title: Siva1 inhibits p53 function by acting as an ARF E3 ubiquitin ligase.
abstract: The tumour suppressor alternative reading frame (ARF) is one of the most frequently mutated proteins in human cancer. It has been well established that ARF is able to stabilize and activate p53 by directly inhibiting Mdm2. ARF-mediated p53 activation in response to oncogenic stress is thought to be an important determinant of protection against cancer. However, little is known regarding the control of ARF in cells. Here, we show that Siva1 is a specific E3 ubiquitin ligase of ARF. Siva1 physically interacts with ARF both in vitro and in vivo. Through direct interaction, Siva1 promotes the ubiquitination and degradation of ARF, which in turn affects the stability of p53. Functionally, Siva1 regulates cell cycle progression and cell proliferation in an ARF/p53-dependent manner. Our results uncover a novel regulatory mechanism for the control of ARF stability, thereby revealing an important function of Siva1 in the regulation of the ARF-Mdm2-p53 pathway.
authors: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors: Xingwu
authors: X
authors: Wang
authors: Meng
authors: M
authors: Zha
authors: Xiaocheng
authors: X
authors: Zhao
authors: Peng
authors: P
authors: Jiang
authors: Wenjing
authors: W
authors: Du
authors: Andrew Y H
authors: AY
authors: Tam
authors: Yide
authors: Y
authors: Mei
authors: Mian
authors: M
authors: Wu
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000172:deficiency / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D025803:Tumor Suppressor Protein p14ARF / Q000737:chemistry / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D051017:Apoptosis Regulatory Proteins; D050505:Mutant Proteins; C106549:SIVA1 protein, human; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases