Description:Dr. Stallcup is studying the mechanisms by which steroid hormones control the activity of specific genes in mammalian cells. In particularly, he is investigating the detailed structure and function of the receptor proteins for steroid hormones. To accomplish this, he uses the tools of modern genetics and cell biology, including recombinant DNA technology, cell culture, and yeast genetics. His lab has also discovered a new class of proteins called transcriptional coactivators that are required to assist the activated steroid receptor proteins to activate expression of target genes. The investigation of these coactivators represents an exciting step forward in understanding how steroid hormones can regulate the activities of cells by controlling the expression of specific genes.
Hormonal regulation of gene expression by nuclear hormone receptors and their transcriptional coactivators
Hormones are chemical messengers that travel through the bloodstream and are one of the primary mechanisms of communication between different organs; thus, they play many crucial roles in the developing and adult organism. Work in this laboratory focuses on how steroid hormones, thyroid hormone, and vitamins A and D modulate the activities of cells by regulating the transcription of specific genes. Steroid hormones include testosterone, estrogen, and progesterone, which control sexual development and function; and cortisol and aldosterone, which serve diverse roles in stress management and other physiological responses to external challenges. All of these hormones share a common mechanism of action. Each hormone binds to and activates a specific receptor protein found inside the target cells; the receptor proteins for all of these hormones are related in structure and function. The activated receptor binds to specific genes and regulates the synthesis of mRNA from those genes.
The focus of this laboratory is the mechanism by which the activated nuclear receptors enhance transcription of specific target genes after binding to the promoters of the genes. We have discovered several new proteins, called transcriptional coactivators, that interact with the activated nuclear receptors and help to remodel chromatin structure and recruit RNA polymerase II and its associated transcription machinery to the promoter. One of the new coactivators, GRIP1, binds directly to nuclear receptors and recruits several other coactivators, including CBP and p300 which help to remodel chromatin and activate transcription by acetylating histones and other proteins in the transcription initiation complex. We also discovered a coactivator called CARM1 which binds to GRIP1 and has the ability to methylate histones, suggesting that histone methylation may also contribute to the transcription activation process. Proteins related to CARM1, which methylate other protein targets, also can function as coactivators.
The study of coactivators has recently become one of the most exciting and fast-moving areas of the nuclear receptor and gene regulation fields; it provides an exciting opportunity to extend our understanding of the mechanism of transcriptional enhancement by hormones. We plan to define the mechanism by which the nuclear receptors and their coactivators activate gene transcription, by defining the functional domains of the coactivators and identifying the cellular proteins that the coactivators interact with. Our lab has also made the exciting finding that methylation of histones and perhaps other proteins by coactivators like CARM1 is an important part of the transcriptional activation process. We will thus investigate what proteins are methylated and how this protein methylation helps to activate transcription.
In addition to their roles in normal function, steroid hormones and vitamins A and D play crucial roles in many types of cancer; both the hormones and their synthetic antagonists (compounds that bind to the receptors but do not activate them) are used in therapy for many types of cancer. A more complete understanding of how these hormones and their receptors and coactivators regulate gene expression should provide new insights into cancer biology and suggest new strategies for therapy.
For further information about Dr. Stallcup's research, please visit his PIBBS Research Faculty webpage.
- Gene Regulation/Transcription
- Signal Transduction
- Cancer Cell Biology
HISTORY & EDUCATION
- University of California - Berkeley, PhD, 1974
- University of California, San Francisco, 1974 – 1979
MEMBERSHIPS & AFFILIATIONS
- American Association for the Advancement of Sciences
- Endocrine Society
- American Society for Biochemistry and Molecular Biology
- Selected Publications
Chen D, Ma H, Hong H, Koh SS, Huang S-M, Schurter BT, Aswad DW, Stallcup MR. 1999 Regulation of transcription by a protein methyltransferase. Science 284:2174-2177
- Ma H, Hong H, Huang S-M, Irvine RA, Webb P, Kushner PJ, Coetzee GA, Stallcup MR. 1999 Multiple signal input and output domains of the 160-kDa nuclear receptor coactivator proteins. Mol Cell Biol 19:6164-6173
- Chen D, Huang S-M, Stallcup MR. 2000 Synergistic, p160 coactivator-dependent enhancement of estrogen receptor function by CARM1 and p300. J Biol Chem 275:40810-40816
- Koh SS, Chen D, Lee Y-H, Stallcup MR. 2001 Synergistic enhancement of nuclear receptor function by p160 coactivators and two coactivators with protein methyltransferase activities. J Biol Chem 276:1089-1098
- Ma H, Baumann CT, Li H, Strahl BD, Rice R, Jelinek MA, Aswad DW, Allis CD, Hager GL, Stallcup MR. 2001 Hormone-dependent, CARM1-directed, arginine-specific methylation of histone H3 on the mouse mammary tumor virus promoter. Curr Biol, 11: 1981-1985.
Direct link to profile: http://keck.usc.edu/profiles?facid=1118