Li H, Gomes P J, Chen J D
Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655-0126, USA.
Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8479-84. doi: 10.1073/pnas.94.16.8479.
Steroids, thyroid hormones, vitamin D3, and retinoids are lipophilic small molecules that regulate diverse biological effects such as cell differentiation, development, and homeostasis. The actions of these hormones are mediated by steroid/nuclear receptors which function as ligand-dependent transcriptional regulators. Transcriptional activation by ligand-bound receptors is a complex process requiring dissociation and recruitment of several additional cofactors. We report here the cloning and characterization of receptor-associated coactivator 3 (RAC3), a human transcriptional coactivator for steroid/nuclear receptors. RAC3 interacts with several liganded receptors through a mechanism which requires their respective ligand-dependent activation domains. RAC3 can activate transcription when tethered to a heterologous DNA-binding domain. Overexpression of RAC3 enhances the ligand-dependent transcriptional activation by the receptors in mammalian cells. Sequence analysis reveals that RAC3 is related to steroid receptor coactivator 1 (SRC-1) and transcriptional intermediate factor 2 (TIF2), two of the most potent coactivators for steroid/nuclear receptors. Thus, RAC3 is a member of a growing coactivator network that should be useful as a tool for understanding hormone action and as a target for developing new therapeutic agents that can block hormone-dependent neoplasia.
类固醇、甲状腺激素、维生素D3和类视黄醇是亲脂性小分子，可调节多种生物学效应，如细胞分化、发育和体内平衡。这些激素的作用由类固醇/核受体介导，这些受体作为配体依赖性转录调节因子发挥作用。配体结合受体的转录激活是一个复杂的过程，需要解离并募集几种额外的辅因子。我们在此报告受体相关共激活因子3（RAC3）的克隆和表征，RAC3是一种类固醇/核受体的人类转录共激活因子。RAC3通过一种需要其各自配体依赖性激活域的机制与几种配体结合的受体相互作用。当与异源DNA结合域相连时，RAC3可以激活转录。RAC3的过表达增强了哺乳动物细胞中受体的配体依赖性转录激活。序列分析表明，RAC3与类固醇受体共激活因子1（SRC-1）和转录中间因子2（TIF2）相关，这是类固醇/核受体最有效的两种共激活因子。因此，RAC3是一个不断发展的共激活因子网络的成员，它应作为理解激素作用的工具以及开发可阻断激素依赖性肿瘤形成的新治疗药物的靶点。
