Caspase-3 mediated cleavage of BRCA1 during UV-induced apoptosis
- 2 August 2002
- journal article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 21 (34), 5335-5345
- https://doi.org/10.1038/sj.onc.1205665
Abstract
The breast cancer suppressor protein, BRCA1 plays an important role in mediating cell cycle arrest, apoptosis and DNA responses to DNA damage signals. In this study, we show that BRCA1 level is downregulated during UV-induced apoptosis by caspase-3 mediated cleavage. Cleavage of BRCA1 by caspase-3 produced a fragment that contained the C-terminal of the molecule. Accordingly, treatment of cells with caspase-3 inhibitor or mutation of a specific caspase-3 cleavage site (DLLD) at amino acid 1151-1154 of BRCA1 abolished cleavage and consequential accumulation of the BRCA1 C-terminal fragment. Whereas expression of the non-cleavable BRCA1 (D/A 1154) mutant conferred the resistance phenotype to UV-induced cell death, expression of the cleaved BRCA1 C-terminus induced cell death in the absence of UV. Examination of the mechanism of C-terminus-induced cell death revealed that the cleaved fragment triggers the apoptotic response through activation of BRCA1 downstream effectors, GADD45 and JNK. Altogether, results of our study demonstrate a functional role for caspase-3 mediated cleavage of BRCA1 during UV-induced apoptosis.This publication has 32 references indexed in Scilit:
- Roles of BRCA1 and its interacting proteinsBioEssays, 2000
- Requirement of JNK for Stress- Induced Activation of the Cytochrome c-Mediated Death PathwayScience, 2000
- Inhibition of Homodimerization of Poly(ADP-ribose) Polymerase by Its C-terminal Cleavage Products Produced during ApoptosisPublished by Elsevier BV ,2000
- Mammalian Caspases: Structure, Activation, Substrates, and Functions During ApoptosisAnnual Review of Biochemistry, 1999
- Centrosome Amplification and a Defective G2–M Cell Cycle Checkpoint Induce Genetic Instability in BRCA1 Exon 11 Isoform–Deficient CellsMolecular Cell, 1999
- The second BRCT domain of BRCA1 proteins interacts with p53 and stimulates transcription from the p21WAF1/CIP1 promoterOncogene, 1999
- Cleavage and Activation of p21-activated Protein Kinase γ-PAK by CPP32 (Caspase 3)Online Journal of Public Health Informatics, 1998
- Down-regulation of BRCA1 and BRCA2 in human ovarian cancer cells exposed to adriamycin and ultraviolet radiationInternational Journal of Cancer, 1998
- Proteolytic Activation of Protein Kinase C δ by an ICE/CED 3-like Protease Induces Characteristics of ApoptosisThe Journal of Experimental Medicine, 1996
- Apoptosis in the Pathogenesis and Treatment of DiseaseScience, 1995