title: NMI mediates transcription-independent ARF regulation in response to cellular stresses.
abstract: The ARF tumor suppressor is a product of the INK4a/ARF locus, which is frequently mutated in human cancer. The expression of ARF is up-regulated in response to certain types of DNA damage, oncogene activation, and interferon stimuli. Through interaction with the p53 negative regulator MDM2, ARF controls a well-described p53/MDM2-dependent checkpoint. However, the mechanism of ARF induction is poorly understood. Using a yeast two-hybrid screen, we identify a novel ARF-interacting protein, N-Myc and STATs interactor (NMI). Previously, NMI was known to be a c-Myc-interacting protein. Here we demonstrate that through competitive binding to the ARF ubiquitin E3 ligase (ubiquitin ligase for ARF [ULF]), NMI protects ARF from ULF-mediated ubiquitin degradation. In response to cellular stresses, NMI is induced, and a fraction of NMI is translocated to the nucleus to stabilize ARF. Thus our work reveals a novel NMI-mediated, transcription-independent ARF induction pathway in response to cellular stresses.
authors.affiliation: State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Zengpeng
authors.initials: Z
authors.lastname: Li
authors.forename: Jingjing
authors.initials: J
authors.lastname: Hou
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Taoyong
authors.initials: T
authors.lastname: Wen
authors.forename: Liqin
authors.initials: L
authors.lastname: Wang
authors.forename: Xinmeng
authors.initials: X
authors.lastname: Zhao
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Xie
authors.forename: Si Qing
authors.initials: SQ
authors.lastname: Zhang
mesh_terms: D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C099927:NMI protein, human; C495901:TP53 protein, human; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases