title: RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated Dnmt1 degradation and promoting apoptosis.
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.
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Stewart
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Maity
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hagen
authors.affiliation: Department of Biochemistry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Fagan
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Quelle
authors.affiliation: Department of Biochemistry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Brenner
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Fisher
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D059748:Proteolysis; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D020710:RGS Proteins / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D020710:RGS Proteins; C485692:Rgs6 protein, mouse; D015534:Trans-Activators; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; D051548:Histone Acetyltransferases; C523065:Kat5 protein, mouse; D000074443:Lysine Acetyltransferase 5; D016283:Proto-Oncogene Proteins p21(ras)