title: Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway.
abstract: 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.
authors.affiliation: Tumor Biology Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey, NJ 07033, USA.
authors.forename: Asra
authors.initials: A
authors.lastname: Mirza
authors.forename: Marnie
authors.initials: M
authors.lastname: McGuirk
authors.forename: Tish N
authors.initials: TN
authors.lastname: Hockenberry
authors.forename: Qun
authors.initials: Q
authors.lastname: Wu
authors.forename: Hena
authors.initials: H
authors.lastname: Ashar
authors.forename: Stuart
authors.initials: S
authors.lastname: Black
authors.forename: Shu Fen
authors.initials: SF
authors.lastname: Wen
authors.forename: Luquan
authors.initials: L
authors.lastname: Wang
authors.forename: Paul
authors.initials: P
authors.lastname: Kirschmeier
authors.forename: W Robert
authors.initials: WR
authors.lastname: Bishop
authors.forename: Loretta L
authors.initials: LL
authors.lastname: Nielsen
authors.forename: Cecil B
authors.initials: CB
authors.lastname: Pickett
authors.forename: Suxing
authors.initials: S
authors.lastname: Liu
mesh_terms: 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
chemical_list: 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