RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

Katelin E Ahlers; Bandana Chakravarti; Rory A Fisher

doi:10.1208/s12248-016-9899-9

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RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

Journal article

Open access

Peer reviewed

RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

Katelin E Ahlers, Bandana Chakravarti and Rory A Fisher

The AAPS journal, Vol.18(3), pp.560-572

05/2016

DOI: 10.1208/s12248-016-9899-9

PMCID: PMC5256616

PMID: 27002730

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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.

Neoplasms - metabolism

RGS Proteins - agonists

Receptors, G-Protein-Coupled - metabolism

Humans

Antineoplastic Agents - administration & dosage

Receptors, G-Protein-Coupled - agonists

Cell Transformation, Neoplastic - metabolism

Central Nervous System Diseases - metabolism

Neoplasms - drug therapy

Antineoplastic Agents - metabolism

Animals

Signal Transduction - drug effects

Central Nervous System Diseases - drug therapy

Receptors, G-Protein-Coupled - antagonists & inhibitors

RGS Proteins - metabolism

Signal Transduction - physiology

RGS Proteins - antagonists & inhibitors

Cell Transformation, Neoplastic - drug effects

Drug Delivery Systems - methods

Details

Title: Subtitle: RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer
Creators: Katelin E Ahlers - 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
Bandana Chakravarti - 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 A Fisher - 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
Resource Type: Journal article
Publication Details: The AAPS journal, Vol.18(3), pp.560-572
DOI: 10.1208/s12248-016-9899-9
PMID: 27002730
PMCID: PMC5256616
NLM abbreviation: AAPS J
ISSN: 1550-7416
eISSN: 1550-7416
Publisher: United States
Grant note: CA161882 / NCI NIH HHS R01 CA161882 / NCI NIH HHS
Language: English
Date published: 05/2016
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040008302771

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