p14(ARF) inhibits the functions of adenovirus E1A oncoprotein.
The tumour suppressor ARF (alternative reading frame) is one of the most important oncogenic stress sensors. ARF provides an 'oncogenic checkpoint' function through both p53-dependent and p53-independent mechanisms. In the present study, we demonstrate a novel p53-independent interaction between p14(ARF) and the adenovirus oncoprotein E1A. p14(ARF) inhibits E1A transcriptional function and promotes ubiquitination-dependent degradation of E1A. p14(ARF) overexpression relocalizes E1A into the nucleolus and inhibits E1A-induced cellular DNA replication independent of p53. Knockdown of endogenous p14(ARF) increases E1A transactivation. In addition, E1A can competitively inhibit ARF-Mdm2 (murine double minute 2) complex formation. These results identify a novel binding partner of p14(ARF) and reveal a mutually inhibitory interaction between p14(ARF) and E1A. We speculate that the ARF-E1A interaction may represent an additional host defence mechanism to limit viral replication. Alternatively, the interaction may allow adenovirus to sense the functional state of p53 in host cells, and fine-tune its own replication activity to prevent the triggering of a detrimental host response.
Institute of Biomedical Sciences, College of Life Science, East China Normal University, Shanghai 200241, PR China.
Jia
J
Shen
Shengping
S
Zhang
Yang
Y
Li
Wen
W
Zhang
Jiandong
J
Chen
Mary
M
Zhang
Ting
T
Wang
Ling
L
Jiang
Xiuqun
X
Zou
Jiemin
J
Wong
Xiaotao
X
Li
Yongping
Y
Cui
Chuangui
C
Wang
D017500:Adenovirus E1A Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D004261:DNA Replication; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000502:physiology
D017500:Adenovirus E1A Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2