Accession Number:

ADA415959

Title:

Bone-97 Alcohol and Skeletal Adaptation to Mechanical Usage

Descriptive Note:

Final rept. 15 Mar 2000-14 Mar 2003

Corporate Author:

MAYO CLINIC ROCHESTER MN

Personal Author(s):

Report Date:

2002-10-01

Pagination or Media Count:

178.0

Abstract:

Using a novel expression cloning strategy and secondary functional screen of a human prostate cancer cDNA library, we have identified one new, functionally relevant caspase substrate the mismatch repair protein MLH1 implicated in a variety of cancers including those of the prostate. We have demonstrated that human MLH1 is specifically cleaved by caspase-3 but not by other caspases at Aspexp 418 in vitro. Furthermore, we have shown that MLH1 is rapidly proteolyzed by caspase-3 in prostate cancer cells induced to undergo apoptosis by treatment with TNF-related apoptotosis-inducing ligand TRAIL or the topoisomerase II inhibitor etoposide, which induces DNA double-strand breaks. Importantly, proteolysis of MLH1 by caspase-3 triggers its partial redistribution from the nucleus to the cytoplasm. In addition, a capase-3 cleavage-resistant D418E MLH1 mutant inhibits etoposide-induced apoptosis but has little effect on TRAIL-induced apoptosis. These results indicate that MLH1 is specifically targeted for proteolysis by caspase-3, and this proteolytic event promotes the execution of apoptotic signals initiated by DNA double-strand breaks. In this way, our results suggest a novel function of MLH1 in the response to DNA double-strand breaks that is deregulated by caspase proteolysis. These experiments, then, may lead to novel treatments for prostate cancer that specifically target MLH1.

Subject Categories:

  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE