title: p300 Modulates the BRCA1 inhibition of estrogen receptor activity.
abstract: We previously reported that expression of the breast cancer susceptibility gene BRCA1 strongly inhibits the transcriptional activity of the estrogen receptor (ER-alpha) in human breast and prostate cancer cell lines but only weakly inhibits ER-alpha activity in cervical cancer cells (S. Fan et al., Science (Wash. DC), 284: 1354-1356, 1999). We now report that the ability of BRCA1 to repress ER-alpha activity correlates with its ability to induce down-regulation of the cellular levels of the transcriptional coactivator p300 in breast and prostate, but not in cervical cancer cells. On the other hand, BRCA1 failed to alter the expression of the CREB binding protein (CBP), the structural and functional homologue of p300, in any of these cell types. Ectopic expression of either p300 or CBP "rescued" (i.e., reversed) the BRCA1 inhibition of ER-alpha activity, whereas two other nuclear receptor coactivators, the p300/CBP-associated factor (PCAF) and the glucocorticoid receptor-interacting protein-1 (GRIP1), failed to rescue the ER-alpha activity. The rescue function mapped to the cysteine-histidine rich domain CH3, a region of p300/CBP that we found to interact directly with the conserved COOH-terminal activation domain (AF-2) of ER-alpha. p300 and ER-alpha were also found to interact in vivo and to colocalize within the nucleus in breast cancer cells. These findings suggest that the cofactors p300 and CBP modulate the ability of the BRCA1 protein to inhibit ER-alpha signaling. They further suggest that the BRCA1 inhibition of ER-alpha activity may be attributable, at least in part, to the down-regulation of p300.
authors.affiliation: Department of Radiation Oncology, Long Island Jewish Medical Center, New Hyde Park, New York 11040, USA.
authors.forename: Saijun
authors.initials: S
authors.lastname: Fan
authors.forename: Yong Xian
authors.initials: YX
authors.lastname: Ma
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Ren-Qi
authors.initials: RQ
authors.lastname: Yuan
authors.forename: Qinghui
authors.initials: Q
authors.lastname: Meng
authors.forename: Ji-An
authors.initials: JA
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Erdos
authors.forename: Itzhak D
authors.initials: ID
authors.lastname: Goldberg
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Kushner
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Eliot M
authors.initials: EM
authors.lastname: Rosen
mesh_terms: D019313:BRCA1 Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D050882:CREB-Binding Protein; D015536:Down-Regulation / Q000502:physiology; D047628:Estrogen Receptor alpha; D019398:Genes, BRCA1 / Q000502:physiology; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000502:physiology; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D019313:BRCA1 Protein; D047628:Estrogen Receptor alpha; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D015534:Trans-Activators; D050882:CREB-Binding Protein; C494363:CREBBP protein, human