Somatic alterations of the SMAD-2 gene in human colorectal cancers

Takagi, Yukihiro; Koumura, Hisashi; Futamura, Manabu; Aoki, Sérgio; Ymaguchi, K; Kida, Hirotaka; Tanemura, Hiromi; Shimokawa, Kuniyasu; Saji, Shigetoyo

doi:10.1038/bjc.1998.645

Cited by 74 publications

(42 citation statements)

References 13 publications

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“…Tumor cells often become resistant to TGF-b-induced growth inhibition and apoptosis due to functional inactivation of TGF-b receptors and Smads. Inactivated Smads 2 and 4 have been found due to deletion or mutation in their genes (Hahn et al, 1996;Riggins et al, 1997;Takagi et al, 1998;Schutte, 1999;Blobe et al, 2000;de Caestecker et al, 2000;Massague´and Chen, 2000;Yanagisawa et al, 2000;Derynck et al, 2001;Fink et al, 2001). In contrast to known tumor suppressors Smads 2 and 4, the tumor suppressive role of Smad3 has not been clarified because mutations in the Smad3 gene have thus far not been discovered in human tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Smad4, located in 18q21, is also altered in colorectal cancers (Calonge and Massague´, 1999) with a higher incidence of mutation in metastatic colon carcinomas (Schutte, 1999;Fink et al, 2001). Studies have shown a mutated Smad2 gene in colorectal and lung cancers although this gene is a less frequent target than Smad4 gene (Riggins et al, 1997;Takagi et al, 1998;Takenoshita et al, 1998;Yanagisawa et al, 2000). However, to date, there is no evidence that Smad3 is the locus of homozygous deletions, functionally inactivating mutations, or amplifications in human malignancy.…”

Section: Introductionmentioning

confidence: 99%

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Loss of the Smad3 expression increases susceptibility to tumorigenicity in human gastric cancer

et al. 2003

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Loss of the Smad3 expression increases susceptibility to tumorigenicity in human gastric cancer

et al. 2003

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“…The loss or mutation of the Smad4 gene in one allele is often accompanied by a genetic alteration of Smad4 in the other allele. The Smad2 gene has been found mutated in colorectal and lung cancers although this gene is a less frequent target than Smad4 gene (Eppert et al, 1996;Riggins et al, 1996;Uchida et al, 1996;Takagi et al, 1998). Mutations in the Smad3 gene have thus far not been discovered in tumors.…”

Section: Smad Mutations In Cancermentioning

confidence: 99%

Regulation of cell proliferation by Smad proteins

Dijke

Goumans

Itoh

2002

Journal Cellular Physiology

399

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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“…10 SMAD2 mutations have been found in less than 10% of cases. 11,12 Thus the observed frequency of alterations in the DCC and SMAD genes does not explain the high proportion of chromosome 18q loss in colorectal cancer. This suggests that other tumor suppressor genes, in addition to the DCC and SMAD genes, may be targets for the 18q loss.…”

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confidence: 92%

The Cables Gene on Chromosome 18q Is Silenced by Promoter Hypermethylation and Allelic Loss in Human Colorectal Cancer

Park

Sasaki

Kirley

et al. 2007

The American Journal of Pathology

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Cables is a cyclin-dependent kinase-binding nuclear protein that maps to chromosome 18q11-12. Here, we assessed Cables expression in 160 colorectal cancers (CRCs), its role in colon cancer cell growth, and the potential mechanisms of Cables inactivation. Expression levels, promoter methylation, and mutational status of Cables were investigated in colon cancer cell lines and primary colon tumors. Chromosome 18q loss of heterozygosity (LOH) was evaluated with multiple polymorphic markers. Cables inhibited cellular proliferation and colony formation in colon cancer cell lines. Colorectal cancer (CRC) is characterized by several unique features that make it well suited for the study of the molecular genetics of tumor progression. A stepwise model of colorectal tumorigenesis has been well defined and validated. 1 The inactivation of the adenomatous polyposis coli tumor suppressor gene is an early event that leads to the development of polyps, followed by oncogenic KRAS mutations in the adenomatous stage. Later events include deletions on chromosome 18q and inactivation of the tumor suppressor gene TP53 on chromosome 17p with the transition to malignancy.Chromosome 18q is lost in a high proportion (approximately 70%) of CRCs. 2 There are many candidate tumor suppressor genes on chromosome 18q, including deleted in colon cancer (DCC), SMAD4 (DPC4), and SMAD2. 3-5 DCC was recently shown to be the netrin-1 receptor. 6 DCC is expressed in normal colonic mucosa and in both primary and metastatic colonic cancer. 7 However, mice lacking the functional DCC gene do not develop colon tumors. 8 The SMAD proteins mediate transforming growth factor-␤ effects and regulate genes involved in cell cycle control. SMAD4 is biallelically inactivated in approximately 60% of pancreatic cancers. 9 However, the number of mutations identified in the SMAD genes has been relatively small in colorectal cancer.

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Somatic alterations of the SMAD-2 gene in human colorectal cancers

Cited by 74 publications

References 13 publications

Loss of the Smad3 expression increases susceptibility to tumorigenicity in human gastric cancer

Loss of the Smad3 expression increases susceptibility to tumorigenicity in human gastric cancer

Regulation of cell proliferation by Smad proteins

The Cables Gene on Chromosome 18q Is Silenced by Promoter Hypermethylation and Allelic Loss in Human Colorectal Cancer

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