Truncation of the TGF-β type II receptor gene results in insensitivity to TGF-β in human gastric cancer cells

Yang, Han Kwang; Kang, Shin-Hyoung; Kim, Yong Seok; Won, Kyungshick; Bang, Yung Jue; Kim, Seong‐Jin

doi:10.1038/sj.onc.1202535

Cited by 32 publications

(28 citation statements)

References 21 publications

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“…All the members of the TGF-␤ family, including activins and BMPs transduce their signal through a set of type I and type II receptors (49). Truncated type II receptors (50) or soluble type II receptors for TGF-␤ (13) display dominant negative activities. These data suggest that soluble type I receptors for TGF-␤ family members could be used to mimic the biological actions of these cytokines.…”

Section: Discussionmentioning

confidence: 99%

A Soluble Transforming Growth Factor-β (TGF-β) Type I Receptor Mimics TGF-β Responses

Docagne

Colloc’h

Bougueret³

et al. 2001

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

A Soluble Transforming Growth Factor-β (TGF-β) Type I Receptor Mimics TGF-β Responses

Docagne

Colloc’h

Bougueret³

et al. 2001

Journal of Biological Chemistry

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“…Among nine gastric cancer cell lines, SNU-16, SNU-620 and SNU-719 retained TGF-b sensitivity. SNU-5 and SNU-668 cell lines demonstrated deletion of the TbRII gene (Yang H-K et al, 1999). A frameshift mutation affecting a 10-base pair (bp) polyadenine repeat that is Step RT-PCR was performed using 100 ng of total RNA isolated from SNU-1, SNU-5, SNU-484, and SNU-638 cells.…”

Section: Smad3 Protein Expression In Primary Human Gastric Cancer Tismentioning

confidence: 99%

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

et al. 2003

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“…More specifically, in vitro studies of epithelial cells have shown TGF-b can decrease cdk4 and cyclin D1 expression and can increase the protein levels of p15, p21 and p27. [22][23][24][25][26][27][28][29][30] TGF-b has also been shown in in vitro systems to affect cell proliferation by inhibiting the phosphorylation of Rb, p107 and p130, presumably through the regulation of cdk2 and cdk4 kinase activity, and to affect the expression of a variety of proteins involved in cell proliferation, including c-myc, cdc25a and E2F. [31][32][33] Thus, in vitro studies of epithelial cells demonstrate that TGF-b can regulate cell cycle progression through a variety of different mechanisms that are contextually specific, and that through these mechanisms TGFBR2 could act to suppress colon cancer formation.…”

mentioning

confidence: 99%

Proliferation and Cdk4 expression in microsatellite unstable colon cancers with TGFBR2 mutations

Grady

Willis

Trobridge

et al. 2005

Intl Journal of Cancer

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Approximately 15% of human colon cancers have microsatellite instability (MSI) and carry frameshift mutations in a polyadenine tract (BAT-RII) in the type II transforming growth factor b (TGFb) receptor (TGFBR2), a required component of the TGF-b receptor. The BAT-RII mutations in MSI colon cancers make the tumors resistant to the effects of TGF-b. In cultured epithelial cells, TGF-b can inhibit cell proliferation and induce apoptosis, and in vitro it can regulate the expression of a variety of cyclins, cyclin-dependent kinases (cdks) and cdk inhibitors. These effects are context-and tissue type-dependent, raising questions about which of these in vitro effects of TGF-b signaling inactivation contribute to the formation of primary colon cancer. Thus, this study sought to determine the pathogenetically relevant effects of TGFBR2 inactivation in primary MSI colon cancers with mutant BAT-RII. Colon cancers with mutant BAT-RII were found to have increased proliferation compared to cancers with wild-type BAT-RII. Assessment of cdk4, cyclin D1 and p27 kip1 expression revealed that only cdk4 expression was increased in the cancers with mutant BAT-RII. In order to determine if TGFBR2 inactivation was the cause of these changes, TGFBR2 was reconstituted in an MSI colon cancer cell line, resulting in decreased proliferation and decreased cdk4 expression and kinase activity. These results suggest that TGFBR2 mutations in primary colon cancers may be responsible for the increased proliferation and cdk4 expression in these tumors and provide evidence that deregulation of cdk4 is a pathogenic in vivo consequence of TGFBR2 inactivation in primary colon cancer. ' 2005 Wiley-Liss, Inc.Key words: colon cancer; TGF-b; cdk4; proliferation TGF-b is a potent negative regulator of epithelial cell growth and in cell culture can cause complete growth inhibition and induce apoptosis of nontransformed colon epithelial cells. 1,2 TGFb mediates its effects through a heteromeric cell surface receptor that consists of 2 serine-threonine kinases, the type I and type II TGF-b receptors. During the malignant transformation of colon epithelial cells, the acquisition of resistance to TGF-b-mediated growth inhibition occurs commonly, suggesting it has a significant pathogenic role in the formation of colon cancer. 2-4 Indeed, previous studies have shown that the malignant progression of colon adenoma cell lines directly correlates with the acquisition of TGFb resistance in the cultured cells. 2,4 Mechanisms of the TGF-b resistance described in colon cancers include mutations in the type II TGF-b receptor (TGFBR2) 5-7 as well as mutations in the TGFb signal transduction molecules MADH2/SMAD2 and MADH4/ SMAD4. [8][9][10] The first of these mutations to be described were TGFBR2 frameshift mutations clustered within a microsatellitelike 10 base pair polyadenine repeat within the TGFBR2 coding region (the BAT-RII tract). Such BAT-RII frameshift mutations are characteristic of colon cancers that arise in the setting of microsatellite instability (MSI), a...

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Truncation of the TGF-β type II receptor gene results in insensitivity to TGF-β in human gastric cancer cells

Cited by 32 publications

References 21 publications

A Soluble Transforming Growth Factor-β (TGF-β) Type I Receptor Mimics TGF-β Responses

A Soluble Transforming Growth Factor-β (TGF-β) Type I Receptor Mimics TGF-β Responses

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

Proliferation and Cdk4 expression in microsatellite unstable colon cancers with TGFBR2 mutations

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