Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factors.
The human ARF/INK4a locus encodes two cell cycle inhibitors, p16(INK4a) and p14(ARF), by using separate promoters. A variety of mitogenic stimuli upregulate ARF but a direct modulation at the transcriptional level has been reported only for E2F-1. We show here that the ARF promoter is strongly responsive also to E2F2 and E2F3, thus providing a strong support to their suggested role in the induction of apoptosis. Through the usage of both deletion mutants and/or site-directed mutants, we surprisingly found that none of the four putative E2F consensus sites is strictly necessary for the upregulation of ARF expression, as a minimal deletion mutant, lacking all the putative E2F binding sites, is still transactivated by E2F. Moreover, our data suggest that the ARF promoter is regulated by E2F through both direct binding to the promoter sequences and indirectly, probably by being tethered to the ARF promoter by Sp1-like factors.
Parisi
Tiziana
T
Department of Genetics, General and Molecular Biology, University of Naples Federico II, via Mezzocannone 8, 80134 Naples, Italy.
Pollice
Alessandra
A
Di Cristofano
Antonio
A
Calabrò
Viola
V
La Mantia
Girolama
G
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D018797:Cell Cycle Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D050703:E2F2 Transcription Factor; C493761:E2F2 protein, human; D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; C493754:E2f1 protein, mouse; C490840:E2f3 protein, mouse; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF