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  • 1. Carthy, Jon M.
    et al.
    Sundqvist, Anders
    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, Angelos
    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.
    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.
    Kletsas, Dimitris
    Natl Ctr Sci Res Demokritos, Inst Biosci & Applicat, Lab Cell Proliferat & Ageing, Athens, Greece..
    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.
    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.
    Tamoxifen Inhibits TGF-beta-Mediated Activation of Myofibroblasts by Blocking Non-Smad Signaling Through ERK1/22015In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 230, no 12, p. 3084-3092Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine which stimulates the differentiation of fibroblasts into myofibroblasts. Myofibroblasts are critical for normal wound healing, but also accumulate pathologically in a number of chronic inflammatory conditions where they are key contributors to aberrant tissue remodeling and fibrosis, and in cancer stroma. In the current study, we identified a role for tamoxifen as a potent inhibitor of the TGF-beta-mediated activation of primary human skin and breast fibroblasts. Our data indicate that tamoxifen does not interfere with canonical Smad signaling downstream of TGF-beta but rather blocks non-Smad signaling through ERK1/2 MAP-kinase and the AP-1 transcription factor FRA2. We further demonstrate by siRNA-mediated knockdown that FRA2 is critical for the induced expression of myogenic proteins in response to TGF-beta. Functionally, TGF-beta-stimulated fibroblast-mediated contraction of collagen gels was impaired in the presence of tamoxifen. Altogether, these data demonstrate that tamoxifen prevents myofibroblast differentiation and, therefore, may provide therapeutic benefits to patients suffering from chronic inflammatory conditions or cancer.

  • 2.
    Lind, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Sundqvist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Hu, Lijuan
    Pejler, Gunnar
    Andersson, Goran
    Jacobson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Vitamin A Is a Negative Regulator of Osteoblast Mineralization2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. e82388-Article in journal (Refereed)
    Abstract [en]

    An excessive intake of vitamin A has been associated with an increased risk of fractures in humans. In animals, a high vitamin A intake leads to a reduction of long bone diameter and spontaneous fractures. Studies in rodents indicate that the bone thinning is due to increased periosteal bone resorption and reduced radial growth. Whether the latter is a consequence of direct effects on bone or indirect effects on appetite and general growth is unknown. In this study we therefore used pair-feeding and dynamic histomorphometry to investigate the direct effect of a high intake of vitamin A on bone formation in rats. Although there were no differences in body weight or femur length compared to controls, there was an approximately halved bone formation and mineral apposition rate at the femur diaphysis of rats fed vitamin A. To try to clarify the mechanism(s) behind this reduction, we treated primary human osteoblasts and a murine preosteoblastic cell line (MC3T3-E1) with the active metabolite of vitamin A; retinoic acid (RA), a retinoic acid receptor (RAR) antagonist (AGN194310), and a Cyp26 inhibitor (R115866) which blocks endogenous RA catabolism. We found that RA, via RARs, suppressed in vitro mineralization. This was independent of a negative effect on osteoblast proliferation. Alkaline phosphatase and bone gamma carboxyglutamate protein (Bglap, Osteocalcin) were drastically reduced in RA treated cells and RA also reduced the protein levels of Runx2 and Osterix, key transcription factors for progression to a mature osteoblast. Normal osteoblast differentiation involved up regulation of Cyp26b1, the major enzyme responsible for RA degradation, suggesting that a drop in RA signaling is required for osteogenesis analogous to what has been found for chondrogenesis. In addition, RA decreased Phex, an osteoblast/osteocyte protein necessary for mineralization. Taken together, our data indicate that vitamin A is a negative regulator of osteoblast mineralization.

  • 3.
    Morikawa, Masato
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Koinuma, Daizo
    Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo 1130033, Japan..
    Mizutani, Anna
    Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo 1130033, Japan..
    Kawasaki, Natsumi
    Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo 1130033, Japan..
    Holmborn, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Sundqvist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Tsutsumi, Shuichi
    Univ Tokyo, Genome Sci Div, Res Ctr Adv Sci & Technol, Tokyo 1538904, Japan..
    Watabe, Tetsuro
    Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo 1130033, Japan.;JST, PRESTO, Kawaguchi, Saitama 3320012, Japan..
    Aburatani, Hiroyuki
    Univ Tokyo, Genome Sci Div, Res Ctr Adv Sci & Technol, Tokyo 1538904, Japan..
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala Univ, Ludwig Inst Canc Res, Sci Life Lab, S-75124 Uppsala, Sweden..
    Miyazono, Kohei
    Uppsala Univ, Ludwig Inst Canc Res, Sci Life Lab, S-75124 Uppsala, Sweden.;Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo 1130033, Japan..
    BMP Sustains Embryonic Stem Cell Self-Renewal through Distinct Functions of Different Kruppel-like Factors2016In: Stem Cell Reports, ISSN 2213-6711, Vol. 6, no 1, p. 64-73Article in journal (Refereed)
    Abstract [en]

