BRCA1 effects on the cell cycle and the DNA damage response are linked to altered gene expression.
The breast and ovarian cancer susceptibility gene product BRCA1 has been reported to be expressed in a cell cycle-dependent manner; possess transcriptional activity; associate with several proteins, including the p53 tumor suppressor; and play an integral role in certain types of DNA repair. We show here that ectopic expression of BRCA1 using an adenovirus vector (Ad-BRCA1) leads to dephosphorylation of the retinoblastoma protein accompanied by a decrease in cyclin-dependent kinase activity. Flow cytometric analysis on Ad-BRCA1-infected cells revealed a G(1) or G(2) phase accumulation. High density cDNA array screening of colon, lung, and breast cancer cells identified several genes affected by BRCA1 expression in a p53-independent manner, including DNA damage response genes and genes involved in cell cycle control. Notable changes included induction of the GADD45 and GADD153 genes and a reduction in cyclin B1 expression. Therefore, BRCA1 has the potential to modulate the expression of genes and function of proteins involved in cell cycle control and DNA damage response pathways.
MacLachlan
T K
TK
Laboratory of Molecular Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Somasundaram
K
K
Sgagias
M
M
Shifman
Y
Y
Muschel
R J
RJ
Cowan
K H
KH
El-Deiry
W S
WS
D000256:Adenoviridae / Q000235:genetics; D019313:BRCA1 Protein / Q000235:genetics / Q000502:physiology*; D022762:CCAAT-Enhancer-Binding Proteins; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000502:physiology*; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics; D015870:Gene Expression / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein / Q000378:metabolism; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein; D000097642:GADD45 Proteins
D019313:BRCA1 Protein; D022762:CCAAT-Enhancer-Binding Proteins; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D000097642:GADD45 Proteins; C497249:DDIT3 protein, human; C495894:CDK2 protein, human; C000606846:PIN1 protein, human