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, 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.