title: RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer.
abstract: Regulator of G protein signaling (RGS) proteins are gatekeepers regulating the cellular responses induced by G protein-coupled receptor (GPCR)-mediated activation of heterotrimeric G proteins. Specifically, RGS proteins determine the magnitude and duration of GPCR signaling by acting as a GTPase-activating protein for Gα subunits, an activity facilitated by their semiconserved RGS domain. The R7 subfamily of RGS proteins is distinguished by two unique domains, DEP/DHEX and GGL, which mediate membrane targeting and stability of these proteins. RGS6, a member of the R7 subfamily, has been shown to specifically modulate Gαi/o protein activity which is critically important in the central nervous system (CNS) for neuronal responses to a wide array of neurotransmitters. As such, RGS6 has been implicated in several CNS pathologies associated with altered neurotransmission, including the following: alcoholism, anxiety/depression, and Parkinson's disease. In addition, unlike other members of the R7 subfamily, RGS6 has been shown to regulate G protein-independent signaling mechanisms which appear to promote both apoptotic and growth-suppressive pathways that are important in its tumor suppressor function in breast and possibly other tissues. Further highlighting the importance of RGS6 as a target in cancer, RGS6 mediates the chemotherapeutic actions of doxorubicin and blocks reticular activating system (Ras)-induced cellular transformation by promoting degradation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) to prevent its silencing of pro-apoptotic and tumor suppressor genes. Together, these findings demonstrate the critical role of RGS6 in regulating both G protein-dependent CNS pathology and G protein-independent cancer pathology implicating RGS6 as a novel therapeutic target.
authors.affiliation: Department of Pharmacology, The Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 2-505 Bowen Science Building, Iowa City, Iowa, 52242, USA.
authors.forename: Katelin E
authors.initials: KE
authors.lastname: Ahlers
authors.affiliation: Department of Pharmacology, The Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 2-505 Bowen Science Building, Iowa City, Iowa, 52242, USA.
authors.forename: Bandana
authors.initials: B
authors.lastname: Chakravarti
authors.affiliation: Department of Pharmacology, The Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 2-505 Bowen Science Building, Iowa City, Iowa, 52242, USA. rory-fisher@uiowa.edu.|Department of Internal Medicine, The Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, 52242, USA. rory-fisher@uiowa.edu.
authors.forename: Rory A
authors.identifier: 0000-0003-3108-4836
authors.initials: RA
authors.lastname: Fisher
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism; D002493:Central Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D020710:RGS Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D020710:RGS Proteins; C400194:RGS6 protein, human; D043562:Receptors, G-Protein-Coupled
keywords: Parkinson’s disease; RGS protein; alcoholism; depression; doxorubicin