Showing papers by "Eric R. Fearon published in 2000"

γ-Catenin is regulated by the APC tumor suppressor and its oncogenic activity is distinct from that of β-catenin

Abstract: β-Catenin and γ-catenin (plakoglobin), vertebrate homologs of Drosophila armadillo, function in cell adhesion and the Wnt signaling pathway. In colon and other cancers, mutations in the APC tumor suppressor protein or β-catenin's amino terminus stabilize β-catenin, enhancing its ability to activate transcription of Tcf/Lef target genes. Though β- and γ-catenin have analogous structures and functions and like binding to APC, evidence that γ-catenin has an important role in cancer has been lacking. We report here that APC regulates both β- and γ-catenin and γ-catenin functions as an oncogene. In contrast to β-catenin, for which only amino-terminal mutated forms transform RK3E epithelial cells, wild-type and several amino-terminal mutated forms of γ-catenin had similar transforming activity. γ-Catenin's transforming activity, like β-catenin's, was dependent on Tcf/Lef function. However, in contrast to β-catenin, γ-catenin strongly activated c-Myc expression and c-Myc function was crucial for γ-catenin transformation. Our findings suggest APC mutations alter regulation of both β- and γ-catenin, perhaps explaining why the frequency of APC mutations in colon cancer far exceeds that of β-catenin mutations. Elevated c-Myc expression in cancers with APC defects may be due to altered regulation of both β- and γ-catenin. Furthermore, the data imply β- and γ-catenin may have distinct roles in Wnt signaling and cancer via differential effects on downstream target genes.

Regulation of β-catenin transformation by the p300 transcriptional coactivator

Abstract: The β-catenin protein plays a critical role in embryonic development and mature tissue homeostasis through its effects on E-cadherin-mediated cell adhesion and Wnt-dependent signal transduction. In colon and other cancers, mutations of β-catenin or the adenomatous polyposis coli (APC) tumor suppressor appear to stabilize β-catenin and enhance its interaction with T cell factor (TCF) or lymphoid enhancer factor (Lef) transcription factors. At present, a complete picture of the means by which β-catenin's interactions with TCF/Lef proteins contribute to neoplastic transformation is lacking. We report that the transcriptional coactivator p300 interacts with β-catenin in vitro and in vivo and is critical for β-catenin-mediated neoplastic transformation. p300 synergistically activates β-catenin/TCF transcription, and their biochemical association requires the CH1 domain of p300 and a region of β-catenin that includes its NH2-terminal transactivation domain and the first two armadillo repeats. Lowering of cellular p300 levels by using a ribozyme directed against p300 reduced TCF transcriptional activity and inhibited the neoplastic growth properties of a β-catenin-transformed rat epithelial cell line and a human colon carcinoma line with a β-catenin mutation. These findings demonstrate a critical role for p300 in β-catenin/TCF transcription and in cancers arising from defects in β-catenin regulation.

BRCA1 and E-Cadherin Promoter Hypermethylation and Gene Inactivation in Cancer—Association or Mechanism?

Abstract: The abnormal properties of cancer cells are attributable to alterations in gene sequence and expression. The genes that are mutated in cancer can be grouped into two classes: protooncogenes and tumor suppressor genes. Proto-oncogenes are affected by gain-of-function mutations in cancer, generating oncogenic variant copies (or alleles) with increased or novel functions, while tumor suppressor genes are inactivated. Tumor suppressor genes were initially hypothesized to be inactivated in cancer cells as a result of genetic defects of both alleles (i.e., the Knudson two-hit hypothesis). Many studies have validated this concept, demonstrating localized mutations in both tumor suppressor gene alleles or a localized mutation in one allele coupled with a loss of heterozygosity (LOH) in the other allele. However, there is now evidence that epigenetic events, such as hypermethylation of cytosine‐guanine (CpG) sites in regulatory regions (e.g., the promoter), may be a critical alternative mechanism of tumor suppressor gene inactivation, including von Hippel‐ Lindau inactivation in some clear-cell renal cancers, p16 INK4a inactivation in some lung and other cancers, and MLH1 inactivation in many sporadic colon cancers with microsatellite instability (1‐3).Two reports (4,5) in this issue of the Journal provide additional data consistent with the view that hypermethylation of the promoter regions of certain tumor suppressor genes may play an important role in extinguishing gene expression in cancer. However, before accepting the conclusion that hypermethylation

Homozygous deletions inactivate DCC, but not MADH4/DPC4/SMAD4, in a subset of pancreatic and biliary cancers.

Abstract: Loss of heterozygosity (LOH) of chromosome arm 18q is frequent in gastrointestinal cancers Over 90% of pancreatic carcinomas have 18q LOH Bi-allelic inactivation of the MADH4/DPC4/SMAD4 gene at 18q211 is seen in about half of pancreatic carcinomas with 18q LOH In the remaining tumors with 18q LOH, MADH4 is not mutated and its expression is unaffected, and no alterations in MADH2/SMAD2, a MADH4-related gene at 18q123, have been found A controversial candidate tumor-suppressor gene at 18q212 is DCC (deleted in colorectal carcinoma), which encodes a netrin-1 receptor component with functions in cell migration and apoptosis Reduced or absent DCC expression has been observed in many cancers, but few somatic mutations that would clearly inactivate DCC function have been reported We studied a panel of 115 pancreatic and 14 biliary cancers for homozygous deletions of DCC exons and flanking 18q regions Seven homozygous deletions were seen in the region that includes the DCC gene In two tumors, the deletions inactivate DCC but not MADH4 A physical and transcript map of the deleted regions was constructed, and DCC was the only known gene affected by all seven deletions These data are the strongest mutational evidence presented yet in support of the hypothesis that DCC or another gene in the region distal to MADH4 is inactivated, playing a causal role in cancer development