Summary of the probe development effort to identify inhibitors of the Steroid Receptor Coactivator 2 (SRC2; NCOA2)
Name: Summary of a probe development effort to identify inhibitors of the Steroid Receptor Coactivator 2 (SRC2; NCOA2). ..more
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: Bert O'Malley, Baylor College of Medicine
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: 5U19DK062434-09
Grant Proposal PI: Bert O'Malley, Baylor College of Medicine
External Assay ID: SRC2_INH_SUMMARY
Name: Summary of a probe development effort to identify inhibitors of the Steroid Receptor Coactivator 2 (SRC2; NCOA2).
The steroid receptor coactivator (SRC) family contains three members, SRC-1 (1), SRC-2/TIF2/GRIP1 (2, 3) and SRC-3/AIB-1/pCIP (4, 5), and each plays broad roles in promoting NR-mediated gene expression. Coactivators are required for NRs to function as transcription factors and play key roles as rheostats that determine the amplitude of biological responses to hormones (6). Consistent with the expansive biological roles that NRs play in reproduction, stress responses, energy metabolism and cell growth, disruption of coactivator biological function results in complex and pleiotropic defects. Small molecule inhibitor (SMI) screens for SRC-1 and SRC-3, which play prominent roles in cancer, have already been performed. While it also has a role in cancer, SRC-2 was found to play a critical role in energy intake by driving the dietary absorption of fat (7). SRC-2 achieves this function in response to post translational modification (PTM)-based activation by the primordial energy-sensing kinase, AMPK (among others) which phosphorylates SRC-2, increasing its intrinsic transcriptional activity. We showed that liver-specific ablation of SRC-2 results in a hypoglycemic phenotype in response to fasting (8). We further demonstrated that that hepatic SRC-2 cooperates with RORalpha to specifically drive expression of glucose-6-phosphatase (G6Pase), an essential rate-limiting enzyme that catalyzes glucose production during fasting. SMIs capable of targeting SRC-2 could serve as novel therapeutic agents to treat obesity and other metabolic diseases.
1. Onate, S.A., Tsai, S.Y., Tsai, M.J. & O'Malley, B.W. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270, 1354-1357 (1995).
2. Voegel, J.J., Heine, M.J., Zechel, C., Chambon, P. & Gronemeyer, H. TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO J 15, 3667-3675 (1996).
3. Hong, H., Kohli, K., Trivedi, A., Johnson, D.L. & Stallcup, M.R. GRIP1, a novel mouse protein that serves as a transcriptional coactivator in yeast for the hormone binding domains of steroid receptors. Proc Natl Acad Sci U S A 93, 4948-4952 (1996).
4. Anzick, S.L., et al. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277, 965-968 (1997).
5. Torchia, J., et al. The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 387, 677-684 (1997).
6. Lonard, D.M. & O'Malley B, W. Nuclear receptor coregulators: judges, juries, and executioners of cellular regulation. Mol Cell 27, 691-700 (2007).
7. Chopra, A.R., et al. Cellular energy depletion resets whole-body energy by promoting coactivator-mediated dietary fuel absorption. Cell Metab 13, 35-43 (2011).
8. Chopra, A.R., et al. Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierke's disease. Science 322, 1395-1399 (2008).
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