The role of coactivator ACTR in the control of transcription and cell proliferation.

摘要

ACTR is a member of the p160/SRC family of transcriptional coactivators, which includes SRC-1 and TIF2. They were initially identified based on their ability to mediate transcription of nuclear hormone receptors (NRs) including estrogen receptors (ERs) and androgen receptor (AR).{09} ACTR interacts with other transcription cofactors, including CBP/p300 and CARM1. The fact that these cofactors posses either histone acetylase or methylase activity, together with the observation that ACTR is also a HAT protein led to the hypothesis that the role of ACTR in transcriptional regulation is primarily mediated through chromatin remodeling. Subsequent studies, however, began to unravel the multi-faceted role of ACTR in transcription. We found that both ACTR and AR are directly recruited to the proximal promoter and enhancer of prostate serum antigen (PSA) in response to androgen. We also demonstrated that RNA polymerase II (pol II) was recruited to the enhancer, independently of the proximal promoter, and that elevated level of ACTR increased Pol II recruitment in a hormone dependent and independent manner. These results suggest that ACTR may play a novel role in the assembly of Pol II complex.; Recent studies have also linked ACTR to cancer because its amplified gene and elevated protein levels are frequently detected in multiple types of human tumors. We initially demonstrated that ectopic expression of ACTR can stimulate proliferation of breast cancer cells in culture and invoke resistance to anti-estrogens. This occurred independent of the ER, but rather through the association of ACTR with E2F proteins. We subsequently found that ACTR is required for S phase progression and that depletion of ACTR strongly inhibits the proliferation of human fibroblast cells. Consistent with its crucial role in regulating the cell cycle, ACTR expression appears to be cell cycle regulated. Interestingly, ACTR is also recruited to its own promoter at the G1-S transition, suggesting a positive feedback mechanism for ACTR action in regulating cell cycle progression. Finally, we also demonstrated that elevated ACTR could transform a line of non-malignant human breast epithelial cells that are devoid of ER. Together, these findings strongly suggest that ACTR can function as an E2F coactivator and regulate cell cycle progression in both cancerous and normal cells. ACTR's role as an E2F coactivator may also account for its oncogenicity observed in many human cancers.