Nuclear Hormone Receptors

For this article, Nadia S. Halim interviewed Ronald Evans, professor in the gene expression laboratory, Salk Institute, La Jolla, Calif., and Hongwu Chen, postdoctoral fellow, Salk Institute. Both are coauthors of this Cell paper. Data from the Web of Science (ISI, Philadelphia) show that this paper has been cited significantly more often than the average paper of the same type and age. H. Chen, R.J. Lin, R.L. Schiltz, D. Chakravarti, A. Nash, L. Nagy, M. L. Privalsky, Y. Nakatani, and R.M. Evans, "Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300," Cell, 90:569-80, Aug. 8, 1997. (Cited in about 300 papers since publication) By interacting with their nuclear receptors, hormones regulate a wide variety of physiological functions, including metabolism, growth, and cell differentiation. Because disruptions often cause disease, this research area has been developing rapidly. Ronald Evans and Hongwu Chen have spent several years dissecting how a lipophilic hormone activates genes. Lipophilic hormones such as steroids, retinoids, thyroids, and vitamin D2 modulate gene transcription inside the cell. A steroid hormone, for example, will enter the cell and bind to its complementary receptor, initiating a complex cascade of events. The hormone-receptor complex forms dimers, which bind to a DNA sequence called the hormone response element (HRE). This binding activates, or in some cases inhibits, transcription of the appropriate gene. The resulting messenger RNA from gene activation can then be translated into the respective protein to produce a physiological response. However, this mechanism is not as simple as it appears. The hormone-receptor complex interacts with other nuclear players, such as transcription factors, adapter proteins, coactivators, and transacetylases. The 1997 Cell paper describes a novel cofactor, ACTR, which directly binds nuclear receptors and stimulates their transcriptional activities in a hormone-dependent fashion. ACTR plays a central role in creating a multisubunit coactivator complex by recruiting two histone acetyltransferases (HATs), CBP/p300 and P/CAF. ACTR independently binds CBP/p300 and P/CAF, serving as a docking platform to bridge the HAT protein complex to DNA-bound hormone-receptor pairs. Surprisingly, the Evans lab found that ACTR is not merely a binding protein but also a HAT. It can acetylate both free histones and histones associated with DNA. "This work suggested we had discovered a new branch of the HAT family, one specifically involved in the activity of nuclear hormone receptors," comments Evans. He adds that the association of multiple HAT proteins had not been observed before this paper. HATs are hot molecules because they are implicated in transcriptional activation. HAT proteins acetylate specific lysines within histone proteins. Histones are small, positively charged proteins that help package DNA into chromatin, the condensed form of DNA. Acetylation appears to decondense chromatin, which allows transcriptional machinery access to the DNA code. Ronald Evans The Evans lab found evidence to support this theory in the follow-up to the 1997 Cell paper.1 They provided in vivo evidence that histone acetylation is essential to hormone-induced gene activation. Both steroid hormones and vitamins A and D induced hyperacetylation of histones at gene promoters. Nuclear receptors and their associated coactivators mediated this process. "Despite all the theories, it had been difficult to pinpoint effects at target genes in cells," explains Evans. Researchers had not previously shown that all the predicted events in hormonal signaling actually occurred at a target gene inside a cell. Unexpectedly, the group also found that hormone-induced histone acetylation is dynamic and can be attenuated by acetylation of ACTR. The HAT, p300, acetylates ACTR, destabilizing the receptor-coactivator interaction and shutting off gene activation. The group continues to explore the function of the different HATs in this complex pathway. "We are currently [creating] mutations in the HAT domain of ACTR. If we have a mutation that inactivates the HAT activity, we will try to address where and how the HAT activity of ACTR functions in terms of mediating nuclear receptor signaling," explains Chen. The study of nuclear receptor signaling is so close to the core of transcription regulation, it affects many different fields. "The link between transcription and physiology makes this a major research area, which will continue advancing for quite some time," comments Evans. Nadia S. Halim can be contacted at nhalim@the-scientist.com. 1. H. Chen et al., "Regulation of hormone-induced histone hyperacetylation and gene activation via acetylation of an acetylase," Cell, 98:675-86, Sept. 3, 1999.

Nuclear Hormone Receptors

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