Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1.
The breast cancer susceptibility gene BRCA1 encodes a protein implicated in the cellular response to DNA damage, with postulated roles in homologous recombination as well as transcriptional regulation. To identify downstream target genes, we established cell lines with tightly regulated inducible expression of BRCA1. High-density oligonucleotide arrays were used to analyze gene expression profiles at various times following BRCA1 induction. A major BRCA1 target is the DNA damage-responsive gene GADD45. Induction of BRCA1 triggers apoptosis through activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), a signaling pathway potentially linked to GADD45 gene family members. The p53-independent induction of GADD45 by BRCA1 and its activation of JNK/SAPK suggest a pathway for BRCA1-induced apoptosis.
Harkin
D P
DP
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown 02129, USA.
Bean
J M
JM
Miklos
D
D
Song
Y H
YH
Truong
V B
VB
Englert
C
C
Christians
F C
FC
Ellisen
L W
LW
Maheswaran
S
S
Oliner
J D
JD
Haber
D A
DA
D017209:Apoptosis; D019313:BRCA1 Protein / Q000096:biosynthesis / Q000235:genetics*; D001943:Breast Neoplasms; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*; D004249:DNA Damage; D004789:Enzyme Activation; D004790:Enzyme Induction; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015723:Gene Library; D019398:Genes, BRCA1; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D020928:Mitogen-Activated Protein Kinases; D012516:Osteosarcoma; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013737:Testis / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000097642:GADD45 Proteins
D019313:BRCA1 Protein; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D011494:Protein Kinases; D011506:Proteins; D000097642:GADD45 Proteins