BRCA1 interaction with human papillomavirus oncoproteins.
Previously, we reported that BRCA1 strongly represses the transcriptional activity of estrogen receptor-alpha (ER-alpha) in human breast and prostate cancer cells but only weakly inhibits ER-alpha in cervical cancer cells. We now report that introduction of the human papillomavirus E7 or E6 oncogenes into human papillomavirus-negative cells rescues the BRCA1 repression of ER-alpha activity and that the E7 and E6 oncoproteins interact directly with BRCA1 in vitro and associate with BRCA1 in vivo in cultured cells. This interaction involves at least two contact points on BRCA1, one within an N-terminal site shown previously to interact with ER-alpha and the other in a C-terminal region of BRCA1 containing the first BRCA1 C-terminal domain. Point mutations within the zinc finger domains of E7 and E6 inactivated the binding to the N terminus of BRCA1 and reduced their ability to rescue BRCA1 inhibition of ER-alpha. E6 and E7 also antagonized the ability of BRCA1 to inhibit c-Myc E-box-mediated transactivation and human telomerase reverse transcriptase promoter activity, in a manner dependent upon the zinc finger domains. Finally, the ability of E6 and E7 to antagonize BRCA1 did not involve proteolytic degradation of BRCA1. These findings suggest functional interactions of BRCA1 with E7 and E6. The potential significance of these findings is discussed.
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057-1469, USA.
Yiyu
Y
Zhang
Saijun
S
Fan
Qinghui
Q
Meng
Yongxian
Y
Ma
Pragati
P
Katiyar
Richard
R
Schlegel
Eliot M
EM
Rosen
D019313:BRCA1 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors; D005260:Female; D019398:Genes, BRCA1; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008297:Male; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D027383:Papillomaviridae / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D019098:Telomerase / Q000037:antagonists & inhibitors; D015533:Transcriptional Activation
D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D009856:Oncogene Proteins, Viral; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D005982:Glutathione Transferase; D019098:Telomerase