BRCA1 and GADD45 mediated G2/M cell cycle arrest in response to antimicrotubule agents.
BRCA1 is a tumour suppressor gene implicated in the predisposition to early onset breast and ovarian cancer. We have generated cell lines with inducible expression of BRCA1 to evaluate its role in mediating the cellular response to various chemotherapeutic drugs commonly used in the treatment of breast and ovarian cancer. Induction of BRCA1 in the presence of Taxol and Vincristine resulted in a dramatic increase in cell death; an effect that was preceded by an acute arrest at the G2/M phase of the cell cycle and which correlated with BRCA1 mediated induction of GADD45. A proportion of the arrested cells were blocked in mitosis suggesting activation of both a G2 and a mitotic spindle checkpoint. In contrast, no specific interaction was observed between BRCA1 induction and treatment of cells with a range of DNA damaging agents including Cisplatin and Adriamycin. Inducible expression of GADD45 in the presence of Taxol induced both G2 and mitotic arrest in these cells consistent with a role for GADD45 in contributing to these effects. Our results support a role for both BRCA1 and GADD45 in selectively regulating a G2/M checkpoint in response to antimicrotubule agents and raise the possibility that their expression levels in cells may contribute to the toxicity observed with these compounds.
Mullan
P B
PB
Department of Oncology, Cancer Research Centre, The Queen's University of Belfast, Belfast BT9 7AB, N. Ireland.
Quinn
J E
JE
Gilmore
P M
PM
McWilliams
S
S
Andrews
H
H
Gervin
C
C
McCabe
N
N
McKenna
S
S
White
P
P
Song
Y H
YH
Maheswaran
S
S
Liu
E
E
Haber
D A
DA
Johnston
P G
PG
Harkin
D P
DP
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D019313:BRCA1 Protein / Q000378:metabolism*; D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D018076:DNA, Complementary / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology; D010641:Phenotype; D011506:Proteins / Q000378:metabolism*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology; D000097642:GADD45 Proteins
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D019313:BRCA1 Protein; D002945:Cisplatin; D018076:DNA, Complementary; D004317:Doxorubicin; D047908:Intracellular Signaling Peptides and Proteins; D017239:Paclitaxel; D011506:Proteins; D014750:Vincristine; D000097642:GADD45 Proteins