Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway.
Survivin is an inhibitor of apoptosis protein, which is over-expressed in most tumors. Aberrant expression of survivin and loss of wild-type p53 in many tumors prompted us to investigate a possible link between these two events. Here we show that wild-type p53 represses survivin expression at both mRNA and protein levels. Transient transfection analyses revealed that the expression of wild-type p53, but not mutant p53, was associated with strong repression of the survivin promoter in various cell types. The over-expression of exogenous survivin protein rescues cells from p53-induced apoptosis in a dose-dependent manner, suggesting that loss of survivin mediates, at least, in part the p53-dependent apoptotic pathway. In spite of the presence of two putative p53-binding sites in the survivin promoter, deletion and mutation analyses suggested that neither site is required for transcriptional repression of survivin expression. This was confirmed by chromatin immunoprecipitation assays. Further analyses suggested that the modification of chromatin within the survivin promoter could be a molecular explanation for silencing of survivin gene transcription by p53.
Mirza
Asra
A
Tumor Biology Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey, NJ 07033, USA.
McGuirk
Marnie
M
Hockenberry
Tish N
TN
Wu
Qun
Q
Ashar
Hena
H
Black
Stuart
S
Wen
Shu Fen
SF
Wang
Luquan
L
Kirschmeier
Paul
P
Bishop
W Robert
WR
Nielsen
Loretta L
LL
Pickett
Cecil B
CB
Liu
Suxing
S
D000256:Adenoviridae; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D001483:Base Sequence; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism; D011233:Precipitin Tests; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; C107489:BIRC5 protein, human; D002868:Chromosomal Proteins, Non-Histone; D015853:Cysteine Proteinase Inhibitors; D017931:DNA Primers; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D008156:Luciferases