Stabilization of β-Catenin by Genetic Defects in Melanoma Cell Lines

Abstract

Signal transduction by beta-catenin involves its posttranslational stabilization and downstream coupling to the Lef and Tcf transcription factors. Abnormally high amounts of beta-catenin were detected in 7 of 26 human melanoma cell lines. Unusual messenger RNA splicing and missense mutations in the beta-catenin gene (CTNNB1) that result in stabilization of the protein were identified in six of the lines, and the adenomatous polyposis coli tumor suppressor protein (APC) was altered or missing in two others. In the APC-deficient cells, ectopic expression of wild-type APC eliminated the excess beta-catenin. Cells with stabilized beta-catenin contained a constitutive beta-catenin-Lef-1 complex. Thus, genetic defects that result in up-regulation of beta-catenin may play a role in melanoma progression.

TSG101 is not mutated in lung cancer but a shortened transcript is frequently expressed in small cell lung cancer

“…Splice-editing of mRNA can regulate gene expression by preventing or promoting translation, or it can produce alternative protein products with disparate functions (Adams et al, 1996). From the number of genes that are now known to be regulated by alternative splicing, it is clear that splicing regulation is an important adjunct to promoter-mediated regulation of gene expression (Rubinfeld et al, 1997;Roberts et al, 1996). Internally deleted TSG101 transcripts may, therefore, represent variants which encode peptides of di ering function.…”

MYC oncogenes and human neoplastic disease

“…In contrast, one report suggests that high level c-myc expression in uveal melanoma is associated with improved outcome (Chana et al, 1998b). Finally, the recent ®nding of b-catenin mutations in some melanoma cell lines (Rubinfeld et al, 1997) mandates that they be corroborated in primary tumors and compared functionally to those mutants associated with colorectal cancers.…”

Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer

“…However, several other Wnt family members are expressed in breast tissue, and some are overexpressed in breast tumors (reviewed by Bergstein and Brown, 1999). In addition, genes encoding several components and targets of the Wnt signaling pathway, including b-catenin, APC, E-cadherin, cyclin D1, cmyc, and WISPs, have been found to be mutated or deregulated in several types of human tumors, such as breast cancer (Bieche et al, 1999), colon cancer (He et al, 1998), melanoma (Rimm et al, 1999;Rubinfeld et al, 1997), hepatocellular carcinoma (de La Coste et al, 1998), and pilomatricoma (Chan et al, 1999).…”