MAPK pathways2015Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Abnormalities in Mitogen Activated Protein Kinase (MAPK) signalling may affect the cells essential processes and influence the cell in acquiring traits to favour tumorigenic transformation and the progression of cancer. Deregulation of the MAPK pathways and uncontrolled crosstalk occurring in cancers may be caused by deregulation by MAP-kinase phosphatases (MKPs) that negatively regulates MAPKs by dephosphorylation. In this study, we were interested in the role of MKP-2 in MAPK-signalling pathways. MKP-2 is known to specifically dephosphorylate the MAP kinases Erk1/2, p38 and JNK. In this study, I was to elucidate key events leading to MKP-2 expression and the role of MKP-2 in regulating and balancing MAPK signaling. Also, I was to analyse the possible involvement of p53 in the deregulation of the MAPK pathways and its correlation with MKP-2 expression. In this report, I suggest a model where the Erk1/2 pathway in conjugation with p53 promote MKP-2 expression. I have also discovered a crosstalk between two different MAPK pathways, i.e between Erk1/2 and Erk5.

  • 677.
    Östman, Arne
    et al.
    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.
    Involvement of platelet-derived growth factor in disease: development of specific antagonists2001In: Advances in Cancer Research, ISSN 0065-230X, E-ISSN 2162-5557, Vol. 80, p. 1-38Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor (PDGF) is a family of dimeric isoforms that stimulates, e.g., growth, chemotaxis and cell shape changes of various connective tissue cell types and certain other cells. The cellular effects of PDGF isoforms are exerted through binding to two structurally related tyrosine kinase receptors. Ligand binding induces receptor dimerization and autophosphorylation. This enables a number of SH2 domain containing signal transduction molecules to bind to the receptors, thereby initiating various signaling pathways. PDGF isoforms have important roles during the embryonic development, particularly in the formation of connective tissue in various organs. In the adult, PDGF stimulates wound healing. Overactivity of PDGF has been implicated in certain disorders, including fibrotic conditions, atherosclerosis, and malignancies. Different kinds of PDGF antagonists are currently being developed and evaluated in different animal disease models, as well as in clinical trials.

  • 678. Östman, Arne
    et al.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    PDGF receptors as targets in tumor treatment2007In: Advances in Cancer Research, ISSN 0065-230X, E-ISSN 2162-5557, Vol. 97, p. 247-274Article, review/survey (Refereed)
    Abstract [en]

    Signaling through platelet-derived growth factor (PDGF) receptors contributes to multiple tumor-associated processes. The recent introduction of clinically useful PDGF inhibitors have the last years validated PDGF receptors in malignant and stromal cells as relevant cancer drug targets. Mutational activation of PDGF receptor signaling in malignant cells has been described in some rare tumor types such as dermatofibrosarcoma protuberans, a subset of GISTs, and some hematologic malignancies. Furthermore, expression of PDGF receptors on pericytes is a common characteristic of solid tumors. The clinical efficacy of novel multikinase inhibitors, such as sunitimb and sorafemb, most likely involves targeting of PDGF receptor-dependent pericytes. Preclinical studies suggest that targeting of stromal PDGF receptors might also constitute a novel strategy to enhance tumor drug uptake. Finally, recent studies have implied both pro- and antimetastatic effects of PDGF receptors on malignant and stromal cells. The studies on the roles of PDGF receptors in cancer signaling are thus presently in a dynamic phase where collaborations between oncologists, pathologists, and tumor biologists are predicted to be highly productive.

  • 679. Östman, Arne
    et al.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Platelet-derived growth factor2013In: Molecular oncology: Causes of cancer and targets for treatment / [ed] Gelmann, EP, Cambridge: Cambridge University Press, 2013, p. 135-143Chapter in book (Refereed)
  • 680.
    Östman, Arne
    et al.
    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.
    Platelet-derived growth factor (PDGF)2004In: Encyclopedia of Endocrine Diseases / [ed] Martini, Luciano, London: Elsevier, 2004, p. 690-696Chapter in book (Other academic)
    Abstract [en]

    PDGFs are growth factors for mesenchymal cells that act through cell surface tyrosine kinase receptors. PDGFs have important functions during development. A number of pathological conditions are associated with overactivity of PDGF receptors.

  • 681. Östman, Arne
    et al.
    Hellberg, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Böhmer, Frank D.
    Protein-tyrosine phosphatases and cancer2006In: Nature Reviews. Cancer, ISSN 1474-175X, E-ISSN 1474-1768, Vol. 6, no 4, p. 307-320Article, review/survey (Refereed)
    Abstract [en]

    Tyrosine phosphorylation is an important signalling mechanism in eukaryotic cells. In cancer, oncogenic activation of tyrosine kinases is a common feature, and novel anticancer drugs have been introduced that target these enzymes. Tyrosine phosphorylation is also controlled by protein-tyrosine phosphatases (PTPs). Recent evidence has shown that PTPs can function as tumour suppressors. In addition, some PTPs, including SHP2, positively regulate the signalling of growth-factor receptors, and can be oncogenic. An improved understanding of how these enzymes function and how they are regulated might aid the development of new anticancer agents.

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