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/p19(ARF) tumor suppressor gene is a key link between oncogenic Ras signaling and the p53 pathway. We explored the involvement of AP4 dimers in the transcriptional regulation of the P14/p19(ARF) 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 e-Jun similar to 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/p19(ARF) promoter. Thus, AP-1 heterodimers may contribute to the regulation of ARF expression upon oncogenic signaling.