title: Oncogenic Ras-mediated downregulation of Gadd153/CHOP is required for Ras-induced cellular transformation.
abstract: Oncogenic Ras proteins transform cells via multiple downstream signaling cascades that are important for cell proliferation and survival. Gadd153, also known as CHOP, is a growth inhibitory and proapoptotic protein and its expression is upregulated by many agents that induce apoptosis. Here, we report our novel findings that oncogenic Ras downregulates Gadd153 expression at both protein and mRNA levels and that such downregulation occurs, at least in part, via decreases in GADD153 mRNA stability. Gadd153 downregulation is specific to oncogenic Ras since another oncogenic family member R-Ras2/TC21 does not downregulate Gadd153. We further demonstrate that the expression of exogenous Gadd153 interferes with Ras-induced oncogenic transformation, which suggests that downregulation of Gadd153 appears to be an important mechanism by which oncogenic Ras promotes cellular transformation. Thus, oncogenic Ras-mediated cellular transformation also involves downmodulation of important molecules such as Gadd153 that negatively regulate cell growth and survival.
authors.affiliation: Department of Pharmacology, State University of New York, Upstate Medical University, 750 E Adams Street, Syracuse, NY 13210, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Rong
authors.forename: JoAnne
authors.initials: J
authors.lastname: Montalbano
authors.forename: Weixin
authors.initials: W
authors.lastname: Jin
authors.forename: Jennifer
authors.initials: J
authors.lastname: Zhang
authors.forename: Maria
authors.initials: M
authors.lastname: Garling
authors.forename: M Saeed
authors.initials: MS
authors.lastname: Sheikh
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
mesh_terms: D016475:3T3 Cells; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation / Q000187:drug effects; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D015689:Oncogene Protein p21(ras); D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D051742:Transcription Factor CHOP; D014157:Transcription Factors; C497250:Ddit3 protein, mouse