FUNCTIONAL ROLE OF TMS1 IN CARCINOGENESIS

Emory University, Atlanta GA

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Abstract

DESCRIPTION Aberrant methylation of CpG island-containing gene promoters is involved in the inactivation of a number of important mediators of tumor development, including the retinoblastoma gene, the estrogen receptor gene, the E-cadherin gene, and the p16INK4a gene. Previous work in the laboratory has led to the development of a system to induce hypermethylation of CpG islands in human fibroblasts. Through this system, our laboratory has identified a novel gene which is a target for methylation- induced silencing, called TMS-1. Expression of TMS-1 is inactivated in a number of cancer cell lines and may play a role in apoptosis, as suggested by the presence of a structural domain specific to proteins that participate in the caspase cascade. Thus, silencing of this gene may contribute to escape from apoptosis, a powerful selective advantage in establishing carcinogenesis. The primary focus of this proposal is to define the functional role of TMS-1. The specific aims are to determine whether TMS-1 contributes to apoptosis or growth arrest when introduced into cultured cells, and to identify proteins with which TMS-1 interacts. The characterization of gene related to cancer development that are targets of methylation-associated silencing can provide a basis for future development of demethylation strategies in the treatment of human neoplastic diseases.