p53-R175H mutant gains new function in regulation of doxorubicin-induced apoptosis.
Mutation of tumor suppressor p53 gene gains new function in regulation of DNA damage-induced apoptotic response in tumor cells, which may lead to a poor response in cancer chemotherapy and radiotherapy. Transfection of mutant p53 (R175H) to p53-null osteosarcoma Saos-2 cells suppressed apoptosis induced by doxorubicin (DOX), cisplatin and gamma radiation. Downregulation of caspase-3 but not -8 or -9 basal protein levels was also observed in Saos-2 cells transfected with p53-R175H. After 48 hr of DOX treatment, the rate of procasapse-3 activation into 17 kDa active form was about 3-fold higher in the control cells than that in the p53-R175H counterpart. Gene silencing of p53-R175H expression by p53 siRNA upregulate the procaspase-3 protein level and restored DOX-induced apoptosis in p53-R175H cells. Our results suggest that p53-R175H mutation may gain new function in decreasing DOX-induced apoptotic response through suppression of caspase-3 level and its activation.
Tsang
Wing-pui
WP
Department of Biochemistry, The Chinese University of Hong Kong, Hong Kong, People's Republic of China.
Ho
Franz Y F
FY
Fung
Kwok-pui
KP
Kong
Siu-kai
SK
Kwok
Tim-tak
TT
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis / Q000494:pharmacology; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D020868:Gene Silencing; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D020125:Mutation, Missense; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases