Professor and Chair
Biochemistry & Molecular Biology, Pathology
Keck School of Medicine
- Cancer Cell Biology
- Signal Transduction
- Gene Regulation/Transcription
Research OverviewHormonal 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 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 steroid receptors enhance transcription of specific target genes after binding to the promoters of the genes. We have discovered several new proteins, called transcriptional coregulators, which interact with the activated steroid receptors and help to remodel chromatin structure and recruit RNA polymerase II and its associated transcription machinery to the promoter. One of the new coregulators, GRIP1, binds directly to steroid receptors and recruits several other coregulators, 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 coregulator called CARM1 which binds to GRIP1 and methylates histones and non-histone proteins, thus contributing in a variety of ways to transcriptional regulation. We also identified several other coregulators and are cureently studying how each of these proteins contributes to the transcriptional regulation process.
In addition to their roles in normal function, steroid hormones play crucial roles in many many diseases and their treatment, including inflammatory diseases and some types of cancer. A more complete understanding of how these hormones and their receptors and coregulators regulate gene expression should provide new insights into disease mechanisms and suggest new strategies for therapy.
The study of coregulators has recently become one of the most exciting and fast-moving areas of the steroid receptor and gene regulation fields; it provides an exciting opportunity to extend our understanding of the mechanism of transcriptional regulation by hormones. In addition, we and others have recently shown that coregulators also control key aspects of normal physiology and disease. We are therefore, trying to understand which coregulators control specific aspects of physiology related to inflammatory diseases and cancer.