Review
Nuclear receptor coregulators: multiple modes of modification

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Abstract

Many proteins have been characterized as coregulators that can be recruited by DNA-binding nuclear receptors to influence transcriptional regulation. Recent genetic and biochemical studies have shown that cellular levels of coregulators are crucial for nuclear receptor-mediated transcription, and many coregulators have been shown to be targets for diverse intracellular signaling pathways and post-translational modifications. This review focuses on the different modes of regulation of nuclear receptor coregulators and the implications for tissue- and context-specific transcriptional responses to hormone and membrane receptor signaling.

Section snippets

Multiple coregulator complexes

The number of coregulators reported in the literature has increased dramatically in the past few years (Table 1), and models for transcriptional regulation have thus become increasingly complicated. It is beyond the scope of this article to review all aspects of current models of the roles for different protein complexes in transcriptional regulation by NRs; for a more thorough review on the subject, see [5]. It is believed that NR-mediated transcription requires several different protein

Variations in cellular levels of coregulators create cell- and temporal-specific transcriptional conditions

Genetic mouse models – transgenic mice with targeted gene deletions – have shown the importance of NR coregulators in development and transcription. Mice lacking CBP or p300 die early in embryogenesis, and show severe defects in hematopoiesis and neural development 8, 9. Subsequent transfection studies in p300-deficient embryonic fibroblasts demonstrated an impairment in retinoic acid receptor signaling [8], confirming a role for p300 in NR-regulated transcription. In addition, p300

Coregulators can shuttle between nucleus and cytoplasm

Several classes of transcription factors, including NRs, are known to translocate between cytoplasm and nucleus. Some of these transcription factors have also been suggested to act as coregulators for NR-mediated transcriptional regulation, such as nfb and certain smads (Table 1). In addition, certain NR coregulators with no known DNA-binding capacity of their own might shuttle between intracellular compartments (Fig. 1), including TRIP4/ASC1/CG11710 [26] and

Regulation of coregulator levels by proteolysis

Another putative mechanism for modulating cellular coregulator levels is regulated proteolysis. Regulated proteolysis of DNA-binding transcription factors has previously been implicated in cell cycle regulation [31]. Interestingly, the corepressor NCoR, which binds to unliganded NRs and antagonist-bound steroid receptors, can be regulated proteolytically. Specifically, the protein mSiah2 binds to the N-terminus of NCoR, and mediates proteasome-dependent proteolysis [32]. This is a good example

Coregulator phosphorylation can alter enzymatic activity and protein interactions

Several investigations have shown that coregulator activity, similar to the function of DNA-binding proteins, can be modulated by phosphorylation (Fig. 1). For example, many coregulators of nuclear receptors, including CBP and p300, can be modulated by kinases involved in the regulation of cell cycle progression [36], suggesting a correlation between the mitotic state of the cell and coregulator function. However, the exact role(s) for such modulation of activity is unclear. In addition to CBP

Acetylation and methylation of transcriptional regulators

During the past three years, it has become clear that acetylation is an alternative mode of post-translational modification of histones and coregulators involved in NR function. Many coregulators, such as CBP, p300, pCAF and gcn5, have acetyltransferase activity. It has been demonstrated that these transferases are capable of acetylating certain lysines in the N-termini of histone tails, thereby enhancing transcriptional activity through dissociation of nucleosome-containing complexes, with a

Conclusion

The formation of protein–protein complexes and subsequent transcriptional regulation is completely dependent on the structure of the promoter. Thus, because different classes of DNA-binding transcription factors use both factor-specific and common coregulators to recruit appropriate enzymatic activity 39, 62, the combinatorial pattern of transcription factors on a promoter, in combination with expression levels and post-translational modifications, will establish context-specific recruitment of

Acknowledgements

The literature on nuclear receptor coregulators is extensive and numerous important studies were not mentioned in this article owing to space limitations, for which we apologize. We thank Bogi Andersen, Rob Burgess and Kristen Jepsen for helpful comments on the article. M.G.R. is an Investigator with the Howard Hughes Medical Institute. Work from our laboratories was supported by the National Institutes of Health and the Swedish Brain Foundation.

Glossary

ACTR
Activator for thyroid hormone and retinoid receptors
AIB
Amplified in breast cancer
AML
Acute myeloid leukemia
ARC
Activator-recruited cofactor
ARIP
Androgen receptor-interacting protein
ASC
Activating signal cointegrator
BRG
Brahma-related gene
CaM
Ca2+–calmodulin
CARM
Coactivator-associated Arg methyltransferase
CASK
Ca2+–calmodulin-dependent serine protein kinase
CBP
CREB-binding protein
CREB
CAMP-response element-binding protein
CRSP
Coactivator required for Sp1 activation
DRIP
vitamin D receptor-interacting

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