Nuclear Receptor Coregulators: Cellular and Molecular Biology*

Abstract

Nuclear receptor coregulators are coactivators or corepressors that are required by nuclear receptors for efficient transcripitonal regulation. In this context, we define coactivators, broadly, as molecules that interact with nuclear receptors and enhance their transactivation. Analogously, we refer to nuclear receptor corepressors as factors that interact with nuclear receptors and lower the transcription rate at their target genes. Most coregulators are, by definition, rate limiting for nuclear receptor activation and repression, but do not significantly alter basal transcription. Recent data have indicated multiple modes of action of coregulators, including direct interactions with basal transcription factors and covalent modification of histones and other proteins. Reflecting this functional diversity, many coregulators exist in distinct steady state precomplexes, which are thought to associate in promoter-specific configurations. In addition, these factors may function as molecular gates to enable integration of diverse signal transduction pathways at nuclear receptor-regulated promoters. This review will summarize selected aspects of our current knowledge of the cellular and molecular biology of nuclear receptor coregulators.

Cofactor competition between the ligand-bound oestrogen receptor and an intron 1 enhancer leads to oestrogen repression of ERBB2 expression in breast cancer

“…DAD1 lacks the p300/CBP interaction domain model we propose to account for repression of ERBB2 does closely resemble the second mechanism. A major role of the p160 proteins appears to be to help recruit the transcriptional cointegrators p300/ CBP to AF2 (McKenna et al, 1999) and it also seems that SRC-1 may play a similar role at the ERBB2 intronic enhancer as a mutant form, DAD1, lacking the p300/CBP binding domain failed to inhibit oestrogen repression (Figure 6b). Consequently, the overall molecular events may be very similar to those described for transrepression between NRs and AP1 (Kamei et al, 1996) although in this system we have apparently identi®ed a distinct, competed cofactor (SRC-1 instead of p300/CBP).…”

“…The conformational change that occurs in helix 12 on binding of ligand results in the recruitment of a number of di erent cofactors, many of which have now been cloned (McKenna et al, 1999). The precise role of some of these factors remains to be determined, but three related 160 kDa proteins (p160 family) named SRC-1/NcoA-1, TIF2/GRIP2 and AIB1/ SRC3/ACTR/RAC3/pCIP clearly potentiate the transcriptional activity of the ER and indeed several other nuclear receptors (McKenna et al, 1999).…”

“…The precise role of some of these factors remains to be determined, but three related 160 kDa proteins (p160 family) named SRC-1/NcoA-1, TIF2/GRIP2 and AIB1/ SRC3/ACTR/RAC3/pCIP clearly potentiate the transcriptional activity of the ER and indeed several other nuclear receptors (McKenna et al, 1999). This interaction, which is tightly ligand-dependent, is mediated by LXXLL motifs present in all of these proteins (Heery et al, 1997;Torchia et al, 1997).…”

Breast Cancer, Estrogen Receptor and Ligands

“…In clinical settings, the bound ligands to ER are not only estrogens but also anti-estrogens including SERMs, and the ER can adopt multiple conformations upon binding different ligands [95,52]. The impact of such conformational changes was further revealed when steroid receptor co-activator-l (SRC-l), and subsequently other cofactor proteins, co-activators and corepressors, were isolated [96,97]. Furthermore, analysis of the crystal structure of the ligand-ER LBD complexes provided the molecular basis of the interaction of the ER with its ligands [37,98,99,100,101] and so that a better understanding of estrogen and anti-estrogen actions through the ER was established.…”

Impact of the nuclear receptor coactivator AIB1 isoform AIB1-Δ3 on estrogenic ligands with different intrinsic activity

“…In addition, the recently discovered tissue-specific nuclear receptor coactivators and corepressors, which can modify the transcriptional activity of the ER and other nuclear receptors, also play a role in SERM activity (McKenna et al, 1999).…”