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Sundqvist, Anders
Publications (9 of 9) Show all publications
Sundqvist, A., Morikawa, M., Ren, J., Vasilaki, E., Kawasaki, N., Kobayashi, M., . . . ten Dijke, P. (2018). JUNB governs a feed-forward network of TGF beta signaling that aggravates breast cancer invasion. Nucleic Acids Research, 46(3), 1180-1195
Open this publication in new window or tab >>JUNB governs a feed-forward network of TGF beta signaling that aggravates breast cancer invasion
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2018 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, no 3, p. 1180-1195Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-349356 (URN)10.1093/nar/gkx1190 (DOI)000425294400020 ()29186616 (PubMedID)
Funder
Swedish Cancer Society, 09 0773, 10 0452, 2016/445Swedish Research Council, 2015-02757
Available from: 2018-05-02 Created: 2018-05-02 Last updated: 2018-05-02Bibliographically approved
Morikawa, M., Koinuma, D., Mizutani, A., Kawasaki, N., Holmborn, K., Sundqvist, A., . . . Miyazono, K. (2016). BMP Sustains Embryonic Stem Cell Self-Renewal through Distinct Functions of Different Kruppel-like Factors. Stem Cell Reports, 6(1), 64-73
Open this publication in new window or tab >>BMP Sustains Embryonic Stem Cell Self-Renewal through Distinct Functions of Different Kruppel-like Factors
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2016 (English)In: Stem Cell Reports, ISSN 2213-6711, Vol. 6, no 1, p. 64-73Article in journal (Refereed) Published
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.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-276812 (URN)10.1016/j.stemcr.2015.12.004 (DOI)000368099500008 ()26771354 (PubMedID)
Funder
Swedish Cancer Society, 100452
Available from: 2016-02-16 Created: 2016-02-16 Last updated: 2017-11-30Bibliographically approved
Carthy, J. M., Sundqvist, A., Heldin, A., Van Dam, H., Kletsas, D., Heldin, C.-H. & Moustakas, A. (2015). Tamoxifen Inhibits TGF-beta-Mediated Activation of Myofibroblasts by Blocking Non-Smad Signaling Through ERK1/2. Journal of Cellular Physiology, 230(12), 3084-3092
Open this publication in new window or tab >>Tamoxifen Inhibits TGF-beta-Mediated Activation of Myofibroblasts by Blocking Non-Smad Signaling Through ERK1/2
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2015 (English)In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 230, no 12, p. 3084-3092Article in journal (Refereed) Published
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.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-262938 (URN)10.1002/jcp.25049 (DOI)000360378000026 ()26096876 (PubMedID)
Funder
Swedish Cancer Society, CAN 2006/1078 CAN 2009/900 CAN 2012/438Swedish Research Council, K2007-66X-14936-04-3 K2010-67X-14936-07-3 K2013-66X-14936-10-5
Available from: 2015-10-02 Created: 2015-09-23 Last updated: 2017-12-01Bibliographically approved
Sundqvist, A., Zieba, A., Vasilaki, E., Herrera Hidalgo, C., Söderberg, O., Koinuma, D., . . . van Dam, H. (2013). Specific interactions between Smad proteins and AP-1 components determine TGFβ-induced breast cancer cell invasion. Oncogene, 32(31), 3606-3615
Open this publication in new window or tab >>Specific interactions between Smad proteins and AP-1 components determine TGFβ-induced breast cancer cell invasion
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2013 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 32, no 31, p. 3606-3615Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-180124 (URN)10.1038/onc.2012.370 (DOI)000322638400005 ()22926518 (PubMedID)
Note

Agata Zieba & Eleftheria Vasilaki contributed equally to this work.

