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Regulator of G protein signaling 6 (RGS6) induces apoptosis via a mitochondrial-dependent pathway not involving its GTPase-activating protein activity
Journal article   Open access   Peer reviewed

Regulator of G protein signaling 6 (RGS6) induces apoptosis via a mitochondrial-dependent pathway not involving its GTPase-activating protein activity

Biswanath Maity, Jianqi Yang, Jie Huang, Ryan W Askeland, Soumen Bera and Rory A Fisher
The Journal of biological chemistry, Vol.286(2), pp.1409-1419
01/14/2011
DOI: 10.1074/jbc.M110.186700
PMCID: PMC3020749
PMID: 21041304
url
https://doi.org/10.1074/jbc.M110.186700View
Published (Version of record) Open Access

Abstract

Regulator of G protein signaling 6 (RGS6) is a member of a family of proteins called RGS proteins, which function as GTPase-activating proteins (GAPs) for Gα subunits. Given the role of RGS6 as a G protein GAP, the link between G protein activation and cancer, and a reduction of cancer risk in humans expressing a RGS6 SNP leading to its increased translation, we hypothesized that RGS6 might function to inhibit growth of cancer cells. Here, we show a marked down-regulation of RGS6 in human mammary ductal epithelial cells that correlates with the progression of their transformation. RGS6 exhibited impressive antiproliferative actions in breast cancer cells, including inhibition of cell growth and colony formation and induction of cell cycle arrest and apoptosis by mechanisms independent of p53. RGS6 activated the intrinsic pathway of apoptosis involving regulation of Bax/Bcl-2, mitochondrial outer membrane permeabilization (MOMP), cytochrome c release, activation of caspases-3 and -9, and poly(ADP-ribose) polymerase cleavage. RGS6 promoted loss of mitochondrial membrane potential (ΔΨ(m)) and increases in reactive oxygen species (ROS). RGS6-induced caspase activation and loss of ΔΨ(m) was mediated by ROS, suggesting an amplification loop in which ROS provided a feed forward signal to induce MOMP, caspase activation, and cell death. Loss of RGS6 in mouse embryonic fibroblasts dramatically impaired doxorubicin-induced growth suppression and apoptosis. Surprisingly, RGS6-induced apoptosis in both breast cancer cells and mouse embryonic fibroblasts does not require its GAP activity toward G proteins. This work demonstrates a novel signaling action of RGS6 in cell death pathways and identifies it as a possible therapeutic target for treatment of breast cancer.
 RGS Proteins - genetics Reactive Oxygen Species - metabolism Carcinoma, Ductal - pathology Humans Molecular Sequence Data Mitochondria - metabolism GTPase-Activating Proteins - metabolism Cell Transformation, Neoplastic - metabolism Breast Neoplasms - metabolism Cell Division - physiology Animals Breast Neoplasms - pathology Cell Line, Tumor Membrane Potential, Mitochondrial - physiology RGS Proteins - metabolism Female Signal Transduction - physiology Carcinoma, Ductal - metabolism Fibroblasts - cytology Mice Apoptosis - physiology Gene Expression Regulation, Neoplastic - physiology Fibroblasts - metabolism

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