Mutations in the tumor suppressors Smad2 and Smad4 inactivate transforming growth factor β signaling by targeting Smads to the ubiquitin–proteasome pathway

Xu, Jin; Attisano, Liliana

doi:10.1073/pnas.97.9.4820

Cited by 183 publications

(111 citation statements)

References 31 publications

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“…Mutant SMAD2 and SMAD4 proteins are degraded more rapidly than their wild-type counterparts, 35 and SMAD4 immunohistochemistry has been found to be a sensitive and specific marker for gene alterations detected in SMAD4. 19 If one allele of these genes is inactivated by mutation and the other allele by allelic loss, one would expect to see decreased or lost protein expression.…”

Section: Discussionmentioning

confidence: 99%

Allelic Analysis of Serous Ovarian Carcinoma Reveals Two Putative Tumor Suppressor Loci at 18q22-q23 Distal to SMAD4, SMAD2, and DCC

Lassus

Salovaara

Aaltonen

et al. 2001

The American Journal of Pathology

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The distal half of chromosome arm 18q is frequently lost in ovarian carcinoma. To define the putative tumor suppressor locus/loci more precisely we performed allelic analysis with 27 polymorphic microsatellite markers located at 18q12.3-q23 in 64 serous and 9 mucinous ovarian carcinomas. Fifty-nine percent of the serous carcinomas, but only one (11%) of mucinous carcinomas, showed allelic loss at one or more loci (P ‫؍‬ 0.018). In serous carcinomas, deletions were found to be associated with tumor grade and poor survival. The highest frequency of losses was detected at the distal part, 18q22-q23. Two minimal common regions of loss (MCRL) were identified at this region: MCRL1 between D18S465 and D18S61 at 18q22 (3.9 cM) and MCRL2 between D18S462 and D18S70 at 18q23 (5.8 cM). At 18q21.1, proximal to the MCRLs, there are three candidate tumor suppressor genes: SMAD4 (DPC4), SMAD2, and DCC. Their protein expression was studied by immunohistochemistry in normal ovarian tissue and serous carcinomas. Lost or very weak expression of SMAD4, SMAD2 and DCC was found in 28, 28, and 30% of serous carcinomas, respectively. Comparison of allelic loss and protein expression status indicated that none of these genes alone could be the target for the frequent allelic loss at 18q21.1. Together, these genes may account for a substantial proportion of the events, but not all of them. Thus, we propose that the frequent allelic loss at 18q is because of the effect of multiple genes, and there is at least one as yet unidentified tumor suppressor gene at 18q residing distal to SMAD4, SMAD2, and DCC involved in serous ovarian carcinoma. (Am J Pathol 2001, 159:35-42) On the basis of comparative genomic hybridization analyses, the distal half of 18q is a site of frequent loss of genetic material in ovarian carcinoma. 1,2 Three candidate tumor suppressor genes have been identified at 18q21.1: SMAD4 (DPC4), SMAD2, and DCC, 3-5 but few mutations in these genes have been detected in ovarian carcinoma. 6 -8 Ovarian carcinoma originates from the surface epithelium of the ovary. DCC has been shown to be expressed in the surface epithelium, 9 but it is not known if SMAD4 and SMAD2 are expressed in these cells. Furthermore, it is unknown if the expression of DCC, SMAD4, and SMAD2 is lost during malignant transformation. Previously, allelic loss has been studied with several markers at 18q21 in ovarian carcinoma, but fine allelotyping has not been performed at more distal regions of 18q (18q22-q23), which is the site of most frequent loss as suggested by comparative genomic hybridization results. 1,2 Ovarian carcinoma shows several different histological types, including serous, mucinous, endometrioid, and clear cell carcinomas. There is an increasing amount of biological and molecular evidence that different histological types of ovarian carcinoma should be regarded as distinct entities. 10 -14 The most common form of ovarian carcinoma is the serous histological type, which accounts for ϳ55% of all cases. In our previous comparative genomic hybri...

