title: Docetaxel and 5-fluorouracil induce human p53 tumor suppressor gene transcription via a short sequence at core promoter element.
abstract: The p53 tumor suppressor protein is involved in cellular defense against agents that can cause genetic damage. Induction of p53 gene expression at transcriptional and post-transcriptional levels by such agents results in p53-regulated gene activation or suppression. Docetaxel (DOC), a member of the taxanes family that is widely used in cancer chemotherapy, activates p53 at the transcriptional level. We demonstrated that p53 is induced by low dose DOC treatment, resulting in MDR-1 gene suppression in human lung cancer cells. To identify the cis-element of p53 promoter that responds to DOC, p53 promoter region was cloned and promoter activity was analyzed on luciferase gene reporter assay. Promoter region (-78 to +129) contained the highest basal p53 promoter activity and deletion of +86 to +129 severely reduced basal promoter activity. Basal promoter region included the 21-bp element (PE21) that determines UV-inducible expression of p53 and mediates DOC-inducible p53 expression. On site-specific mutagenesis of PE21 (-78 to -58), with mutation of ATTG (-62 to -59) to CGGT, completely diminished the response to DOC. The same mutations also inhibited 5-fluorouracil (5-FU)-inducible p53 expression. Our data revealed that a sequence located at PE21 of p53 core promoter regulates p53 induction by chemotherapeutic agents.
authors.affiliation: Department of Pharmacy, Pojen General Hospital No. 66, Kwang Fu N. Road, Taipei City 105, Taiwan. giuanchuan@pojengh.com.tw
authors.forename: Jui-Chuan
authors.initials: JC
authors.lastname: Chuang
authors.forename: Gwo-Tarng
authors.initials: GT
authors.lastname: Sheu
authors.forename: Pi-Chieh
authors.initials: PC
authors.lastname: Wang
authors.forename: Fu-Tien
authors.initials: FT
authors.lastname: Liao
authors.forename: Wen-Shan
authors.initials: WS
authors.lastname: Liu
authors.forename: Chuan-Fu
authors.initials: CF
authors.lastname: Huang
authors.forename: Mei-Hui
authors.initials: MH
authors.lastname: Tseng
authors.forename: Ming-Fang
authors.initials: MF
authors.lastname: Wu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D005472:Fluorouracil / Q000494:pharmacology*; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D043823:Taxoids / Q000494:pharmacology*; D014158:Transcription, Genetic
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D005472:Fluorouracil