A short amino-acid sequence in MH1 domain is responsible for functional differences between Smad2 and Smad3

Dennler, Sylviane; Huet, Stéphane; Gauthier, Jean-Michel

doi:10.1038/sj.onc.1202729

Cited by 168 publications

(143 citation statements)

References 33 publications

(46 reference statements)

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“…9B, we observed that the overexpression of Smad2, Smad3, or Smad4 in the absence of TGF␤1 did not significantly affect the basal novH promoter activity. This is consistent with previous studies of CAGA-mediated transcription (61,66). More importantly, TGF␤1 still down-regulated novH promoter activity as efficiently as it does in the absence of co-transfected Smad proteins.…”

Section: The Smad Pathway Is Not Required For the Down-regulation Of supporting

confidence: 81%

The Expression of novH in Adrenocortical Cells Is Down-regulated by TGFβ1 through c-Jun in a Smad-independent Manner

Lafont

Laurent

Thibout

et al. 2002

Journal of Biological Chemistry

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The human NOV secreted glycoprotein (NOVH) is abundant in the fetal and adult adrenal cortex. The amount of NOVH increases in benign adrenocortical tumors and decreases in malignant adrenocortical tumors, suggesting that NOVH plays a role in tumorigenesis in the adrenal cortex. Transforming growth factor ␤1 (TGF␤1), fibroblast growth factor 2 (FGF2), and insulin growth factors (IGFs) play crucial roles in the physiology of the adrenal cortex. We investigated the effects of these factors on the expression of novH in the NCI H295R adrenocortical cell line. The amounts of NOVH protein and novH transcripts were down-regulated by TGF␤1 and up-regulated by FGF2, whereas IGFs had no effect. Furthermore, the TGF␤1-dependent inhibition of novH promoter activity was completely abrogated following site-directed mutation of two activating protein (AP-1) sequences (positions ؊473 and ؊447), whereas the stimulatory effect of FGF2 was not affected. Co-transfection with dominant negative forms of c-Jun and MEKK1 also abrogated novH-targeted regulation by TGF␤1, whereas the overproduction of Smad proteins or dominant negative forms of Smad had no effect. Taken together, these results suggest that c-Jun and MEKK1 signaling but not Smad signaling are involved in the TGF␤1-dependent decrease in NOVH in NCI H295R cells. In conclusion, our data provide evidence that novH is a new target of TGF␤1; unlike other members of the CCN (cyr61, ctgf, nov) family, however, its expression is repressed rather than induced.

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Section: The Smad Pathway Is Not Required For the Down-regulation Of supporting

confidence: 81%

The Expression of novH in Adrenocortical Cells Is Down-regulated by TGFβ1 through c-Jun in a Smad-independent Manner

Lafont

Laurent

Thibout

et al. 2002

Journal of Biological Chemistry

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“…In contrast, on the basis of our in vitro findings, one would anticipate a developmental podocyte defect in Smad3Ϫ/Ϫ mice. A possible explanation may be provided by recent elegant studies providing new insights into relative functions of full-length Smad2, alternatively spliced short form of Smad2 lacking exon 3 (41), and Smad3 (42). On the basis of genetic isoform replacement experiment in mice, short form of Smad2 and Smad3 but not fulllength Smad2 is sufficient to mediate all transcriptional responses of TGF-␤ required for normal development in the absence of Smad3 (42).…”

Section: Discussionmentioning

confidence: 99%

TGF-β Concentration Specifies Differential Signaling Profiles of Growth Arrest/Differentiation and Apoptosis in Podocytes

