Bert W. O'Malley, M.D.
Professor and Chair
Department of Molecular and Cellular Biology
M.D.: University of Pittsburgh, Pittsburgh
Hormone Action and Gene Expression: Nulcear Receptors/Coactivators/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 define 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 one of the largest families (48 members) of human transcription factors. When bound to DNA, the transactivation domains of the receptor dimer are exposed and available to recruit coregulator proteins (coactivators and corepressors). Our lab pioneered the discovery of corepressors-coactivators and the coactivation theory for gene activation. The coactivators are power boosters for the transcriptional regulation exerted by nuclear receptors; our lab has cloned/studied 15 different subfamilies of these molecules. We study primarily SRC-1, -2, -3, nuclear coactivators which bind directly to receptors and act as ‘platform coactivators’ for assembly of other co-coactivators (e.g., CBP/p300) in a complex that regulates gene expression.
Coactivators stimulate transcription by two mechanisms: 1) via enzymatic activities which modify local chromatin and other proteins in the regulatory complex to permit access of general transcription factors (GTFs) and polymerase 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 of target genes. We defined the sub-steps in gene expression controlled by the steroid receptors/coactivator complex, including histone epigenomic modifications and nucleosome remodeling, initiation and re-initiation of RNA synthesis, elongation of RNA chains, mRNA splicing and processing, and transcription termination.
Since many of the coregulators are controlled at the posttranslational level, we also study the ubiquitin ligases and proteolytic systems that are responsible for degradation and turnover of the coactivators. 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, a single coactivator can bind to multiple different DNA-bound transcription factors and activate different gene sets.
The coactivators have great relevance to human physiology and disease and therapy. They act as ‘Master Regulators’ of cell physiology by regulating distinct processes oriented towards common goals - such as reproduction, metabolism, inflammation, or cancer. The tissue selectivity of SRM (Selective Receptor Modulator) drugs lies in the cellular fingerprint of coactivators and corepressors contained in different tissues. Antihormones block transcription at the step of coregulator complex formation by destabilizing receptor-coactivator interactions and promoting binding of corepressors.
Coactivators lie at the heart of many diseases. Our coactivator knockouts in mice have led to syndromes of 'partial resistance' to hormones and to developmental defects in endocrine pathways. The coactivators have been shown to have important applications to humans in genetic and reproductive diseases, inflammation, CNS function and the diurnal cycle, and multiple metabolic diseases. The role of coactivators for metabolic gene sets is expanding greatly, indicating higher order control of carbohydrate, lipid, and protein metabolism.
Perhaps most importantly, many coactivators are driver oncogenes in human cancers. For example, breast (SRC-3; >60%) and prostate metastases (SRC-2; >30%) and numerous other tumors overexpress oncogenic coactivators because the overexpression provides those cells a selective growth advantage over normal cells. (SRC-3 is now the second most overexpressed oncogene among all human cancers.) The totality of recent evidence also substantiates coactivators as ‘master genes’ for human disease. For this reason, certain current projects in the lab are oriented to developing coactivator-selective drugs for therapeutic purposes.
Baylor College of Medicine
One Baylor Plaza
DeBakey M613, MS:BCM502
Houston, TX 77030
- Han SJ, Hawkins SM, Begum K, Jung SY, Kovanci E, Qin J, Lydon JP, DeMayo FJ and O’Malley BW. (summer 2012). A novel isoform of steroid receptor coactivator-1 is critical for pathogenic progression of endometriosis. Nature Medicine, In Press.
- Long W, Foulds CE, Qin J, Liu J, Ding C, Lonard DM, Solis LM, Wistuba II, Qin J, Tsai SY, Tsai M-J and O’Malley BW. (2012). ERK3 signals through SRC-3-coactivator to promote human lung cancer cell invasion. J. Clin. Inv. 122(5):1869-80. PMID: 22505454
- York B, Reineke EL, Sagen JV, Nikolai BC, Zhou S, Louet J-F, Chopra AR, Chen X, Reed G, Noebels J, Adesina AM, Tsimelzon A, Hilsenbeck S, Stevens RD, Wenner BR, Ilkayeva O, Xu J, Newgard CB and O’Malley BW. (2012). Ablation of steroid receptor coactivator-3 phenocopies the human CACT metabolic myopathy. Cell Metabolism 15(5):752-63. PMID:22560224
- Malovannaya A, Lanz RB, Yung SY, Bulynko Y, Le NT, Chan DW, Ding C, Shi Y, Yucer N, Krenciute G, Kim BJ, Li C, Chen R, Li W, Wang Y, O'Malley BW and Qin J. (2011). Analysis of the human endogenous coregulator complexome. Cell. 145(5):787-99 PMID: 21620140 PMCID: PMC 3131083.
- Wang Y, Lonard DM, Chow D-C, Palzkill TG and O’Malley BW. (2011). Small molecule inhibition of the steroid receptor coactivators, SRC-3 and SRC-1. Molecular Endocrinology 25(12):2041-53. PMID:22053001
- Li C, Ao J, Fu J, Lee D-F, Xu J, Lonard D and O’Malley BW. (2011) Tumor suppressor role for the SPOP ubiquitin ligase in signal-dependent proteolysis of the oncogenic coactivator SRC-3/AIB1. Oncogene 30(42):4350-64. PMID: 21577200
- York B and O’Malley BW. (2010). Steroid receptor coactivator (SRC) Family: Masters of systems biology. J. Biol. Chem. 285:(50) 38743-38750. PMID: 20956538
- 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.
- Yu C, York B, Wang S, Feng Q, Xu J and O'Malley BW. (2007). An essential function of the SRC-3 coactivator in suppression of cytokine mRNA translation and inflammatory response. Mol Cell. 25:765-778. PMID: 17349961
- 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.