Accession Number:

ADA411247

Title:

Gadd45 Mediates the BRCA1-Induced Cell Cycle Arrest

Descriptive Note:

Annual rept. 1 Aug 2001-31 Jul 2002

Corporate Author:

PITTSBURGH UNIV PA

Personal Author(s):

Report Date:

2002-08-01

Pagination or Media Count:

47.0

Abstract:

Our previous studies demonstrate that BRCA1 regulates GADD45, a p53-regulated and stress-inducible gene that plays an important role in cellular response to DNA damage. Currently, we investigated the biochemical mechanisms involved in the GADD45-activated G2-M arrest and found that expression of GADD45 protein via the tet-off inducible system resulted in cell cycle G2M arrest. GADD45-induced G2-M arrest was shown to require normal cellular p53 function, but is independent of p38 kinase activity. Interestingly, induction of GADD45 protein resulted in a reduction of nuclear cyclin B1 protein, whose nuclear localization is critical for the completion of G2-M transition. The reduced nuclear cyclin B1 levels correlated with inhibition of Cdc2cyclin B1 kinase activity. In addition, we demonstrated that BRCA1 activation of the CADD45 promoter was mediated through the OCT-1 and CAAT motifs located at the CADD45 promoter region. Site-directed mutations of both OCT-l and CAAT motifs abrogated induction of the GADD45 promoter by 1. Further more, BRCA1 was found associated with the GADD45 promoter, probably through physical interaction with Oct-1 and NF-YA, which directly bind to the GADD45 promoter. The current study demonstrates a novel pathway BRCA1-GADD45 involved in cellular response to DNA damage.

Subject Categories:

  • Biochemistry
  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE