The p53-p21(Cip1/WAF1) pathway is necessary for cellular senescence induced by the inhibition of protein kinase CKII in human colon cancer cells.
We have previously shown that the down-regulation of protein kinase CKII activity is tightly associated with cellular senescence of human fibroblast IMR-90 cells. Here, we examined the roles of p53 and p21(Cip1/WAF1) in senescence development induced by CKII inhibition using wild-type, isogenic p53-/- and isogenic p21-/- HCT116 human colon cancer cell lines. A senescent marker appeared after staining for senescence-associated beta-galactosidase activity in wild-type HCT116 cells treated with CKII inhibitor or CKIIalpha siRNA, but this response was almost abolished in p53- or p21(Cip1/WAF1)-null cells. Increased cellular levels of p53 and p21(Cip1/WAF1) protein occurred with the inhibition of CKII. CKII inhibition upregulated p53 and p21(Cip1/WAF1) expression at post-transcriptional level and transcription level, respectively. RB phosphorylation significantly decreased in cells treated with CKII inhibitor. Taken together, this study shows that the activation of the p53-p21(Cip1/WAF1) pathway acts as a major mediator of cellular senescence induced by CKII inhibition.
School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 702-701, Korea.
Ji-Young
JY
Kang
Jin Joo
JJ
Kim
Seok Young
SY
Jang
Young-Seuk
YS
Bae
D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016922:Cellular Senescence; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D047390:Casein Kinase II