RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2

TLDR

Steroids, thyroid hormones, vitamin D₃, and retinoids are lipophilic molecules that regulate cell differentiation, development, and homeostasis through ligand‑dependent transcriptional regulation by steroid/nuclear receptors. The study aims to clone and characterize RAC3, a human transcriptional coactivator for steroid/nuclear receptors. RAC3 was cloned and characterized, revealing its ability to interact with ligand‑bound receptors via their activation domains and to activate transcription when tethered to a heterologous DNA‑binding domain. RAC3 interacts with ligand‑bound receptors, activates transcription when tethered to a heterologous DNA‑binding domain, and its overexpression enhances ligand‑dependent transcriptional activation, making it a useful tool for hormone action studies and a potential therapeutic target.

Abstract

Steroids, thyroid hormones, vitamin D 3 , 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.