title: Shifting p53-induced senescence to cell death by TIS21(/BTG2/Pc3) gene through posttranslational modification of p53 protein.
abstract: Cellular senescence and apoptosis can be regulated by p53 activity, although the underlying mechanism of the switch between the two events remains largely unknown. Cells exposed to cancer chemotherapy can escape to senescence phenotype rather than undergoing apoptosis. By employing adenoviral transduction of p53 or TIS21 genes, we observed shifting of p53 induced-senescence to apoptosis in EJ bladder cancer cells, which express H-RasV12 and mutant p53; transduction of p53 increased H-RasV12 expression along with senescence phenotypes, whereas coexpression with TIS21 (p53+TIS21) induced cell death rather than senescence. The TIS21-mediated switch of senescence to apoptosis was accompanied by nuclear translocation of p53 protein and its modifications on Ser-15 and Ser-46 phosphorylation and acetylations on Lys-120, -320, -373 and -382 residues. Mechanistically, TIS21(/BTG2) regulated posttranslational modification of p53 via enhancing miR34a and Bax expressions as opposed to inhibiting SIRT1 and Bcl2 expression. At the same time, TIS21 increased APAF-1 and p53AIP1 expressions, but inhibited the interaction of p53 with iASPP. In vitro tumorigenicity was significantly reduced in the p53+TIS21 expresser through inhibiting micro-colony proliferation by TIS21. Effect of TIS21 on the regulation of p53 activity was confirmed by knockdown of TIS21 expression by RNA interference. Therefore, we suggest TIS21 expression as an endogenous cell death inducer at the downstream of p53 gene, which might be useful for intractable cancer chemotherapy.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine and Graduate School of Medical Sciences, Ajou University, Suwon 16499, Republic of Korea.
authors.forename: Ok Ran
authors.initials: OR
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine and Graduate School of Medical Sciences, Ajou University, Suwon 16499, Republic of Korea.
authors.forename: Min Sook
authors.initials: MS
authors.lastname: Ryu
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine and Graduate School of Medical Sciences, Ajou University, Suwon 16499, Republic of Korea. Electronic address: iklim@ajou.ac.kr.
authors.forename: In Kyoung
authors.initials: IK
authors.lastname: Lim
mesh_terms: D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D016923:Cell Death; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D016922:Cellular Senescence; D015536:Down-Regulation / Q000235:genetics; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D017874:Immediate-Early Proteins; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070114:BTG2 protein, human; D056564:Sirtuin 1
keywords: Bcl2; Proapoptotic genes; SIRT1; miR34a; p53-K-acetylations; p53-S(46) phosphorylation