p14ARF regulates E2F-1 ubiquitination and degradation via a p53-dependent mechanism.
Alterations in the ARF tumor suppressor protein (also known as p14ARF in humans and p19ARF in the mouse) occur frequently in cancer and are associated with susceptibility to melanoma, pancreatic cancer and nervous system tumors. ARF proteins interact with the E2F-1, -2 and -3 transcription activators to inhibit their transcriptional activity and induce their degradation via the 26S proteasome pathway. The impact of ARF on the E2F proteins may provide a mechanism for p53-independent ARF activity on cell cycle progression and tumor susceptibility. In this report we explored the effects of ARF on E2F ubiquitination and degradation in relationship to cell cycle effects and p53 status. We now show that ARF induced the rapid ubiquitination and degradation of E2F-1 only in the presence of functional p53. E2F-1 continued to be ubiquitinated following ARF induction in cycling p53-wild-type, p21-null cells, showing that effects of ARF were not simply a result of p14ARF induced cell-cycle arrest. Importantly, these data establish that the ARF-E2F-1 pathway is an extension of the p53-mdm2-ARF tumor suppressor network and is unlikely to constitute a p53-independent pathway for ARF function.
Rizos
Helen
H
Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, Australia. helen_rizos@wmi.usyd.edu.au
Scurr
Lyndee L
LL
Irvine
Mal
M
Alling
Nikki J
NJ
Kefford
Richard F
RF
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D045744:Cell Line, Tumor; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D015398:Signal Transduction / Q000502:physiology; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination
D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin