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Review
. 2010 Oct 30;62(13):1227-37.
doi: 10.1016/j.addr.2010.09.016. Epub 2010 Oct 7.

Nuclear receptor coregulators as a new paradigm for therapeutic targeting

Elaine Y Hsia  1 , Michael L Goodson, June X Zou, Martin L Privalsky, Hong-Wu Chen
Affiliations
Review

Nuclear receptor coregulators as a new paradigm for therapeutic targeting

Elaine Y Hsia et al. Adv Drug Deliv Rev. .

Abstract

The complex function and regulation of nuclear receptors cannot be fully understood without a thorough knowledge of the receptor-associated coregulators that either enhance (coactivators) or inhibit (corepressors) transcription. While nuclear receptors themselves have garnered much attention as therapeutic targets, the clinical and etiological relevance of the coregulators to human diseases is increasingly recognized. Aberrant expression or function of coactivators and corepressors has been associated with malignant and metabolic disease development. Many of them are key epigenetic regulators and utilize enzymatic activities to modify chromatin through histone acetylation/deacetylation, histone methylation/demethylation or chromatin remodeling. In this review, we showcase and evaluate coregulators--such as SRCs and ANCCA--with the most promising therapeutic potential based on their physiological roles and involvement in various diseases that are revealed thus far. We also describe the structural features of the coactivator and corepressor functional domains and highlight areas that can be further explored for molecular targeting.

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Figures

Fig 1
Fig 1
The functional domains of coactivators featured in the review and their involvement in interactions with nuclear receptors and secondary coregulators. The locations of conserved structural and functional domains for the full-length human coactivator proteins are indicated by filled or textured boxes and bars, with amino acid residues numbered. bHLH, basic helix-loop-helix; PAS, Per/ARNT/Sim domain; S/T, serine/threonine-rich regions; RID, receptor interaction domain; L1–L6 (L7), LXXLL alpha-helix motifs, indicated by the black vertical lines;Q, glutamine-rich regions; HAT, histone acetyltransferase domains; AD1 and AD2, transcriptional activation domains; AR (androgen receptor); AOL (amine oxidase-like); JMJ (Jumonji); PHD (plant homeodomain); AAA (ATPases associated with various cellular activities); R/S (arginine/serine-rich region); RRM (RNA recognition motif). Interaction partners for RID, AD1, and AD2 are outlined inside ovals in the schematic for the three p160 coactivators. For the remaining coactivators, the domains highlighted by the lines or arrow are involved in binding the indicated NR or secondary coactivator, and the corepressor CoREST binds the Tower domain in LSD1. TRAP220 is the PPARγ-interacting subunit of TRAP/DRIP/Mediator complex. Baf60a is a core subunit of the SWI/SNF complex. * indicates that the domain’s presence or activity is required for coactivation function. References in [] are included in the table specifying interactions for each NR-coactivator pair.
Fig 2
Fig 2
The functional domains of corepressors featured in the review and their involvement in interactions with nuclear receptors and secondary corepressors. The transcriptional repression and NR interaction domains are indicated by gray-filled bars and black vertical lines, respectively, with associated secondary corepressors outlined inside the ovals. Other structural domains are indicated by black or white-filled bars, with amino acid residues numbered. The location of conserved SANT domains A and B in NCoR and SMRT are marked by the horizontal lines. The approximate location of CtBP binding sites are indicated in striped vertical bars. With the exception of MTA1s, the schematics for all corepressors represent full-length isoforms. * indicates recently identified NR interaction domains that bind the DBD in ERα. † indicates a required domain for corepression function. SANT (SWI3, ADA2, N-CoR and TFIIIB DNA binding domain); HLH (helix loop helix); BAH (bromo-adjacent homology); ELM (Egl-27 and MTA1 homology). The consensus NR interaction motif sequences for each corepressor are reported on the right along with the NR domain(s) that they bind and relevant references in [].
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References

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