Smad3 mediates immediate early induction of Id1 by TGF-β

Liang, Yao-Yun; Brunicardi, F. Charles; Lin, Xia

doi:10.1038/cr.2008.321

Cited by 64 publications

(53 citation statements)

References 45 publications

(52 reference statements)

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“…The dose of cycloheximide used in this study was previously shown to inhibit protein synthesis in MCF-10A cells (36). We corroborated this finding by demonstrating inhibition of TGF-␤ 1 -induced expression of Id-1, a known transcriptional induction in MCF-10A cells (28).…”

Section: Discussionsupporting

confidence: 78%

Progesterone stimulates mitochondrial activity with subsequent inhibition of apoptosis in MCF-10A benign breast epithelial cells

Behera

Dai

Garde

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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As an example, progesterone levels correlate with increased epithelial cell proliferation, but there is discordance between the dividing cells and the cells with nuclear progesterone receptor expression. The release of paracrine growth factors from nuclear receptor-positive cells has been postulated as a mechanism, since in vitro studies show a lack of growth effect by progesterone in breast epithelial cells lacking nuclear receptors. This study examined possible nongenomic effects of progesterone in breast epithelia by using MCF-10A cells known to lack nuclear progesterone receptor expression. Treatment for 30 -60 min with progesterone or the progestin, R5020, increased mitochondrial activity as shown by an increase in mitochondrial membrane potential (hyperpolarization) with a concordant increase in total cellular ATP. The reaction was inhibited by a specific progesterone receptor antagonist and not affected by the translation inhibitor cycloheximide. Progestin treatment inhibited apoptosis induced by activation of the FasL pathway, as shown by a decrease in sub-G 1 cell fraction during fluorescence-activated cell sorting and a decrease in caspase 3/7 levels. Progestin treatment did not alter the cell cycle over 48 h. Our study demonstrates a nongenomic action of progesterone on benign breast epithelial cells, resulting in enhanced cellular respiration and protection from apoptosis.progesterone; MCF-10A cells; mitochondria; apoptosis; cellular respiration PREVIOUS STUDIES HAVE SHOWN a discordance between the proliferative action of progesterone in the breast and the content of nuclear progesterone receptors (PR-B and PR-A) in breast epithelial cells. As examples, the mitotic rate of breast epithelial cells is greatest in the progesterone-dominant luteal phase (44). Exogenous administration of estrogen plus progestin results in greater breast epithelial proliferation than estrogen alone (15, 18). The progesterone receptor knockout (PRKO) mouse, an excellent model for the function of nuclear PR in mammary gland development, supports a proliferative role. PR-B is primarily responsible for gland development, with PRKO-B mice showing less extensive ductal development and lack of alveolar terminal end buds (7,29). In contrast to these physiological effects, very few breast epithelial cells appear to express nuclear PR. In immunocytochemical studies of human breast tissue, from 6 to 13% of ductal epithelial cells express PR (6, 37), with the two PR isoforms, B and A, typically localizing in the same cell (14). Immunocytochemical analysis of proliferation by detection of Ki67 antigen in human breast or autoradiographs of [ 3 H]thymidine incorporation in rodent mammary samples show nuclear PR-expressing cells to be nonproliferating. Adjacent cells lacking nuclear PR expression have greater mitotic activity (23). This disassociation between nuclear PR expression and proliferation led to the hypothesis that nuclear PR-expressing cells regulate proliferation of adjacent cells via the control of paracrine factors (4).This ...

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Section: Discussionsupporting

confidence: 78%

Progesterone stimulates mitochondrial activity with subsequent inhibition of apoptosis in MCF-10A benign breast epithelial cells

Behera

Dai

Garde

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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“…In the presence of the translation inhibitor cycloheximide Smad7 induction was partly blunted, but importantly, all three genes were still upregulated in response to TGFβ (Fig 2B-D), confirming that they are direct targets of TGFβ signaling. This has previously been reported for Smad7 25 and Id1 27 , while Gata2 has not been implicated in this context.…”

Section: Global Gene Expression Profiling Reveals Gata2 As a Target Osupporting

confidence: 69%

A network including TGFβ/Smad4, Gata2, and p57 regulates proliferation of mouse hematopoietic progenitor cells

Billing

Rörby

May

et al. 2016

Experimental Hematology

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“…In epithelial cells, Smad3 mediates the early ID response and also drives ATF3 transcription, which subsequently represses ID1 (32,33). However, our data using cycloheximide suggested that transcription is not required for the TGF-b 1 -mediated repression.…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β₁ Represses Bone Morphogenetic Protein–Mediated Smad Signaling in Pulmonary Artery Smooth Muscle Cells via Smad3

