Mechanism of TGF-β signaling to growth arrest, apoptosis, and epithelial–mesenchymal transition

Heldin, Carl‐Henrik; Landström, Maréne; Moustakas, Aristidis

doi:10.1016/j.ceb.2009.01.021

Cited by 575 publications

(494 citation statements)

References 102 publications

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“…16 In the vascular system, TGF-␤ inhibits the proliferation of endothelial cells while it stimulates that of the adjacent smooth muscle cells, 33,34 despite their close proximity. Conversely, it has a pro-apoptotic effect on endothelial cells while being anti-apoptotic in smooth muscle cells.…”

Section: Discussionmentioning

confidence: 99%

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Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

Gotlieb

2011

The American Journal of Pathology

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Although valve interstitial cell (VIC) growth is an essential feature of injured and diseased valves, the regulation of VIC growth is poorly understood. Transforming growth factor (TGF)-␤ promotes VIC proliferation in early-stage wound repair; thus, herein, we tested the hypothesis that TGF-␤ regulates VIC proliferation under normal nonwound conditions using low-density porcine VIC monolayers. Cell numbers were counted during a 10-day period, whereas proliferation and apoptosis were quantified by bromodeoxyuridine staining and TUNEL, respectively. The extent of retinoblastoma protein phosphorylation and expression of cyclin D1, CDK 4, and p27 were compared using Western blot analysis. Adhesion was quantified using a trypsin adhesion assay, and morphological change was demonstrated by immunofluorescence localization of ␣-smooth muscle actin and vinculin. TGF-␤-treated VICs were rhomboid; significantly decreased in number, proliferation, and retinoblastoma protein phosphorylation; and concomitantly had decreased expression of cyclin D1/CDK4 and increased expression of p27. TGF-␤-treated VICs adhered better to substratum and had more vinculin plaques and ␣-smooth muscle actin stress fibers than did controls. Thus, the regulation of VIC growth by TGF-␤ is context dependent. TGF-␤ prevents excessive heart valve growth under normal physiological conditions while it promotes cell proliferation in the early stages of repair, when increased VICs are required.

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Section: Discussionmentioning

confidence: 99%

“…14,15 TGF-␤ regulates a wide range of cellular processes, including cell proliferation, apoptosis, differentiation, migration, and ECM remodeling. 8,12,14,16 This multifunctionality allows TGF-␤ to participate in wound repair in multiple tissues and organs of the body. 12,17 Overexpression of TGF-␤ is often observed in in vivo wound sites.…”

mentioning

confidence: 99%

Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

Gotlieb

2011

The American Journal of Pathology

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“…ERα prevents apoptosis by controlling both the extrinsic and intrinsic apoptotic pathways and by promoting cell survival [228], whereas TGF-β causes cell cycle arrest by inhibiting cyclin-dependent kinase activities and by reducing the expression levels of c-Myc in epithelial cells [228]. TGF-β can also promote apoptosis or cell survival in a cell-type and context-dependent manner [229]. In order to explore the relationship between proliferation and both ERα and TGF-β signaling, ewan and colleagues sought to determine their expression in mouse mammary glands at estrus, and discovered co-localization with phosphorylated Smads and nuclear ERα.…”

Section: Crosstalk With Tgf-β Signalingmentioning

confidence: 99%

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

Zhou

Qiao

Shetty

et al. 2013

Cell. Mol. Life Sci.

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Estrogen and estrogen receptors (ERs) are critical regulators of breast epithelial cell proliferation, differentiation, and apoptosis. Compromised signaling vis-à-vis the estrogen receptor is believed © Springer Basel 2013 yow4@pitt.edu. ), which predicts for response to endocrine-based therapy; however, innate or acquired resistance to endocrinebased drugs remains a serious challenge. The complexity of regulation for estrogen signaling coupled with the crosstalk of other oncogenic signaling pathways is a reason for endocrine therapy resistance. Alternative strategies that target novel molecular mechanisms are necessary to overcome this current and urgent gap in therapy. A thorough analysis of estrogen-signaling regulation is critical. In this review article, we will summarize current insights into the regulation of estrogen signaling as related to breast carcinogenesis and breast cancer therapy. NIH Public Access

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“…43 Once phosphorylated, SMAD2 and SMAD3 bind to the co-SMAD, SMAD4, in the cytoplasm and then translocate into the nucleus. The TGFbR1-mediated activation and nuclear localization of SMAD2 and SMAD3 is prevented by an inhibitory SMAD (I-SMAD), SMAD7 ( Fig.…”

Section: Osm/stat3-induced Senescence Requires Smad3/smad4mentioning

confidence: 99%

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

et al. 2017

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Cytokines in the developing tumor microenvironment (TME) can drive transformation and subsequent progression toward metastasis. Elevated levels of the Interleukin-6 (IL-6) family cytokine Oncostatin M (OSM) in the breast TME correlate with aggressive, metastatic cancers, increased tumor recurrence, and poor patient prognosis. Paradoxically, OSM engages a tumor-suppressive, Signal Transducer and Activator of Transcription 3 (STAT3)-dependent senescence response in normal and non-transformed human mammary epithelial cells (HMEC). Here, we identify a novel link between OSM-activated STAT3 signaling and the Transforming Growth Factor-b (TGF-b) signaling pathway that engages senescence in HMEC. Inhibition of functional TGF-b/SMAD signaling by expressing a dominant-negative TGF-b receptor, treating with a TGF-b receptor inhibitor, or suppressing SMAD3 expression using a SMAD3-shRNA prevented OSMinduced senescence. OSM promoted a protein complex involving activated-STAT3 and SMAD3, induced the nuclear localization of SMAD3, and enhanced SMAD3-mediated transcription responsible for senescence. In contrast, expression of MYC (c-MYC) from a constitutive promoter abrogated senescence and strikingly, cooperated with OSM to promote a transformed phenotype, epithelial-mesenchymal transition (EMT), and invasiveness. Our findings suggest that a novel STAT3/SMAD3-signaling axis is required for OSM-mediated senescence that is coopted during the transformation process to confer aggressive cancer cell properties. Understanding how developing cancer cells bypass OSM/STAT3/SMAD3-mediated senescence may help identify novel targets for future "pro-senescence" therapies aiming to reengage this hidden tumor-suppressive response.

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Mechanism of TGF-β signaling to growth arrest, apoptosis, and epithelial–mesenchymal transition

Cited by 575 publications

References 102 publications

Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

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