Coactivators and nuclear receptor transactivation

Abstract

A variety of coregulator proteins serve as partners for nuclear receptors orchestrating the molecular events required for receptor-dependent transcriptional regulation. Some coregulators directly interact with nuclear receptors and provide a platform for recruitment of other factors that provide distinct biochemical activities that influence transcriptional efficiency. Coregulators can influence chromatin structure and activity via direct modification of histone proteins or by facilitating ATP-dependent chromatin remodeling. They also have the capacity to impact multiple steps in the transcription process including initiation, elongation, and mRNA splicing. Genetic analysis in humans and animal models are revealing the important cell and tissue-type specific actions of nuclear receptor coregulators as well and their role in human physiology and disease.

Identification of a Novel LXXLL Motif in α-Actinin 4-spliced Isoform That Is Critical for Its Interaction with Estrogen Receptor α and Co-activators

“…2A shows that ACTN4 (Iso) was also capable of potentiating transcriptional activation by ER␣ in a dose-dependent manner. However, the LXXAA mutant failed to potentiate ER␣ activity (lanes 1-4 versus lanes [5][6][7]. Indeed, overexpression of LXXAA partially inhibited basal and E2-induced reporter activity.…”

“…There are three main classes of co-activators associated with NRs: the p160 family, cAMP-responsive element-binding protein (CBP)/p300, and p300/CBP-associated factor (PCAF). The well characterized p160 family proteins include steroid receptor coactivator 1 (SRC-1), glucocorticoid receptor interacting protein 1 (GRIP1), and the activator of thyroid and retinoic acid receptor (ACTR) (7). The functional importance of the p160 family lies in the fact that mice lacking p160 genes are defective in nuclear receptor-mediated developmental processes (8 -10).…”

Hic-5 is a transcription coregulator that acts before and/or after glucocorticoid receptor genome occupancy in a gene-selective manner

“…Together, these environmental determinants influence the recruitment of and requirement for specific coregulators that regulate transcription complex assembly. Current evidence suggests that scores of coregulators cooperate in the transcriptional regulation of each gene, with each coregulator contributing a specific molecular function, e.g., remodeling of chromatin or transcription complex assembly/disassembly (1). Moreover, coregulators act gene specifically, using different activation and repression domains to perform different actions on different genes, as specified by the bound GR (2)(3)(4)(5)(6).…”

“…Combinatorial regulation by nuclear receptors is determined by interaction of the coregulator with various surfaces of the receptor (1,9). Multiple functional surfaces have been implied by biochemical, molecular, genetic, and structural studies (8,10), but only one of these surfaces, termed "AF2," has been defined in detail (9).…”

The Tissue Specific Role of Estrogen and Progesterone in Human Endometrium and Mammary Gland

“…Binding of a steroid hormone to its cognate receptor results in a conformational change in the nuclear receptor that allows the ligand-receptor complex to bind with high affinity to response elements in DNA and regulate transcription of target genes. In the absence of ligand, NRs are held in a multi-subunit complex containing heatshock proteins such as Hsp90, SP70, HSP40, Hop, and p23 (Wolf et al, 2008). After binding to ligand, these receptors, undergo conformational changes, dissociate themselves from chaperone proteins, dimerize and in some cases translocate into the nucleus (if not already locked into the nucleus) (Bain et al, 2007).…”