Upton

Davies

Tajsic

et al. 2013

Am J Respir Cell Mol Biol

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Previous studies of pulmonary arterial hypertension (PAH) have implicated excessive transforming growth factor (TGF)-b 1 signaling and reduced bone morphogenetic protein (BMP) signaling in the disease pathogenesis. Reduced BMP signaling in pulmonary artery smooth muscle cells (PASMCs) from patients with heritable PAH is a consequence of germline mutations in the BMP type II receptor (BMPR-II). We sought to establish whether the TGF-b 1 and BMP4 pathways interact in PASMCs, and if this is altered in cells with BMPR-II mutations. Control PASMCs or from patients with PAH harboring BMPR-II mutations were treated with BMP4, TGF-b 1 , or cotreated with both ligands. Signaling was assessed by examination of Smad phosphorylation, luciferase reporters, and the transcription of BMP4 or TGF-b 1 -responsive genes. TGF-b 1 attenuated BMP4-mediated inhibitors of differentiation 1/2 induction and abolished the response in BMPR-II mutant PASMCs, whereas BMP4 did not alter TGF-b 1 -mediated transcription. Activin-like kinase 5 inhibition blocked this effect, whereas cycloheximide or pharmacological inhibitors of TGF-b-activated kinase 1, extracellular signal-regulated kinase 1/2, or p38 mitogen-activated protein kinase were ineffective. BMP4 and TGF-b 1 cotreatment did not alter the activation or nuclear translocation of their respective Smad signaling proteins. Small interfering RNA for Smad3, but not Smad2, Smad6, or Smad7, reversed the inhibition by TGF-b 1 . In addition, TGF-b-activated kinase 1 inhibition blocked Smad3 phosphorylation, implying that C-terminal Smad3 phosphorylation is not required for the inhibition of BMP4 signaling by TGF-b 1 . TGF-b 1 reduces BMP4 signaling in PASMCs, a response that is exacerbated on the background of reduced BMP responsiveness due to BMPR-II mutations. These data provide a rationale for therapeutic inhibition of TGF-b 1 signaling in PAH.Keywords: pulmonary arterial hypertension; transforming growth factor beta; bone morphogenetic protein; inhibitor of differentiation Transforming growth factor (TGF)-b 1 is a pleiotropic cytokine involved in embryonic development, inflammation, angiogenesis, immune cell function, and wound healing via the regulation of cell processes, such as growth, differentiation, adhesion, migration, and apoptosis (1). Excessive TGF-b 1 production is associated with fibrotic diseases of several organs, including the lung (2) and kidney (3). Dysregulated TGF-b 1 signaling is also emerging as a key pathological process in pulmonary arterial hypertension (PAH). We recently reported enhanced pulmonary vascular TGF-b 1 signaling in the monocrotaline (MCT) rat model of PAH (MCT-PAH) (4), and inhibitors of the TGF-b 1 type I receptor, activin-like kinase 5 (ALK5), attenuated disease progression in MCT-PAH, implicating TGF-b as a pathogenic cytokine in PAH (4-6). In man, most heritable PAH (HPAH) cases are associated with germline mutations in the gene encoding bone morphogenetic protein (BMP) receptor (BMPR)-II, a member of the TGF receptor superfamily (7). Furthermore, BM...

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Smad3 mediates immediate early induction of Id1 by TGF-β

Cited by 64 publications

References 45 publications

Progesterone stimulates mitochondrial activity with subsequent inhibition of apoptosis in MCF-10A benign breast epithelial cells

Progesterone stimulates mitochondrial activity with subsequent inhibition of apoptosis in MCF-10A benign breast epithelial cells

A network including TGFβ/Smad4, Gata2, and p57 regulates proliferation of mouse hematopoietic progenitor cells

Transforming Growth Factor-β₁ Represses Bone Morphogenetic Protein–Mediated Smad Signaling in Pulmonary Artery Smooth Muscle Cells via Smad3

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Smad3 mediates immediate early induction of Id1 by TGF-β

Cited by 64 publications

References 45 publications

Progesterone stimulates mitochondrial activity with subsequent inhibition of apoptosis in MCF-10A benign breast epithelial cells

Progesterone stimulates mitochondrial activity with subsequent inhibition of apoptosis in MCF-10A benign breast epithelial cells

A network including TGFβ/Smad4, Gata2, and p57 regulates proliferation of mouse hematopoietic progenitor cells

Transforming Growth Factor-β1 Represses Bone Morphogenetic Protein–Mediated Smad Signaling in Pulmonary Artery Smooth Muscle Cells via Smad3

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Transforming Growth Factor-β₁ Represses Bone Morphogenetic Protein–Mediated Smad Signaling in Pulmonary Artery Smooth Muscle Cells via Smad3