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Section: Discussionmentioning

confidence: 99%

Allelic Analysis of Serous Ovarian Carcinoma Reveals Two Putative Tumor Suppressor Loci at 18q22-q23 Distal to SMAD4, SMAD2, and DCC

Lassus

Salovaara

Aaltonen

et al. 2001

The American Journal of Pathology

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“…This suggests that the MH1 domain as a whole is important for DNA binding. In addition, some Smad mutants showed decreased protein stability Xu and Attisano, 2000). In particular, Smad4.R100T and Smad2.R133C are rapidly cleared through the ubiquitin-proteasome pathway (Xu and Attisano, 2000).…”

Section: Smad Mutations In Cancermentioning

confidence: 99%

“…In addition, some Smad mutants showed decreased protein stability Xu and Attisano, 2000). In particular, Smad4.R100T and Smad2.R133C are rapidly cleared through the ubiquitin-proteasome pathway (Xu and Attisano, 2000). Moreover, certain Smad4 mutants (Smad4.G65V and Smad4.P130S) showed an inef®cient nuclear accumulation upon TGF-b stimulation, although they associated with Smad3 upon TGF-b receptor stimulation .…”

Section: Smad Mutations In Cancermentioning

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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“…Deregulation of any of the above-mentioned proteins impacts on either normal embryonic development or, alternatively, on a pathogenic process of human disease. As already discussed above, the first demonstration of ubiquitination as a regulatory mechanism of TGFb pathways came from studies of Smad4 mutants in human tumors [90,91].…”

Section: Relevance Of Stability Regulation Of Tgfβ Pathway Componentsmentioning

confidence: 99%

Regulating the stability of TGFβ receptors and Smads

et al. 2008

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Abbreviations: AIP4 (atrophin 1-interacting protein 4); BMP (bone morphogenetic protein); CHIP (carboxyl terminus of Hsc70-interacting protein); GSK3b (glycogen synthase kinase 3-b); HECT (homologous to E6-AP carboxyl terminus); MAPK (mitogen-activated protein kinase); NEDD4-2 (neural precursor cell expressed, developmentally downregulated 4-2); PIAS (protein inhibitor of activated Stat); Smurf (Smad ubiquitylation regulatory factor); STRAP (serine-threonine kinase receptorassociated protein); SUMO (small ubiquitin-like modifier); TbRI/TbRII (TGFb receptor type I and II); TGFb (transforming growth factor b); WWP1 (WW domain-containing protein 1); Ub (ubiquitin) npg Transforming growth factor β (TGFβ) controls cellular behavior in embryonic and adult tissues. TGFβ binding to serine/threonine kinase receptors on the plasma membrane activates Smad molecules and additional signaling proteins that together regulate gene expression. In this review, mechanisms and models that aim at explaining the coordination between several components of the signaling network downstream of TGFβ are presented. We discuss how the activity and duration of TGFβ receptor/Smad signaling can be regulated by post-translational modifications that affect the stability of key proteins in the pathway. We highlight links between these mechanisms and human diseases, such as tissue fibrosis and cancer. Regulating the stability of TGFβ receptors and Smads

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Mutations in the tumor suppressors Smad2 and Smad4 inactivate transforming growth factor β signaling by targeting Smads to the ubiquitin–proteasome pathway

Cited by 183 publications

References 31 publications

Allelic Analysis of Serous Ovarian Carcinoma Reveals Two Putative Tumor Suppressor Loci at 18q22-q23 Distal to SMAD4, SMAD2, and DCC

Allelic Analysis of Serous Ovarian Carcinoma Reveals Two Putative Tumor Suppressor Loci at 18q22-q23 Distal to SMAD4, SMAD2, and DCC

Regulation of cell proliferation by Smad proteins

Regulating the stability of TGFβ receptors and Smads

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