c-Myc represses the proximal promoters of GADD45a and GADD153 by a post-RNA polymerase II recruitment mechanism.
The c-Myc cellular oncogene has diverse activities, including transformation, proliferation, and apoptosis. These activities are dependent on the ability of c-Myc to regulate gene transcription. c-Myc downregulates the GADD45a and GADD153 (DDTI3) genes that are induced in response to genotoxic stresses and that encode protein products with antiproliferative activities. We show that c-Myc represses the expression of GADD45a and GADD153 in response to thapsigargin, a nongenotoxic stress, as well as other endoplasmic reticulum (ER) stress agents. c-Myc represses both the basal expression and the magnitude of ER stress induction of GADD gene transcription. This repression requires the minimal promoter region of GADD45a and GADD153 and is not dependent on the ER stress element or p53-binding sites in the regulatory regions of these genes. Further analysis by chromatin immunoprecipitation shows that c-Myc binds to the minimal promoter region of GADD45a and GADD153 in vivo. c-Myc-associated protein X (Max) is also bound to both GADD gene promoters, whereas c-Myc interacting zinc-finger protein 1 (Miz-1) is bound to the GADD153, but not GADD45a, promoter. RNA polymerase II (RNAPII) is recruited to the GADD gene promoters in the presence and absence of c-Myc, which suggests that c-Myc represses these genes through a post-RNAPII recruitment mechanism.
Barsyte-Lovejoy
Dalia
D
Division of Cellular and Molecular Biology, Ontario Cancer Institute/Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada M5G 2M9.
Mao
Daniel Y L
DY
Penn
Linda Z
LZ
D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000502:physiology; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D012319:RNA Polymerase II / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics*; D000097642:GADD45 Proteins
D022762:CCAAT-Enhancer-Binding Proteins; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D012319:RNA Polymerase II; D012097:Repressor Proteins; D051742:Transcription Factor CHOP; D014157:Transcription Factors; C497249:DDIT3 protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins