E2F and Ras synergize in transcriptionally activating p14ARF expression.
The INK4a/ARF locus, which is frequently inactivated in human tumors, encodes two distinct tumor suppressive proteins, ARF and p16INK4a. ARF stabilizes and activates p53 by negating the effects of mdm2 on p53. Furthermore, its function is not restricted to the p53 pathway and it also inhibits cell proliferation in cells lacking p53. Expression of ARF is up-regulated in response to a number of oncogenic stimuli including E2F1. We show here that while oncogenic Ras does not significantly affect p1(4AR)F expression in normal human cells it activates p1(4AR)F in cells containing deregulated E2F. Moreover, oncogenic Ras and E2F1 synergize in activating p1(4AR)F expression. Activation of p1(4AR)F promoter by E2F1 persists in the absence of the consensus E2F-binding sites in this promoter, indicating that this activation also occurs through non- canonical binding sites. The activation by oncogenic Ras requires both E2F and Sp-1 activity, demonstrating the complex regulation of p14(ARF) in response to oncogenic stimuli.
Berkovich
Eli
E
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovat, Israel.
Lamed
Yocheved
Y
Ginsberg
Doron
D
D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D011905:Genes, ras; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF