Bert W. O'Malley, M.D.
Professor and Chairman, Department of Molecular and Cellular Biology
M.D., University of Pittsburgh
Research Interests:
My laboratory group is interested in determining the fundamental mechanisms for regulation of eucaryotic gene expression. Our early work defined the "primary molecular endocrine pathway" by which steroid hormones act in target cells. We showed that steroid hormones regulate de novo synthesis of specific proteins by regulating the levels of specific mRNAs in target cells. Using cell-free transcription methods, we substantiated "initiation of transcription" as the rate-limited step at which nuclear receptors regulate gene expression and defined steroid hormone receptors as transcription factors.
As a model system we study genes regulated by the Nuclear Receptor (steroid/thyroid/vitamin/orphan receptor) Superfamily. These intracellular receptors comprise the largest (~49) family of human transcription factors. They are cell- and gene-specific transcriptional regulators that act by binding to enhancers in the 5'-flanking region of DNA of target genes.
When bound to DNA, the transactivation domains of the receptor dimer are exposed and available to interact with coregulator proteins (coactivators and corepressors). Our lab pioneered the discovery of corepressors-coactivators and the coactivation theory for gene activation. These proteins include SRC-1, a nuclear receptor family coactivator cloned in our laboratory which forms a complex with receptors, other coactivators and CBP/p300 to greatly enhance gene expression. The coactivators are power boosters (amplifiers) of the transcriptional regulation exerted by nuclear receptors; our lab has cloned/studied 15 different subfamilies of these molecules.
Coactivators stimulate transcription by two mechanisms: 1) via enzymatic activity which, for example, modifies local chromatin and other proteins in the regulatory complex to permit access of general transcription factors (GTFs) to the promoter; and 2) via interactions with other coactivators and GTFs which stabilize the complex of TATA-based transcription factors and lead to repeated initiations of transcription at the target gene by RNA polymerase. The steps in gene expression currently thought to be affected by steroid receptors/coactivators are initiation, re-initiation, mRNA processing, and termination.
Recent work in our laboratory has demonstrated that steroid receptors also regulate alternative mRNA splicing by recruiting coactivators to the target genes that are dedicated to this function. Depending upon the specific coactivator recruited, an exon is either left in the mRNA or spliced out. We also study a number of coactivators that are ubiquitin ligases and are responsible for degradation and turnover of the transcription apparatus, including receptors and coactivators. These molecules bind to and turn over specific coactivators. Finally, coactivators are the main targets for membrane signaling pathways and when phosphorylated by kinase cascades become active partners with downstream transcription factors to regulate transcription. Depending upon the pattern of phosphorylation, the coactivator binds to different DNA-bound transcription factors and activates different gene sets.
The tissue selectivity of SRMs (selective receptor modulators) lies in the cellular fingerprint of coactivator/corepressor functions in different tissues. Antihormones block transcription at the step of coregulator complex formation by destabilizing receptor-coactivator interactions and promoting binding of corepressors. Genetic defects in members of this receptor superfamily lead to diseases of hormone resistance. Our coactivator knockouts in mice lead to syndromes of 'partial resistance' to hormones and to developmental defects in endocrine pathways. The coactivators have important applications to humans in genetic diseases, CNS function and aging. Perhaps most importantly, coactivators are intimately associated with oncogenesis. Breast (>60%) and prostate (and many other) tumors overexpress coactivators such as SRC-1/AIB1, which are 'oncogenes' because they give those cells selective growth advantages over normal cells when overexpressed. Finally, we are using genetic variants of members of this receptor family to treat metabolic diseases and breast cancer via new regulatable (GeneSwitch) approaches to human gene therapy.
Selected Publications:
Li X, Lonard DM, Jung SY, Malovannaya A, Feng Q, Qin J, Tsai SY, Tsai M-J, and O’Malley BW. (2006). The SRC-3/AIB1 coactivator is degraded in an ubiquitin- and ATP-independent manner by the REGg-proteasome. Cell 27:381-92.
Lonard D. and O’Malley BW. (2006). The expanding cosmos of nuclear receptor coactivators. Cell. 125:411-414.
Auboeuf D, Dowhan DH, Dutertre M, Martin N, Berget SM and O'Malley BW. (2005) Minireview: A Subset of Nuclear Receptor Coregulators Act as Coupling Proteins during Synthesis and Maturation of RNA Transcripts. Mol. Cell. Biol. 25: 5307-5316.
Dowhan DH, Hong EP, Auboeuf D, Dennis AP, Wilson MM, Berget SM and O'Malley BW . (2005) Steroid hormone receptor coactivation and alternative RNA splicing by U2AF65-related proteins CAPER and CAPER?. Mol. Cell. 17:1-20.
O'Malley BW. (2005) Perspectives: A life-long search for the molecular pathways of steroid hormone action. Mol. Endo. 19: 1402 - 1411.
Kuang S-Q, Liao L, Wang S, Medina D, O'Malley BW and Xu J . (2005). Mice lacking the cancer-amplified coactivator AIB1/SRC-3 are resistant to chemical carcinogen-induced mammary tumorigenesis. Cancer Research;65(17):7993-8002.
Auboeuf D, Dowhan D, Li X, Larkin K, Berget SM and O'Malley BW. (2004). CoAA: a coactivator protein at the interface of transcriptional coactivation and RNA splicing. Molecular and Cellular Biology 24:442-453.
Smith CL and O'Malley BW. (2004). Coregulator function: a key to understanding specificity of selective receptor modulators (SRMs). Endocrine Reviews 25(1):45-71.
Wu R-C, Qin J, Yi P, Wong J, Tsai SY, Tsai M-J,O'Malley BW (2004) Selective phosphorylations of the SRC-3/AIB1 coactivator integrate genomic responses to multiple cellular signaling pathways. Mol. Cell 15:1-20.
Li X, Wong J, Tsai SY, Tsai M-J and O'Malley BW (2003) Progesterone and glucocorticoid receptors recruit distinct coactivator complexes and promote distinct chromatin modifications. Molecular and Cellular Biology 23:3763-3773.
Auboeuf, D, Hönig A, Berget SM, and O'Malley BW (2002) Coordinate regulation of transcription and splicing by steroid receptor coregulators. Science 298:416-419.
McKenna NJ and O'Malley BW (2002) Combinatorial control of gene expression by nuclear receptors and coregulators. Cell 108:465-474
Wu, R-C, et al. (2002) Regulation of SRC-3 coactivator activity by IkB kinase. Mol. and Cellular Biology 22:3549-3561.
Lonard D, Nawaz Z, Smith CL and O'Malley BW. (2000) The 26S proteasome is required for ER coactivator turn-over and for efficient ER transcriptional activity. Molecular Cell. 5:939-948.
Lanz RB, McKenna NJ, Onate SA, Albrecht U, Wong J, Tsai SY, Tsai M-J and O'Malley BW. (1999). A novel steroid receptor coactivator, SRA, functions as an RNA and is associated with SRC-1. Cell 97:17-27.
Xu J, Qui Y, DeMayo FJ, Tsai SY, Tsai M-J and O'Malley BW. (1998) Disruption of the Steroid Receptor Coactivator 1 (SRC-1) Gene in Mice Results in A Syndrome of Partial Hormone Resistance. Science 279:1922-1925.
Onate SA, Tsai SY, Tsai M-J and O'Malley BW. (1995) Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270:1354-1357.
For more publications, see listing on PubMed.
Contact Information:
Bert W. O'Malley, M.D.
(713) 798-6205
Fax: (713) 798-5599
E-mail: berto@bcm.eduUpdated: 7/07