The SRC family of nuclear receptor coactivators

Nuclear hormone receptors are ligand-dependent transcription factors that regulate genes critical to such biological processes as development, reproduction, and homeostasis. Interestingly, these receptors can function as molecular switches, alternating between states of transcriptional repression and activation, depending on the absence or presence of cognate hormone, respectively. In the absence of hormone, several nuclear receptors actively repress transcription of target genes via interactions with the nuclear receptor corepressors SMRT and NCoR. Upon binding of hormone, these corepressors dissociate away from the DNA-bound receptor, which subsequently recruits a nuclear receptor coactivator (NCoA) complex. Prominent among these coactivators is the SRC (steroid receptor coactivator) family, which consists of SRC-1, TIF2/GRIP1, and RAC3/ACTR/pCIP/AIB-1. These cofactors interact with nuclear receptors in a ligand-dependent manner and enhance transcriptional activation by the receptor via histone acetylation/methylation and recruitment of additional cofactors such as CBP/p300. This review focuses on the mechanism of action of SRC coactivators in terms of interactions with receptors and activation of transcription. Specifically, the roles of the highly conserved LXXLL motifs in mediating SRC function will be detailed. Additionally, potential diversity among SRC family members, as well as several recently cloned SRC-associated cofactors, will be discussed.