Gadd45 Mediates the BRCA1-Induced Cell Cycle Arrest
Abstract
We have previous demonstrated that Gadd45, a p53-regulated stress protein that plays an important role in cell cycle G2-M checkpoint, is transcriptionally up-regulated by BRAC1. In this report, we have shown that BRAC1-induced cell cycle G2-M arrest is disrupted in Gadd45 deficient cells, indicating that Gadd45 mediates BRAC1's role in the control of cell cycle G2-M arrest. In agreement with this finding, disruption of endogenous of Gadd45 in cells is found to result in impaired capability of BRAC1 in growth suppression. These results further support Gadd45 as a BRAC1 downstream effector gene. In addition, we have demonstrated that BRAC1 activation of the Gadd45 gene is mediated through OCT-1 and CAAT motifs that localize at the Gadd45 promoter. BRAC1 protein can directly bind to the Gadd45 promoter and this binding is mediated via the associations of BRAC1 with Oct-1 and NF-YA transcription factors. Importantly, ATR kinase is found to be involved in the signaling pathway that mediates BRCA1 activation of the Gadd45 promoter. The current study demonstrates a novel pathway (BRAC1-GADD45) involved in cellular response to DNA damage, particularly in the control of cell cycle checkpoint.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2003
- Accession Number
- ADA420106
Entities
People
- Qimin Zhan
Organizations
- University of Pittsburgh