p14ARF interacts with E2F factors to form p14ARF-E2F/partner-DNA complexes repressing E2F-dependent transcription.
Primarily, E2F factors such as E2F1, -2, and -3 stimulate cell-cycle progression, while ARF tumor suppressor mediates growth suppression. The ARF gene can be induced by oncogenic signal through activating E2F-dependent transcription. In turn, ARF may target E2F for its degradation via a p53-dependent mechanism. However, it remains unclear how the cell keeps the balance between the functional opposites of E2F and ARF. In this study, we demonstrate that p14ARF interacts with E2F1-3 factors to directly repress their transcriptional activities through forming p14ARF-E2F/partner-DNA super complexes, regardless of E2F protein degradation. The inhibition of E2F transcriptional activities by p14ARF in this manner occurs commonly in a variety of cell types, including p53-deficient and p53-wild type cells. Thus, E2F-mediated activation of the ARF gene and ARF-mediated functional inhibition of E2F compose a feedback loop, by which the two opposites act in concert to regulate cell proliferation and apoptosis, depending on the cellular context and the environment.
Zhang
Hai-Jun
HJ
Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, PR China.
Li
Wen-Juan
WJ
Gu
Yan-Yan
YY
Li
Shu-Yan
SY
An
Guo-Shun
GS
Ni
Ju-Hua
JH
Jia
Hong-Ti
HT
D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004247:DNA / Q000378:metabolism*; D050684:E2F Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D006801:Humans; D014158:Transcription, Genetic; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53
D050684:E2F Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D004247:DNA