Two major Smad pathways in TGF‐β superfamily signalling

Miyazawa, Keiji; Shinozaki, Masahiko; Hara, Takehisa; Furuya, Toshio; Miyazono, Kohei

doi:10.1046/j.1365-2443.2002.00599.x

Cited by 629 publications

(520 citation statements)

References 139 publications

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“…Binding of ligand to the receptor complex leads to the phosphorylation of the type II receptor kinase and activation of type I receptor kinase that leads to the propagation of signaling. The canonical, Smad‐mediated, TGF‐β signaling pathway implies phosphorylation of Smad2 and Smad3 proteins, formation of a complex with Smad4, and translocation into the nucleus, where transcription of target genes is activated (Derynck & Miyazono, 2008; Miyazawa, Shinozaki, Hara, Furuya, & Miyazono, 2002; Moustakas & Heldin, 2009, reviewed in Akhurst & Hata, 2012). However, TGF‐β may also signal through other signaling pathways, such as ERK, p38, JNK, and MAPK pathways (Yang et al, 2003) that may act independently or in co‐operation with the canonical pathway.…”

Section: Introductionmentioning

confidence: 99%

TGF‐β signaling directly regulates transcription and functional expression of the electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), via Smad4 in mouse astrocytes

Khakipoor

Ophoven

Schrödl-Häußel

et al. 2017

Glia

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The electrogenic sodium bicarbonate cotransporter NBCe1 (SLC4A4) expressed in astrocytes regulates intracellular and extracellular pH. Here, we introduce transforming growth factor beta (TGF‐β) as a novel regulator of NBCe1 transcription and functional expression. Using hippocampal slices and primary hippocampal and cortical astrocyte cultures, we investigated regulation of NBCe1 and elucidated the underlying signaling pathways by RT‐PCR, immunoblotting, immunofluorescence, intracellular H(+) recording using the H(+) ‐sensitive dye 2′,7′‐bis‐(carboxyethyl)‐5‐(and‐6)‐carboxyfluorescein, mink lung epithelial cell (MLEC) assay, and chromatin immunoprecipitation. Activation of TGF‐β signaling significantly upregulated transcript, protein, and surface expression of NBCe1. These effects were TGF‐β receptor‐mediated and suppressed following inhibition of JNK and Smad signaling. Moreover, 4‐aminopyridine (4AP)‐dependent NBCe1 regulation requires TGF‐β. TGF‐β increased the rate and amplitude of intracellular H+ changes upon challenging NBCe1 in wild‐type astrocytes but not in cortical astrocytes from Slc4a4‐deficient mice. A Smad4 binding sequence was identified in the NBCe1 promoter and Smad4 binding increased after activation of TGF‐β signaling. The data show for the first time that NBCe1 is a direct target of TGF‐β/Smad4 signaling. Through activation of the canonical pathway TGF‐β acts directly on NBCe1 by binding of Smad4 to the NBCe1 promoter and regulating its transcription, followed by increased protein expression and transport activity.

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Section: Introductionmentioning

confidence: 99%

TGF‐β signaling directly regulates transcription and functional expression of the electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), via Smad4 in mouse astrocytes

Khakipoor

Ophoven

Schrödl-Häußel

et al. 2017

Glia

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“…TGF-b type I receptor activated by TbRII phosphorylates Smad2 and Smad3, which interact with Smad4 and translocate to the nucleus. Nuclear Smad2/3-Smad4 complexes bind to transcription factors and transcriptional co-activators/ repressors, and regulate transcription of target genes (Miyazawa et al, 2002;Derynck and Zhang, 2003;Massague´, 2008). In epithelial cells, TGF-b inhibits cell proliferation, induces apoptosis and mediates differentiation, suggesting that components of the TGF-b signaling pathways have tumor-suppressive activity in epithelial tumors (Wakefield and Roberts, 2002;Bierie and Moses, 2006).…”

Section: Introductionmentioning

confidence: 99%

Transforming growth factor-β decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells

et al. 2010

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Stem cells in normal tissues and cancer-initiating cells (CICs) are known to be enriched in side population (SP) cells. However, the factors responsible for the regulation of expression of ABCG2, involved in efflux of dyes, in SP cells have not been fully investigated. Here, we characterized the SP cells within diffuse-type gastric carcinoma, and examined the effects of transforming growth factor-b (TGF-b) on SP cells. Diffuse-type gastric carcinoma cells established from four independent patients universally contained SP cells between 1 and 4% of total cells, which displayed greater tumorigenicity than non-SP cells did. TGF-b repressed the transcription of ABCG2 through direct binding of Smad2/3 to its promoter/enhancer, and the number of SP cells and the tumor-forming ability of cancer cells were decreased by TGF-b, although ABCG2 is not directly involved in the tumor-forming ability of SP cells. Cancer cells from metastatic site expressed much higher levels of ABCG2 and included a greater percentage of SP cells than parental cancer cells did. SP cells are thus responsible for the progression of diffuse-type gastric carcinoma, and TGF-b negatively contributes to maintain the CICs within the cancer.

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“…Both domains have been shown to associate with a large number of intracellular proteins (Shi and Massague´, 2003). Some of them regulate the activity of Smads in cytoplasm, while the others can function as transcriptional activators or repressors in nucleus together with Smads (Moustakas et al, 2001;ten Dijke et al, 2002;Miyazawa et al, 2002).…”

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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Two major Smad pathways in TGF‐β superfamily signalling

Cited by 629 publications

References 139 publications

TGF‐β signaling directly regulates transcription and functional expression of the electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), via Smad4 in mouse astrocytes

TGF‐β signaling directly regulates transcription and functional expression of the electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), via Smad4 in mouse astrocytes

Transforming growth factor-β decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells

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

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