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Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials.

ABSTRACT: G protein-coupled receptors (GPCRs) play critical roles in regulating processes such as cellular homeostasis, responses to stimuli, and cell signaling. Accordingly, GPCRs have long served as extraordinarily successful drug targets. It is therefore not surprising that the discovery in the mid-1990s of a family of proteins that regulate processes downstream of GPCRs generated great excitement in the field. This finding enhanced the understanding of these critical signaling pathways and provided potentially new targets for pharmacological intervention. These regulators of G-protein signaling (RGS) proteins were viewed by many as nodes downstream of GPCRs that could be targeted with small molecules to tune signaling processes. In this review, we provide a brief overview of the discovery of RGS proteins and of the gradual and continuing discovery of their roles in disease states, focusing particularly on cancer and neurological disorders. We also discuss high-throughput screening efforts that have led to the discovery first of peptide-based and then of small-molecule inhibitors targeting a subset of the RGS proteins. We explore the unique mechanisms of RGS inhibition these chemical tools have revealed and highlight the most up-to-date studies using these tools in animal experiments. Finally, we discuss the future opportunities in the field, as there are clearly more avenues left to be explored and potentials to be realized.

SUBMITTER: O'Brien JB

PROVIDER: S-EPMC6901330 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials.

O'Brien Joseph B JB Wilkinson Joshua C JC Roman David L DL

The Journal of biological chemistry 20191021 49

G protein-coupled receptors (GPCRs) play critical roles in regulating processes such as cellular homeostasis, responses to stimuli, and cell signaling. Accordingly, GPCRs have long served as extraordinarily successful drug targets. It is therefore not surprising that the discovery in the mid-1990s of a family of proteins that regulate processes downstream of GPCRs generated great excitement in the field. This finding enhanced the understanding of these critical signaling pathways and provided po ...[more]

PMID: 31636120

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Project description:BackgroundAlterations in the regulator of G-protein signaling (RGS) pathway have been implicated in several cancers; therefore, the authors investigated the role of such alterations in overall bladder cancer risk, recurrence, progression, and survival.MethodsIn this case-control series, 803 patients with bladder cancer were frequency-matched with a control cohort of 803 healthy individuals. Ninety-five single-nucleotide polymorphisms (SNPs) in 17 RGS genes were investigated for an association with overall bladder cancer risk, recurrence, and progression in patients who had nonmuscle-invasive bladder cancer (NMIBC) and for an association with death in patients who had muscle-invasive bladder cancer (MIBC). Cumulative effects and classification and regression tree analyses were performed for SNPs that were associated with overall bladder cancer risk. Kaplan-Meier plots were created to evaluate differences in the survival of patients with MIBC.ResultsReference SNP 10759 (rs10759) on the RGS4 gene demonstrated the greatest association with overall bladder cancer risk, conferring a 0.77-fold reduced risk with an increasing number of variant alleles (P < .001). A cumulative effects analysis that included all 5 significant SNPs demonstrated an increasing risk with the number of unfavorable genotypes (odds ratio, 4.13; 95% confidence interval, 2.14-7.98). In patients with NMIBC, 11 SNPs were identified that had an association with disease recurrence, and 13 SNPs were associated with disease progression. Of the 10 SNPs that were associated with death in patients with MIBC, rs2344673 in an additive model was the most significant and was associated with a decreased median survival of 13.3 months compared with 81.9 months in individuals without a variant allele.ConclusionsGenetic variations in the RGS pathway were associated with the overall risk of bladder cancer, recurrence, and progression in patients with NMIBC and with the risk of death in patients with MIBC.

Dataset Information

Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials.

Publications

Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials.

Similar Datasets

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