Accession Number:

ADA409807

Title:

Linking Sister Chromatid Cohesion to Apoptosis and Aneuploidy in the Development of Breast Cancer

Descriptive Note:

Annual summary 1 Jul 2001-30 Jun 2002

Corporate Author:

BAYLOR COLL OF MEDICINE HOUSTON TX

Personal Author(s):

Report Date:

2002-07-01

Pagination or Media Count:

37.0

Abstract:

The purpose of the study is to identify the effector molecules that act as a link between cell proliferation, cell survival and chromosomes stability. We have hypothesized that chromosomal segregation and apoptotic pathways are linked and have a role in the development of aneuploidy in breast tumors. Rad2l is one of the major cohesin subunits that holds sister chromatids together until anaphase, when proteolytic cleavage by separase, allows chromosomal separation. We show that cleavage of human Rad2l hRad2l also occurs during apoptosis. Induction of apoptosis in multiple human cell lines results in the early generation of 64 kDa and 60 kDa carboxy terminal hRad2l cleavage products. We biochemically mapped a apoptotic cleavage site at residue Asp D279 of hRad2 1. This apoptotic cleavage site is distinct from mitotic cleavage sites previously described. hRad2 1 is a nuclear protein, however, the cleaved 64 kDa carboxy-terminal product is translocated to the cytoplasm early in apoptosis before chromatin condensation and nuclear fragmentation. Overexpression of the 64 kDa cleavage product results in apoptosis in MCF-7 breast cancer cells. Given the role of hRad2 1 in chromosome cohesion, the cleaved C-terminal product and its translocation to the cytoplasm may act as a nuclear signal for apoptosis. Deregulation of Rad2l cleavage may play a role in breast cancer pathogenesis.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE