RGS (Regulator of G protein Signaling) proteins represent a novel protein family believed to function as GTPase-activating proteins (GAPs) for heterotrimeric G protein 1 subunits, thereby negatively regulating the duration and intensity of G protein signaling. Little is known concerning the precise physiological roles of all but a few RGS proteins, why nearly thirty different mammalian RGS proteins exist if these proteins function only as GAPs, or the role of structural diversity outside of the hallmark RGS domain (RGD) responsible for RGS protein GAP activity. Abberant activation of GPCRs and G proteins has been implicated as a cause of a variety of human cancers. Therefore, it is surprising that RGS proteins have not been considered previously as growth or tumor suppressor proteins. Here we provide new evidence suggesting such a role for a member of the RGS protein family, RGS6, which exists in thirty-six splice forms possessing identical RGDs but structural variations in other protein domains. Humans with an RGS6 polymorphism that increases mRNA translation have a significant reduction in the risk of bladder cancer, and transcripts of RGS6 are down- regulated in various human cancers. Our preliminary data show that RGS6 protein expression is absent or greatly reduced in human glioma and breast cancer relative to normal tissue, and have identified two RGS6 mutants in human glioblastoma cells. Expression of RGS6 in cancer cell lines, which either lack or express aberrant molecular forms RGS6, leads to growth suppression, cell cycle arrest, activation of signaling pathways during DNA damage that prevent proliferation of abnormal cells, and inhibition of growth of tumor xenografts. We hypothesize that RGS6 plays an important role in protecting cells against abnormal proliferation and that its loss or mutation contributes to tumor formation.
Aim 1 will ascertain the role of RGS6 as a tumor suppressor and modulator of DNA damage responses. We will identify how RGS6 gene expression is dysregulated in human cancers and the structural features and protein interactions required for its ability to suppress tumor growth.
Aim 2 will determine the molecular mechanisms by which RGS6 promotes growth arrest and modulates DNA damage signaling in cells. We will identify the structural features of RGS6 and signaling pathways involved in growth suppression, cell cycle arrest and modulation of DNA damage responses by RGS6 and we will test novel functional roles of RGS6 in the nucleus where G proteins are not present.
Aim 3 will determine how global deletion of RGS6 or deletion in mammary tissue or glial cells of mice modulates tumorigenesis. The proposed research would provide new structural and mechanistic insights into the role of RGS6 as a growth suppressor and the biological manifestations of its actions in vivo. This project may implicate RGS6 and other other RGS proteins as gatekeepers to G-protein-dependent tumorigenesis or define novel roles of RGS6 in this process. These studies could contribute to novel approaches in cancer therapy. PROJECT NARRATIVE: This project will study the role of a protein called RGS6 that may function to prevent cancer in humans. Our preliminary results lead us to hypothesize that RGS6 plays an important role in protecting cells against abnormal proliferation and that its loss or mutation contributes to tumors in humans. This work will determine how RGS6 works and will determine the basis for loss of RGS6 expression in human cancers. These studies could contribute to novel approaches in cancer therapy.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CB-J (02))
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Maas, Stefan
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University of Iowa
Schools of Medicine
Iowa City
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Stewart, Adele; Huang, Jie; Fisher, Rory A (2012) RGS Proteins in Heart: Brakes on the Vagus. Front Physiol 3:95
Maity, Biswanath; Stewart, Adele; Yang, Jianqi et al. (2012) Regulator of G protein signaling 6 (RGS6) protein ensures coordination of motor movement by modulating GABAB receptor signaling. J Biol Chem 287:4972-81
Shim, Hoon; Wang, Chih-Ting; Chen, Yen-Lin et al. (2012) Defective retinal depolarizing bipolar cells in regulators of G protein signaling (RGS) 7 and 11 double null mice. J Biol Chem 287:14873-9
Huang, Jie; Yang, Jianqi; Maity, Biswanath et al. (2011) Regulator of G protein signaling 6 mediates doxorubicin-induced ATM and p53 activation by a reactive oxygen species-dependent mechanism. Cancer Res 71:6310-9
Maity, Biswanath; Yang, Jianqi; Huang, Jie et al. (2011) Regulator of G protein signaling 6 (RGS6) induces apoptosis via a mitochondrial-dependent pathway not involving its GTPase-activating protein activity. J Biol Chem 286:1409-19
Freisinger, Christina M; Fisher, Rory A; Slusarski, Diane C (2010) Regulator of g protein signaling 3 modulates wnt5b calcium dynamics and somite patterning. PLoS Genet 6:e1001020
Yang, Jianqi; Huang, Jie; Chatterjee, Tapan K et al. (2010) A novel mechanism involving coordinated regulation of nuclear levels and acetylation of NF-YA and Bcl6 activates RGS4 transcription. J Biol Chem 285:29760-9
Yang, Jianqi; Huang, Jie; Maity, Biswanath et al. (2010) RGS6, a modulator of parasympathetic activation in heart. Circ Res 107:1345-9
Fisher, Rory A (2009) Preface. Prog Mol Biol Transl Sci 86:xiii-xiv
Huang, Jie; Fisher, Rory A (2009) Nuclear trafficking of regulator of G protein signaling proteins and their roles in the nucleus. Prog Mol Biol Transl Sci 86:115-56