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Oncogene. 2014 Jul 3;33(27):3604-11. doi: 10.1038/onc.2013.324. Epub 2013 Sep 2.

RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated Dnmt1 degradation and promoting apoptosis.

Author information

1
Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
2
Department of Biochemistry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.

Abstract

The RAS protooncogene has a central role in regulation of cell proliferation, and point mutations leading to oncogenic activation of Ras occur in a large number of human cancers. Silencing of tumor-suppressor genes by DNA methyltransferase 1 (Dnmt1) is essential for oncogenic cellular transformation by Ras, and Dnmt1 is overexpressed in numerous human cancers. Here we provide new evidence that the pleiotropic regulator of G protein signaling (RGS) family member RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated degradation of Dmnt1 and promoting apoptosis. Employing mouse embryonic fibroblasts from wild-type and RGS6(-/-) mice, we found that oncogenic Ras induced upregulation of RGS6, which in turn blocked Ras-induced cellular transformation. RGS6 functions to suppress cellular transformation in response to oncogenic Ras by downregulating Dnmt1 protein expression leading to inhibition of Dnmt1-mediated anti-apoptotic activity. Further experiments showed that RGS6 functions as a scaffolding protein for both Dnmt1 and Tip60 and is required for Tip60-mediated acetylation of Dnmt1 and subsequent Dnmt1 ubiquitylation and degradation. The RGS domain of RGS6, known only for its GTPase-activating protein activity toward Gα subunits, was sufficient to mediate Tip60 association with RGS6. This work demonstrates a novel signaling action for RGS6 in negative regulation of oncogene-induced transformation and provides new insights into our understanding of the mechanisms underlying Ras-induced oncogenic transformation and regulation of Dnmt1 expression. Importantly, these findings identify RGS6 as an essential cellular defender against oncogenic stress and a potential therapeutic target for developing new cancer treatments.

PMID:
23995786
PMCID:
PMC4232305
DOI:
10.1038/onc.2013.324
[Indexed for MEDLINE]
Free PMC Article

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