TGF-β signalling from cell membrane to nucleus through SMAD proteins

Heldin, Carl‐Henrik; Miyazono, Kohei; Dijke, Peter ten

doi:10.1038/37284

Cited by 3,487 publications

(2,958 citation statements)

References 97 publications

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“…Transforming growth factor‐β (TGF‐β) is one of the main cytokines that promotes the EMT (Heldin et al ., 2012; Lamouille et al ., 2014). Specifically, TGF‐β binds to type I and type II receptors and transduces signals through Smad and non‐Smad signaling pathways (Derynck and Zhang, 2003; Heldin et al ., 1997; Massague, 2012). The TGF‐β type I receptor is activated by ligand stimulation and induces the phosphorylation of the receptor‐regulated Smads (R‐Smads), Smad2 and Smad3, which form trimeric complexes with the common‐partner Smad, Smad4.…”

Section: Introductionmentioning

confidence: 99%

ZEB1‐regulated inflammatory phenotype in breast cancer cells

et al. 2017

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Zinc finger E‐box binding protein 1 (ZEB1) and ZEB2 induce epithelial‐mesenchymal transition (EMT) and enhance cancer progression. However, the global view of transcriptional regulation by ZEB1 and ZEB2 is yet to be elucidated. Here, we identified a ZEB1‐regulated inflammatory phenotype in breast cancer cells using chromatin immunoprecipitation sequencing and RNA sequencing, followed by gene set enrichment analysis (GSEA) of ZEB1‐bound genes. Knockdown of ZEB1 and/or ZEB2 resulted in the downregulation of genes encoding inflammatory cytokines related to poor prognosis in patients with cancer, including IL6 and IL8, therefore suggesting that ZEB1 and ZEB2 have similar functions in terms of the regulation of production of inflammatory cytokines. Antibody array and ELISA experiments confirmed that ZEB1 controlled the production of the IL‐6 and IL‐8 proteins. The secretory proteins regulated by ZEB1 enhanced breast cancer cell proliferation and tumor growth. ZEB1 expression in breast cancer cells also affected the growth of fibroblasts in cell culture, and the accumulation of myeloid‐derived suppressor cells in tumors in vivo. These findings provide insight into the role of ZEB1 in the progression of cancer, mediated by inflammatory cytokines, along with the initiation of EMT.

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Section: Introductionmentioning

confidence: 99%

ZEB1‐regulated inflammatory phenotype in breast cancer cells

et al. 2017

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“…Deregulation of TGF-b signaling has been implicated in oncogenesis, fibrosis, immune-and vascular disorders (Massagueé t al., 2000). Transforming growth factor-b family members transduce their signals across the plasma membrane by inducing the formation of heteromeric complexes of specific type I and type II serine/threonine kinase receptors (Heldin et al, 1997). The type I receptor (also termed activin receptor-like kinase (ALK)) is phosphorylated and activated by the type II receptor (Wrana et al, 1994), and initiates intracellular signaling through activation of downstream signaling components, including the phosphorylation of receptor-regulated (R-) Smads at their extreme carboxyl-terminal serine residues.…”

Section: Introductionmentioning

confidence: 99%

ELAC2, a putative prostate cancer susceptibility gene product, potentiates TGF-β/Smad-induced growth arrest of prostate cells

et al. 2006

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Transforming growth factor-b (TGF-b) elicits a potent growth inhibitory effect on many normal cells by binding to specific serine/threonine kinase receptors and activating specific Smad proteins, which regulate the expression of cell cycle genes, including the p21 cyclin-dependent kinase (CDK) inhibitor gene. Interestingly, cancer cells are often insensitive to the anti-mitogenic effects of TGF-b for which the molecular mechanisms are not well understood. In this study, we found that the candidate prostate cancer susceptibility gene ELAC2 potentiates TGF-b/Smadinduced transcriptional responses. ELAC2 associates with activated Smad2; the C-terminal MH2 domain of Smad2 interacts with the N-terminal region of ELAC2. Small interfering siRNA-mediated knock-down of ELAC2 in prostate cells suppressed TGF-b-induced growth arrest. Moreover, ELAC2 was shown to specifically associate with the nuclear Smad2 partner, FAST-1 and to potentiate the interaction of activated Smad2 with transcription factor Sp1. Furthermore, activation of the p21 CDK inhibitor promoter by TGF-b is potentiated by ELAC2. Taken together our data indicate an important transcriptional scaffold function for ELAC2 in TGF-b/ Smad signaling mediated growth arrest.

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“…Following phosphorylation by the type I receptor, Smad2 or Smad3 forms a heteromeric complex with Smad4. The complex formed then translocates to the nucleus where it can directly or indirectly regulate gene transcription [16][17][18][19]. In addition to the Smad pathway, another signaling pathway of TGF-β involves the TGF-β activated kinase 1(TAK1), which was identified as a member of MAP kinase family [20].…”

Section: Introductionmentioning

confidence: 99%

The involvement of p38 MAPK in transforming growth factor β1-induced apoptosis in murine hepatocytes

et al. 2001

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We reported in this manuscript that TGF-β1 induces apoptosis in AML12 murine hepatocytes, which is associated with the activation of p38 MAPK signaling pathway. SB202190, a specific inhibitor of p38 MAPK, strongly inhibited the TGF-β1-induced apoptosis and PAI-1 promoter activity. Treatment of cells with TGF-β1 activates p38. Furthermore, over-expression of dominant negative mutant p38 also reduced the TGF-β1-induced apoptosis. The data indicate that the activation of p38 is involved in TGF-β1-mediated gene expression and apoptosis.

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TGF-β signalling from cell membrane to nucleus through SMAD proteins

Cited by 3,487 publications

References 97 publications

ZEB1‐regulated inflammatory phenotype in breast cancer cells

ZEB1‐regulated inflammatory phenotype in breast cancer cells

ELAC2, a putative prostate cancer susceptibility gene product, potentiates TGF-β/Smad-induced growth arrest of prostate cells

The involvement of p38 MAPK in transforming growth factor β1-induced apoptosis in murine hepatocytes

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