title: Mdm2 links genotoxic stress and metabolism to p53.
abstract: Mouse double minute 2 (Mdm2) gene was isolated from a cDNA library derived from transformed mouse 3T3 cells, and was classified as an oncogene as it confers 3T3 and Rat2 cells tumorigenicity when overexpressed. It encodes a nucleocytoplasmic shuttling ubiquitin E3 ligase, with its main target being tumor suppressor p53, which is mutated in more than 50% of human primary tumors. Mdm2's oncogenic activity is mainly mediated by p53, which is activated by various stresses, especially genotoxic stress, via Atm (ataxia telangiectasia mutated) and Atr (Atm and Rad3-related). Activated p53 inhibits cell proliferation, induces apoptosis or senescence, and maintains genome integrity. Mdm2 is also a target gene of p53 transcription factor. Thus, Mdm2 and p53 form a feedback regulatory loop. External and internal cues, through multiple signaling pathways, can act on Mdm2 to regulate p53 levels and cell proliferation, death, and senescence. This review will focus on how Mdm2 is regulated under genotoxic stress, and by the Akt1-mTOR-S6K1 pathway that is activated by insulin, growth factors, amino acids, or energy status.
authors.affiliation: Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Zhongfeng
authors.initials: Z
authors.lastname: Wang
authors.forename: Baojie
authors.initials: B
authors.lastname: Li
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D016922:Cellular Senescence; D004249:DNA Damage; D004734:Energy Metabolism; D025461:Feedback, Physiological; D015723:Gene Library; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D016159:Tumor Suppressor Protein p53; C559132:March8 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; C546843:mTOR protein, mouse; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases