title: MicroRNA 17-92 cluster mediates ETS1 and ETS2-dependent RAS-oncogenic transformation.
abstract: The ETS-family transcription factors Ets1 and Ets2 are evolutionarily conserved effectors of the RAS/ERK signaling pathway, but their function in Ras cellular transformation and biology remains unclear. Taking advantage of Ets1 and Ets2 mouse models to generate Ets1/Ets2 double knockout mouse embryonic fibroblasts, we demonstrate that deletion of both Ets1 and Ets2 was necessary to inhibit HrasG12V induced transformation both in vitro and in vivo. HrasG12V expression in mouse embryonic fibroblasts increased ETS1 and ETS2 expression and binding to cis-regulatory elements on the c-Myc proximal promoter, and consequently induced a robust increase in MYC expression. The expression of the oncogenic microRNA 17-92 cluster was increased in HrasG12V transformed cells, but was significantly reduced when ETS1 and ETS2 were absent. MYC and ETS1 or ETS2 collaborated to increase expression of the oncogenic microRNA 17-92 cluster in HrasG12V transformed cells. Enforced expression of exogenous MYC or microRNA 17-92 rescued HrasG12V transformation in Ets1/Ets2-null cells, revealing a direct function for MYC and microRNA 17-92 in ETS1/ETS2-dependent HrasG12V transformation.
authors: Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America; Graduate Program in Molecular Cellular and Developmental Biology, The Ohio State University, Columbus, Ohio, United States of America; Solid Tumor Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.
authors: Mohamed
authors: M
authors: Kabbout
authors: Graduate Program in Molecular Cellular and Developmental Biology, The Ohio State University, Columbus, Ohio, United States of America; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.
authors: Duaa
authors: D
authors: Dakhlallah
authors: Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America; Solid Tumor Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.
authors: Sudarshana
authors: S
authors: Sharma
authors: Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America; Solid Tumor Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.
authors: Agnieszka
authors: A
authors: Bronisz
authors: Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America; Graduate Program in Molecular Cellular and Developmental Biology, The Ohio State University, Columbus, Ohio, United States of America; Solid Tumor Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.
authors: Ruchika
authors: R
authors: Srinivasan
authors: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America; Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors: Melissa
authors: M
authors: Piper
authors: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America; Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors: Clay B
authors: CB
authors: Marsh
authors: Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America; Solid Tumor Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.
authors: Michael C
authors: MC
authors: Ostrowski
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D055786:Gene Knockout Techniques; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D050784:Proto-Oncogene Protein c-ets-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050787:Proto-Oncogene Protein c-ets-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D050784:Proto-Oncogene Protein c-ets-1; D050787:Proto-Oncogene Protein c-ets-2; D016271:Proto-Oncogene Proteins c-myc; D015689:Oncogene Protein p21(ras)