Differential repression of c-myc and cdc2 gene expression by ERF and PE-1/METS.
The molecular mechanisms that control the proliferation and differentiation of specific cell types remain poorly understood. Positive ETS factors play important roles in mediating proliferative responses to Ras/MAPK signaling in many cell types following mitogenic stimulation. PE-1/METS, a member of the ETS-domain family transcription factors that functions as a transcriptional repressor, can block mitogenic responses mediated by positively acting Ets factors. The anti-proliferative functions of PE-1/METS require its interaction with DP103, a multifunctional DEAD-box protein that mediates interactions with corepressor proteins and acts in a cooperative manner with Rb family members and to repress cell cycle control genes. ETS-2 repressor factor (ERF) is structurally related to and also functions as a transcriptional repressor, but endogenous target genes and mechanisms of repression remain unknown. Here, we demonstrate that like PE-1/METS, ERF-mediated repression also requires DP103, and that ERF negatively regulates the c-myc and cdc2 genes. In contrast to PE-1/METS, however, ERF-mediated repression of these genes is inactivated by MAPK signaling through phosphorylation sites that are ERF-specific. Furthermore, constitutive activation of the Ras/MAPK pathway in RAW 264.7 cells transformed by the v-Abelson leukemia virus is associated with constitutive inactivation of ERF in this cell type. We propose that ERF and PE-1/METS function to impose 'repression checkpoints' on a subset of cell cycle control genes that are differentially regulated by growth factor signaling pathways that control proliferation and differentiation and that ERF is targeted for inactivation by transforming oncogenes such as vAbl.
Hester
Kelly D
KD
Biomedical Sciences Graduate Program, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, USA.
Verhelle
Dominique
D
Escoubet-Lozach
Laure
L
Luna
Rosa
R
Rose
David W
DW
Glass
Christopher K
CK
D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics*; D002478:Cells, Cultured; D055541:DEAD Box Protein 20; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects; D016259:Genes, myc; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008954:Models, Biological; D016374:Oncogene Proteins v-abl / Q000502:physiology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
D004268:DNA-Binding Proteins; C107465:ERF protein, human; C088164:ETV3 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D016374:Oncogene Proteins v-abl; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D014157:Transcription Factors; D016203:CDC2 Protein Kinase; C120168:DDX20 protein, human; D055541:DEAD Box Protein 20; D053487:DEAD-box RNA Helicases