Michael R. Stallcup Professor and Chair Biochemistry & Molecular Biology, Pathology Keck School of Medicine

Education:
BA 1969 Chemistry- Yale University, New Haven, CT
PhD 1974 Biochemistry- University of California, Berkeley

Postdoctoral Research Fellowship:
1974-1979 University of California, San Francisco

Started at USC: 1985

Research Topics: Cancer Cell Biology, Signal Transduction, Gene Regulation/Transcription, Epigenetics

Research Description

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.

Selected Publications

Collins RE, Northrop JP, Horton JR, Lee DY, Zhang X, Stallcup MR, Cheng X. - The ankyrin repeats of G9a and GLP histone methyltransferases are mono- and dimethyllysine binding modules. - Nat Struct Mol Biol [ 2008 ] Feb 10; . PubMed

Yang CK, Kim JH, Ann DK, Stallcup MR. - Differential regulation of the two transcriptional activation domains of the coiled-coil coactivator CoCoA by sumoylation. - BMC Mol Biol [ 2008 ] Jan 25;9(1):12 . PubMed

Lee DY, Ianculescu I, Purcell D, Zhang X, Cheng X, Stallcup MR. - Surface-scanning mutational analysis of protein arginine methyltransferase 1: roles of specific amino acids in methyltransferase substrate specificity, oligomerization, and coactivator function. - Mol Endocrinol [ 2007 ] Jun;21(6):1381-93 . PubMed

Chen YH, Yang CK, Xia M, Ou CY, Stallcup MR. - Role of GAC63 in transcriptional activation mediated by beta-catenin. - Nucleic Acids Res [ 2007 ] 35(6):2084-92 . PubMed

Luo Y, Arita K, Bhatia M, Knuckley B, Lee YH, Stallcup MR, Sato M, Thompson PR. - Inhibitors and inactivators of protein arginine deiminase 4: functional and structural characterization. - Biochemistry [ 2006 ] Oct 3;45(39):11727-36 . PubMed

Lee YH, Stallcup MR. - Interplay of Fli-I and FLAP1 for regulation of beta-catenin dependent transcription. - Nucleic Acids Res [ 2006 ] 34(18):5052-9 . PubMed

Yang CK, Kim JH, Stallcup MR. - Role of the N-terminal activation domain of the coiled-coil coactivator in mediating transcriptional activation by beta-catenin. - Mol Endocrinol [ 2006 ] Dec;20(12):3251-62 . PubMed

Kim JH, Yang CK, Stallcup MR. - Downstream signaling mechanism of the C-terminal activation domain of transcriptional coactivator CoCoA. - Nucleic Acids Res [ 2006 ] May 22;34(9):2736-50 . PubMed

Chen YH, Beischlag TV, Kim JH, Perdew GH, Stallcup MR. - Role of GAC63 in transcriptional activation mediated by the aryl hydrocarbon receptor. - J Biol Chem [ 2006 ] May 5;281(18):12242-7 . PubMed

Lee DY, Northrop JP, Kuo MH, Stallcup MR. - Histone H3 lysine 9 methyltransferase G9a is a transcriptional coactivator for nuclear receptors. - J Biol Chem [ 2006 ] Mar 31;281(13):8476-85 . PubMed