Inactivation of the Type II TGF-β Receptor in Colon Cancer Cells with Microsatellite Instability

Abstract

Transforming growth factor-beta (TGF-beta) is a potent inhibitor of epithelial cell growth. Human colon cancer cell lines with high rates of microsatellite instability were found to harbor mutations in the type II TGF-beta receptor (RII) gene. Eight such examples, due to three different mutations, were identified. The mutations were clustered within small repeated sequences in the RII gene, were accompanied by the absence of cell surface RII receptors, and were usually associated with small amounts of RII transcript. RII mutation, by inducing the escape of cells from TGF-beta-mediated growth control, links DNA repair defects with a specific pathway of tumor progression.

Microsatellite instability and the PTEN1 gene mutation in a subset of early onset gliomas carrying germline mutation or promoter methylation of the hMLH1 gene

“…The 24 microsatellite markers examined were BAT25T, BAT26T, D2S123, D5S346, D10S189, D10S191, D10S507, D10S509, D10S547, D10S552, D10S558, D10S585, D10S591, D10S594, D10S602, D10S1136, D10S1649, D10S1653, D10S1664, D10S1691, D10S1713, D10S1714, D10S1751 and D17S250. Primer sequences for the mononucleotide repeats at the TGFb RII, BAX, IGFIIR and E2F4 genes were described by others (Markowitz et al, 1995;Souza et al, 1996;Rampino et al, 1997;Yoshitaka et al, 1996).…”

“…For example, mutational inactivation of the APC and TP53 genes is often associated with chromosomal aberrations in colon cancers (Kinzler and Vogelstein, 1996). In contrast, slippage mutations of the TGFb RII and BAX genes at their mononucleotide repeat sequences have been detected almost exclusively in colon cancers with MSI (Markowitz et al, 1995;Rampino et al, 1997). Deletion or insertion of one to several base pairs within the microsatellite sequences of the IGFIIR, E2F4 or PTEN1 gene was also reported in colorectal cancers or endometrial cancers with MSI (Rampino, et al, 1997;Yoshitaka et al, 1996;Kong et al, 1997).…”

The αE-catenin gene (CTNNA1) acts as an invasion-suppressor gene in human colon cancer cells

“…Remarkably, HNPCC tumours and cell lines derived therefrom are pseudodiploid in stead of aneuploid (Shibata et al, 1994;Kouri et al, 1990;Frei, 1992). They lack one or more DNA repair enzymes (Rhyu, 1996), explaining the multiplicity of mutations, as evidenced by microsatellite instability and by sequencing of genes such as APC, HPRT, TGFb1-RII, IGF,-IIR and p53 (Bhattacharyya et al, 1994(Bhattacharyya et al, , 1995Lazar et al, 1994;Markowitz et al, 1995;Parsons et al, 1995;Souza et al, 1996). These mutations are considered to be relatively early events and they tend to persist during tumour development (Kinzler and Vogelstein, 1996;Rhyu, 1996).…”

TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

“…Expression of mutated ras alleles is characteristic of colorectal cancers (Bos et al, 1987), and such alleles convey resistance to TGF-b1 inhibition of cell proliferation in culture (Filmus et al, 1992). Some cancer cells are deleted of the TGF-b type II receptor, and reconstitution of type II receptor expression can attenuate the transformed phenotype (Inagaki et al, 1993;Sun et al, 1994;Markowitz et al, 1995;Wang et al, 1995). Observations such as these indicate that TGF-b1 is an important physiological regulator of intestinal cell proliferation, and loss of TGF-b1 responsiveness has a profound pathological signi®cance.…”