    Bone morphogenetic protein (BMP) signaling exerts paradoxical roles in pluripotent stem cells (PSCs); it sustains self-renewal of mouse embryonic stem cells (ESCs), while it induces differentiation in other PSCs, including human ESCs. Here, we revisit the roles of BMP-4 using mouse ESCs (mESCs) in naive and primed states. SMAD1 and SMAD5, which transduce BMP signals, recognize enhancer regions together with KLF4 and KLF5 in naive mESCs. KLF4 physically interacts with SMAD1 and suppresses its activity. Consistently, a subpopulation of cells with active BMP-SMAD can be ablated without disturbing the naive state of the culture. Moreover, Smad1/5 double-knockout mESCs stay in the naive state, indicating that the BMP-SMAD pathway is dispensable for it. In contrast, the MEK5-ERK5 pathway mediates BMP-4-induced self-renewal of mESCs by inducing Klf2, a critical factor for the ground state pluripotency. Our study illustrates that BMP exerts its self-renewing effect through distinct functions of different Kruppel-like factors.

  • 4.
    Naber, Hildegonda P H
    et al.
    Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, Postzone S-1-P, PO Box 9600, 2300 RC Leiden, The Netherlands.
    Wiercinska, Eliza
    Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, Postzone S-1-P, PO Box 9600, 2300 RC Leiden, The Netherlands.
    Pardali, Evangelia
    Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, Postzone S-1-P, PO Box 9600, 2300 RC Leiden, The Netherlands.
    van Laar, Theo
    Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, Postzone S-1-P, PO Box 9600, 2300 RC Leiden, The Netherlands.
    Nirmala, Ella
    Division of Toxicology, Leiden Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, 2300 RA Leiden, The Netherlands.
    Sundqvist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    van Dam, Hans
    Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, Postzone S-1-P, PO Box 9600, 2300 RC Leiden, The Netherlands.
    van der Horst, Geertje
    Department of Urology and Endocrinology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
    van der Pluijm, Gabri
    Department of Urology and Endocrinology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
    Heckmann, Bertrand
    Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
    Danen, Erik H J
    Division of Toxicology, Leiden Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, 2300 RA 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.
    BMP-7 inhibits TGF-β-induced invasion of breast cancer cells through inhibition of integrin β(3) expression2012In: Cellular Oncology, ISSN 2211-3428, E-ISSN 2211-3436, Vol. 35, no 1, p. 19-28Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The transforming growth factor (TGF)-β superfamily comprises cytokines such as TGF-β and Bone Morphogenetic Proteins (BMPs), which have a critical role in a multitude of biological processes. In breast cancer, high levels of TGF-β are associated with poor outcome, whereas inhibition of TGF-β-signaling reduces metastasis. In contrast, BMP-7 inhibits bone metastasis of breast cancer cells.

    METHODS: In this study, we investigated the effect of BMP-7 on TGF-β-induced invasion in a 3 dimensional invasion assay.

    RESULTS: BMP-7 inhibited TGF-β-induced invasion of the metastatic breast cancer cell line MCF10CA1a, but not of its premalignant precursor MCF10AT in a spheroid invasion model. The inhibitory effect appears to be specific for BMP-7, as its closest homolog, BMP-6, did not alter the invasion of MCF10CA1a spheroids. To elucidate the mechanism by which BMP-7 inhibits TGF-β-induced invasion, we analyzed invasion-related genes. BMP-7 inhibited TGF-β-induced expression of integrin α(v)β(3) in the spheroids. Moreover, targeting of integrins by a chemical inhibitor or knockdown of integrin β(3) negatively affected TGF-β-induced invasion. On the other hand, overexpression of integrin β(3) counteracted the inhibitory effect of BMP7 on TGF-β-induced invasion.

    CONCLUSION: Thus, BMP-7 may exert anti-invasive actions by inhibiting TGF-β-induced expression of integrin β(3).

  • 5.
    Sundqvist, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Bengoechea-Alonso, Maria T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Ye, Xin
    Lukiyanchuk, Vasyl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Jin, Jianping
    Harper, J Wade
    Ericsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCF(Fbw7)2005In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 1, no 6, p. 379-391Article in journal (Refereed)
    Abstract [en]

    The sterol regulatory element binding protein (SREBP) family of transcription factors controls cholesterol and lipid metabolism. The nuclear forms of these proteins are rapidly degraded by the ubiquitin-proteasome pathway, but the signals and factors required for this are unknown. Here, we identify a phosphodegron in SREBP1a that serves as a recognition motif for the SCF(Fbw7) ubiquitin ligase. Fbw7 interacts with nuclear SREBP1a and enhances its ubiquitination and degradation in a manner dependent on the phosphorylation of T426 and S430 by GSK-3. Fbw7 also degrades nuclear SREBP1c and SREBP2, and inactivation of endogenous Fbw7 results in stabilization of nuclear SREBP1 and -2, enhanced expression of SREBP target genes, enhanced synthesis of cholesterol and fatty acids, and enhanced receptor-mediated uptake of LDL. Thus, our results suggest that Fbw7 may be a major regulator of lipid metabolism through control of the phosphorylation-dependent degradation of the SREBP family of transcription factors.

