AP-1 dimers regulate transcription of the p14/p19ARF tumor suppressor gene.
Evidence is accumulating about the role of individual AP-1 components in cell proliferation and transformation. Notably, Ras-mediated transformation is characterized by the upregulation of particular AP-1 members, such as c-Jun and Fra-1. The p14/p19ARF tumor suppressor gene is a key link between oncogenic Ras signaling and the p53 pathway. We explored the involvement of AP-1 dimers in the transcriptional regulation of the p14/p19ARF gene. We demonstrate that both the human and mouse ARF promoters are transcriptional targets of selective AP-1 dimers. The ARF promoter is regulated specifically by AP-1 heterodimers containing Fra-1. Overexpression of c-Jun approximately Fra-1 dimers in primary murine fibroblast cells led to the upregulation of the endogenous ARF protein and growth arrest. Conversely, inhibition of c-Jun or Fra-1 protein levels resulted in decreased ARF expression. In addition, we show that AP-1 dimers cooperate with oncogenic Ras in the transcriptional activation of the p14/p19ARF promoter. Thus, AP-1 heterodimers may contribute to the regulation of ARF expression upon oncogenic signaling.
Ameyar-Zazoua
Maya
M
Unit of Gene Expression and Disease, Department of Developmental Biology, Pasteur Institute, 25, rue du Docteur Roux, 75724 Paris Cedex 15, France.
Wisniewska
Marta B
MB
Bakiri
Latifa
L
Wagner
Erwin F
EF
Yaniv
Moshe
M
Weitzman
Jonathan B
JB
D000818:Animals; D001483:Base Sequence; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D019281:Dimerization; D016147:Genes, Tumor Suppressor; D051379:Mice; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D018808:Transcription Factor AP-1 / Q000737:chemistry / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D018808:Transcription Factor AP-1; D025803:Tumor Suppressor Protein p14ARF