ASC-1 and 2, Novel Transcription Coactivators of Nuclear Receptors.

다국어 초록 (Multilingual Abstract)

We have isolated two nuclear factors(designated ASC-1 and ASC-2) by using the ligand binding domain of retinoid X receptor as a bait in the yeast two hybrid screening. They also interacted with other nuclear receptors, including retinoic acid receptor(RAR), thyroid hormone receptor(TR), estrogen receptor α(ERα) and glucocorticoid receptor, basal factors TFIIA and TBP, and transcription integrators CBP/p300 and SRC-1. In transient cotransfections, these factors, either alone or in conjunction with CBP/p300 and SRC-1, stimulated ligand-dependent transactivation by wild type nuclear receptors but not mutant receptors lacking the AF2 domain. ASC-1 harbors an autonomous transactivation domain that contains a putative zinc-finger motif, which serves as binding sites for transcription integrators SRC-1 and CBP/p300, and nuclear receptors. The ASC-1 binding sites involve the hinge domain but not the C-terminal AF2 core domain of nuclear receptors. By using indirect immunofluorescence, we further show that ASC-1, a nuclear protein, is localized to the cytoplasm under serum-deprivation but retained in the nucleus when serum-starved in the presence of ligand or coexpressed CBP or SRC-1. Consistent with an idea that ASC-2 is essential for the nuclear receptor function in vivo, microinjection of anti-ASC-2 antibody abrogated the ligand-dependent transactivation of RAR and this repression was fully relieved by co-injection of ASC-2-expression vector. Surprisingly, ASC-2 was identical to a gene previously identified during a search for genes amplified and overexpressed in breast and other human cancers. From these results, we concluded that ASC-1 and ASC-2 are bona fide transcription coactivator molecules of nuclear receptors. We also concluded that ASC-1 may play an important role to establish distinct coactivator complexes under different cellular conditions and altered expression of ASC-2 may contribute to the development of cancers.