  • 6.
    Sundqvist, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Ericsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Transcription-dependent degradation controls the stability of the SREBP family of transcription factors2003In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 100, no 24, p. 13833-13838Article in journal (Refereed)
    Abstract [en]

    Cholesterol metabolism is tightly controlled by members of the sterol regulatory element-binding protein (SREBP) family of transcription factors. Here we demonstrate that the ubiquitination and degradation of SREBPs depend on their transcriptional activity. Mutations in the transactivation or DNA-binding domains of SREBPs inhibit their transcriptional activity and stabilize the proteins. The transcriptional activity and degradation of these mutants are restored when fused to heterologous transactivation or DNA-binding domains. When SREBP1a was fused to the DBD of Gal4, the ubiquitination and degradation of the fusion protein depended on coexpression of a promoter-reporter gene containing Gal4-binding sites. In addition, disruption of the interaction between WT SREBP and endogenous p300/CBP resulted in inhibition of SREBP-dependent transcription and stabilization of SREBP. Chemical inhibitors of transcription reduced the degradation of transcriptionally active SREBP1a, whereas they had no effect on the stability of transcriptionally inactive mutants, demonstrating that transcriptional activation plays an important role in the degradation of SREBPs. Thus, transcription-dependent degradation of SREBP constitutes a feedback mechanism to regulate the expression of genes involved in cholesterol metabolism and may represent a general mechanism to regulate the duration of transcriptional responses.

  • 7.
    Sundqvist, Anders
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Morikawa, Masato
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo 1130033, Japan..
    Ren, Jiang
    Leiden Univ, Med Ctr, Canc Genom Ctr Netherlands, Dept Mol Cell Biol, POB 9600, NL-2300 RC Leiden, Netherlands..
    Vasilaki, Eleftheria
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kawasaki, Natsumi
    Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo 1130033, Japan..
    Kobayashi, Mai
    Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo 1130033, Japan..
    Koinuma, Daizo
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo 1130033, Japan..
    Aburatani, Hiroyuki
    Univ Tokyo, Res Ctr Adv Sci & Technol, Genome Sci Div, Tokyo 1538904, Japan..
    Miyazono, Kohei
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo 1130033, Japan..
    Heldin, Carl-Henrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    van Dam, Hans
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Leiden Univ, Med Ctr, Canc Genom Ctr Netherlands, Dept Mol Cell Biol, POB 9600, NL-2300 RC Leiden, Netherlands..
    ten Dijke, Peter
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Leiden Univ, Med Ctr, Canc Genom Ctr Netherlands, Dept Mol Cell Biol, POB 9600, NL-2300 RC Leiden, Netherlands..
    JUNB governs a feed-forward network of TGF beta signaling that aggravates breast cancer invasion2018In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, no 3, p. 1180-1195Article in journal (Refereed)
    Abstract [en]

    It is well established that transforming growth factor-beta (TGF beta) switches its function from being a tumor suppressor to a tumor promoter during the course of tumorigenesis, which involves both cell-intrinsic and environment-mediated mechanisms. We are interested in breast cancer cells, in which SMAD mutations are rare and interactions between SMAD and other transcription factors define pro-oncogenic events. Here, we have performed chromatin immunoprecipitation (ChIP)-sequencing analyses which indicate that the genome-wide landscape of SMAD2/3 binding is altered after prolonged TGF beta stimulation. De novo motif analyses of the SMAD2/3 binding regions predict enrichment of binding motifs for activator protein (AP) 1 in addition to SMAD motifs. TGF beta-induced expression of the AP1 component JUNB was required for expression of many late invasion-mediating genes, creating a feed-forward regulatory network. Moreover, we found that several components in the WNT pathway were enriched among the late TGF beta-target genes, including the invasion-inducing WNT7 proteins. Consistently, overexpression of WNT7A or WNT7B enhanced and potentiated TGF beta-induced breast cancer cell invasion, while inhibition of the WNT pathway reduced this process. Our study thereby helps to explain how accumulation of pro-oncogenic stimuli switches and stabilizes TGF beta-induced cellular phenotypes of epithelial cells.

  • 8.
    Sundqvist, Anders
    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.
    van Dam, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Key signaling nodes in mammary gland development and cancer: Smad signal integration in epithelial cell plasticity2012In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 14, no 1, article id 204Article, review/survey (Refereed)
    Abstract [en]

    Smad proteins are the key intermediates of transforming growth factor-beta (TGF-β) signaling during development and in tissue homeostasis. Pertubations in TGF-β/Smad signaling have been implicated in cancer and other diseases. In the cell nucleus, Smad complexes trigger cell type- and context-specific transcriptional programs, thereby transmitting and integrating signals from a variety of ligands of the TGF-β superfamily and other stimuli in the cell microenvironment. The actual transcriptional and biological outcome of Smad activation critically depends on the genomic integrity and the modification state of genome and chromatin of the cell. The cytoplasmic and nuclear Smads can also modulate the activity of other signal transducers and enzymes such as microRNA-processing factors. In the case of breast cancer, the role of Smads in epithelial plasticity, tumor-stroma interactions, invasion, and metastasis seems of particular importance.

  • 9.
    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, p. 3606-3615Article 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.

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