Steroid hormones are well known for their important roles in mammalian physiology and in cancer. Their functions are mediated by structurally related transcription factors called the steroid/nuclear receptor superfamily. These receptors mediate hormonal signaling by controlling gene expression. Recent findings suggest that receptors recruit coactivators to activate transcription and associate with corepressors to repress gene expression. One class of coactivators is the p160/SRC-1 family, which possesses histone acetylase activity and associate with p300/CBP and PCAF acetylases. Histone acetylation and acetylation of transcription factors have been demonstrated as critical regulatory mechanisms of transcriptional regulation. The hypothesis of this proposal is that p160 coactivators such as ACTR play key roles in control of gene expression and cell growth mediated by steroid/nuclear receptors and that protein acetylation is an important regulatory mechanism of coactivator function. Our long-term objectives are (1) to determine the functions of ACTR and other related cofactors in control of gene expression and cell proliferation and (2) to elucidate molecular mechanisms of coactivator actions in hormone signaling. Accordingly, the specific aims of this proposal are: 1) To determine the role of ACTR in androgen and estrogen receptor-mediated control of cell proliferation; 2) To elucidate the molecular mechanism of ACTR action in hormone-induced gene activation; 3) To determine the role of cofactor acetylation in hormone signaling. The results obtained will undoubtedly advance our understanding of the functional mechanisms of nuclear receptors in physiological processes. As ACTR/AIB1 has been found to be overexpressed in breast and ovarian cancers, our findings will provide valuable insights into their roles in cancer development.
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