Wu¹,

Bitzer²,

Ju³

et al. 2005

Journal of the American Society of Nephrology

123

100

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Podocyte depletion occurs in most progressive glomerular diseases and is thought to result from podocyte loss while the remaining podocytes are unable to proliferate. The underlying mechanisms for podocyte growth arrest/differentiation and depletion remain poorly understood but may involve TGF-␤, which is typically upregulated in injured glomeruli. The TGF-␤ are multifunctional cytokines that regulate growth, differentiation, and apoptosis in most cells. Determinants of functional specificity of TGF-␤ signaling in cell-cycle control and apoptosis remain poorly understood. Using a unique system of conditionally immortalized podocytes, it is demonstrated that autocrine TGF-␤2 induces G0/G1 arrest and differentiation under nonpermissive culture through Smad3-dependent induction of the cyclin-dependent kinase inhibitor p15 Ink4b (Cdkn2b). When exposed to recombinant TGF-␤1 (or TGF-␤2), nonpermissive culture podocytes switch to G2/M arrest and apoptosis, selectively at advanced TGF-␤ concentrations and specifically in association with suppression of Cdkn2b and activation of proapoptotic p38 mitogen-activated protein kinase. Thus, distinct signaling profiles activated in a concentrationdependent manner by TGF-␤ were identified. Autocrine TGF-␤2/Smad3/Cdkn2b signaling in podocytes specifies G0/G1 arrest associated with podocyte differentiation, whereas increasing TGF-␤ concentrations beyond a critical threshold induces G2/M block and apoptosis associated with selective p38 mitogen-activated protein kinase activation and with suppression of Cdkn2b. In summary, the results suggest a new functional requirement of TGF-␤2 in growth arrest and differentiation of murine podocytes in vitro and demonstrate that a critical TGF-␤ concentration threshold may specify a molecular switch to proapoptotic signaling profiles and apoptosis.

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“…The DNAbinding b-hairpin is highly conserved among R-Smads and Smad4, which suggests that the MH1 domain of other Smads might also use the same motif to recognize SBE. Interestingly, Smad2 has 30-amino acid insertion immediately prior to the DNA-binding b-hairpin, which inhibits the capacity of Smad2 to bind to DNA (Shi et al, 1998;Dennler et al, 1999;Yagi et al, 1999). BMP RSmads (and also Smad3 and Smad4) have also been shown to bind to GC-rich sequence motifs (Kim et al, 1997;Labbe Â et al, 1998;Ishida et al, 2000;Kusanagi et al, 2000), suggesting that DNA binding speci®city of Smads is not so strict (Qing et al, 2000).…”

Section: Transcriptional Control By Smadsmentioning

confidence: 99%

Regulation of cell proliferation by Smad proteins

Dijke

Goumans

Itoh

2002

Journal Cellular Physiology

395

278

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Transforming growth factor-b (TGF-b) family members which include TGF-bs, activins, and bone morphogenetic proteins (BMPs) regulate a broad spectrum of biological responses on a large variety of cell types. TGF-b family members initiate their cellular responses by binding to distinct receptors with intrinsic serine/ threonine kinase activity and activation of speci®c downstream intracellular effectors termed Smad proteins. Smads relay the signal from the cell membrane to the nucleus, where they affect the transcription of target genes. Smad activation, subcellular distribution, and stability have been found to be intricately regulated and a broad array of transcription factors have been identi®ed as Smad partners. Important activities of TGF-b are its potent anti-mitogenic and pro-apoptotic effects that, at least in part, are mediated via Smad proteins. Escape from TGF-b/ Smad-induced growth inhibition and apoptosis is frequently observed in tumors. Certain Smads have been found to be mutated in speci®c types of cancer and gene ablation of particular Smads in mice has revealed increased rate of tumorigenesis. In late stage tumors, TGF-b has been shown to function as a tumor promoter. TGFb can stimulate the de-differentiation of epithelial cells to malignant invasive and metastatic ®broblastic cells. Interestingly, TGF-b may mediate these effects directly on tumor cells via subverted Smad-dependent and/or Smad-independent pathways.

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A short amino-acid sequence in MH1 domain is responsible for functional differences between Smad2 and Smad3

Cited by 168 publications

References 33 publications

The Expression of novH in Adrenocortical Cells Is Down-regulated by TGFβ1 through c-Jun in a Smad-independent Manner

The Expression of novH in Adrenocortical Cells Is Down-regulated by TGFβ1 through c-Jun in a Smad-independent Manner

TGF-β Concentration Specifies Differential Signaling Profiles of Growth Arrest/Differentiation and Apoptosis in Podocytes

Regulation of cell proliferation by Smad proteins

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