Shifting p53-induced senescence to cell death by TIS21/BTG2/Pc3 gene through posttranslational modification of p53 protein

• Published in: Cellular signalling 2016-09, Vol.28 (9), p.1172-1185
• Main Authors: Choi, Ok Ran, Ryu, Min Sook, Lim, In Kyoung
• Format: Article
• Language: English
• Subjects: Bcl2; miR34a; p53-K-acetylations; p53-S46 phosphorylation; Proapoptotic genes; SIRT1
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2016.05.014

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. •TIS21 plays an endogenous inducer of cell death at the downstream of p53 gene.•TIS21 induces S46 phosphorylation of p53 protein.•TIS21 induces lysine acetylations of p53 protein.•TIS21-enhanced miR34a expression downregulates SIRT1 expression.•TIS21 triggers transcription of proapoptotic genes by p53 protein.