Bert W. O'Malley, M.D.
Professor and Chair, Department of Molecular and Cellular Biology
M.D., University of Pittsburgh
Hormone Action and Gene Expression: Coactivators and Corepressors
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 nuclear receptors act in target cells to regulate the levels of specific mRNAs and proteins 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 Superfamily (steroid/thyroid/vitamin/orphan receptors). These intracellular receptors comprise the largest (48) family of human transcription factors. 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, -2, -3, nuclear coactivators cloned which form complexes with receptors and other coactivators (e.g.,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 and re-initiation of RNA synthesis, elongation of RNA chains, mRNA processing, and termination.
Recent work in our laboratory demonstrated that steroid receptors regulate alternative mRNA splicing by recruiting coactivators to the target genes that are dedicated to this function. 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 and transcription factors. Finally, coactivators are the main downstream targets for membrane signaling pathways and when phosphorylated by kinase cascades become active partners with 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 coactivators have great relevance to human physiology and disease and therapy. 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 and reproductive diseases, inflammation, CNS function and metabolic diseases. Perhaps most importantly, coactivators are intimately associated with oncogenesis. Breast (>60%) and prostate (and numerous 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. The role of coactivators for metabolic genes is expanding greatly, indicating control of carbohydrate, lipid, and protein metabolism. In all aspects, they appear to function as ‘master genes’ for physiology and disease.
Long W, Yi P, Amazit L, LaMarca HI, Ashcroft F, Kumar R, Mancini M, Tsai SY, Tsai M-J and O’Malley BW. (2010). SRC-3Δ4 mediates the interaction of EGFR with FAK to promote cell migration. Molecular Cell 37(3):321-32. PMID: 20159552
Chopra AR, Louet JF, Saha P, An J, Demayo F, Xu J, York B, Karpen S, Finegold M, Moore D, Chan L, Newgard CB and O'Malley BW. (2008). Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierke's disease. Science. Nov 28;322(5906):1395-9. PMID: 19039140
Yi P, Feng Q, Amazit L, Lonard DM, Tsai SY, Tsai M-J and O’Malley BW. (2008). Atypical protein kinase C regulates dual pathways for degradation of the oncogenic coactivator SRC-3/AIB1. Molecular Cell 29:465-478.
Lonard DM, Lanz RB and O’Malley BW. (2007). Nuclear Receptor Coregulators and Human Disease. Endocrine Rev. 28(5):575-587.
Lonard DM and O’Malley BW. (2007). Nuclear receptor coregulators: Judges, juries and executioners of transcriptional regulation. Molecular Cell 27:691-700.
Wu R-C, Feng Q, Lonard DM and O’Malley BW. (2007). SRC-3 Coactivator Functional Lifetime Is Regulated by a Phospho-Dependent Ubiquitin Time Clock. Cell 129:1125-40.
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 REGγ-proteasome. Cell 124:381-92.
Lonard D and O’Malley BW. (2006). The expanding cosmos of nuclear receptor coactivators. Cell. 125:411-414.
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.
Wu R-C, Qin J, Yi P, Wong J, Tsai SY, Tsai M-J and 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.
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.
Bert W. O'Malley, M.D.
Fax: (713) 798-5599