Available from: 2012-08-30 Created: 2012-08-30 Last updated: 2017-12-07Bibliographically approved
Lind, T., Sundqvist, A., Hu, L., Pejler, G., Andersson, G., Jacobson, A. & Melhus, H. (2013). Vitamin A Is a Negative Regulator of Osteoblast Mineralization. PLoS ONE, 8(12), e82388
Open this publication in new window or tab >>Vitamin A Is a Negative Regulator of Osteoblast Mineralization
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. e82388-Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-217667 (URN)10.1371/journal.pone.0082388 (DOI)000328707400074 ()
Available from: 2014-02-05 Created: 2014-02-04 Last updated: 2017-12-06Bibliographically approved
Naber, H. P., Wiercinska, E., Pardali, E., van Laar, T., Nirmala, E., Sundqvist, A., . . . ten Dijke, P. (2012). BMP-7 inhibits TGF-β-induced invasion of breast cancer cells through inhibition of integrin β(3) expression. Cellular Oncology, 35(1), 19-28
Open this publication in new window or tab >>BMP-7 inhibits TGF-β-induced invasion of breast cancer cells through inhibition of integrin β(3) expression
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2012 (English)In: Cellular Oncology, ISSN 2211-3428, E-ISSN 2211-3436, Vol. 35, no 1, p. 19-28Article in journal (Refereed) Published
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).

Place, publisher, year, edition, pages
Springer, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-168807 (URN)10.1007/s13402-011-0058-0 (DOI)000299920300003 ()21935711 (PubMedID)
Available from: 2012-02-15 Created: 2012-02-15 Last updated: 2017-12-07Bibliographically approved
Sundqvist, A., ten Dijke, P. & van Dam, H. (2012). Key signaling nodes in mammary gland development and cancer: Smad signal integration in epithelial cell plasticity. Breast Cancer Research, 14(1), Article ID 204.
Open this publication in new window or tab >>Key signaling nodes in mammary gland development and cancer: Smad signal integration in epithelial cell plasticity
2012 (English)In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 14, no 1, article id 204Article, review/survey (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-174020 (URN)10.1186/bcr3066 (DOI)000307444100008 ()22315972 (PubMedID)
Available from: 2012-05-09 Created: 2012-05-09 Last updated: 2017-12-07Bibliographically approved
Sundqvist, A., Bengoechea-Alonso, M. T., Ye, X., Lukiyanchuk, V., Jin, J., Harper, J. W. & Ericsson, J. (2005). Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCF(Fbw7). Cell Metabolism, 1(6), 379-391
Open this publication in new window or tab >>Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCF(Fbw7)
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2005 (English)In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 1, no 6, p. 379-391Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-74138 (URN)10.1016/j.cmet.2005.04.010 (DOI)16054087 (PubMedID)
Available from: 2005-08-31 Created: 2005-08-31 Last updated: 2017-12-14Bibliographically approved
Sundqvist, A. & Ericsson, J. (2003). Transcription-dependent degradation controls the stability of the SREBP family of transcription factors. Proceedings of the National Academy of Sciences of the United States of America, 100(24), 13833-13838
Open this publication in new window or tab >>Transcription-dependent degradation controls the stability of the SREBP family of transcription factors
2003 (English)In: 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) Published
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.

Keywords
Animals, CCAAT-Enhancer-Binding Proteins/chemistry/*genetics/*metabolism, COS Cells, Cell Line, Cholesterol/metabolism, DNA-Binding Proteins/chemistry/*genetics/*metabolism, Drug Stability, Feedback, Genes; Reporter, Hela Cells, Humans, Models; Biological, Mutagenesis; Site-Directed, Protein Structure; Tertiary, Recombinant Fusion Proteins/chemistry/genetics/metabolism, Sequence Deletion, Sterol Regulatory Element Binding Protein 1, Transcription Factors/chemistry/*genetics/*metabolism, Transcription; Genetic, Ubiquitin/metabolism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-10502 (URN)10.1073/pnas.2335135100 (DOI)14615581 (PubMedID)
Available from: 2007-03-27 Created: 2007-03-27 Last updated: 2017-12-11Bibliographically approved
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