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TIS21 shifts H-RasV12 oncogene-induced senescence to apoptosis in EJ bladder cancer cells in a p53 dependent manner

Choi, Ok Ran; Lim, In Kyoung
Department of Biochemistry & Molecular Biology, Ajou University School of Medicine
Here we present steering of wild type p53 (p53) function from induction of senescence to apoptosis by coexpressing antiproliferative gene, TIS21/BTG2/PC3 (TIS21). When p53 and/or TIS21 were transduced to EJ bladder cancer cells containing oncogenic H-RAS and mutant p53, expression of p53+TIS21 significantly enhanced EJ cell death, as opposed to induction of senescence phenotypes by p53. TIS21 mediated shift of p53 function from senescence to apoptosis was supported by the nuclear translocation of p53 and its modifications via phosphorylation on S15 and 46 and acetylation on K120, 320, 373 and 382 residues in the p53+TIS21 expresser than those of the p53 alone. Interestingly, TIS21 significantly reduced HDAC2 and SIRT1 expressions in p53 dependent manner, suggesting the possibility of p53 activation by the changes. Indeed, p53 binding to Bax promoter was increased as opposed to reduced interaction of p53 with iASPP in the p53+TIS21 expresser compared with p53 alone, which resulted in the upregulation of Bax, APAF-1 and p53AIP1 expression. Furthermore, the p53+TIS21 expresser reduced in vitro tumorigenecity of EJ cells than that of the p53 alone in the focus formation and soft agar colony forming assays. Above molecular changes were confirmed by knockdown of TIS21 expression, indicating that TIS21 regulates p53 function in EJ cells. Based on the evidences presented herein, TIS21/BTG2/PC3 upregulated transcriptional activity of p53 via induction of acetylation on lysine residues along with the inhibition of HDAC2 and SIRT1 expression and the reduced interaction of p53 with iASPP, resulting in apoptosis in EJ cells. Considering induction of senescence as a barrier of malignancy, TIS21-induced cell death might be much smart maneuver of cancer treatment to protect carcinogenesis.
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