title: p53 regulates FAK expression in human tumor cells.
abstract: Attenuation of the p53 protein is one of the most common abnormalities in human tumors. Another important marker of tumorigenesis is focal adhesion kinase (FAK), a 125-kDa tyrosine kinase that is overexpressed at the mRNA and protein levels in a variety of human tumors. FAK is a critical regulator of adhesion, motility, metastasis, and survival signaling. We have characterized the FAK promoter and demonstrated that p53 can inhibit the FAK promoter activity in vitro. In the present study, we showed that p53 can bind the FAK promoter-chromatin region in vivo by chromatin immunoprecipitation (ChIP) assay. Furthermore, we demonstrated down-regulation of FAK mRNA and protein levels by adenoviral overexpression of p53. We introduced plasmids with different mutations in the DNA-binding domain of p53 (R175H, p53 R248W and R273H) into HCTp53(-/-) cells and showed that these mutations of p53 did not bind FAK promoter and did not inhibit FAK promoter activity, unlike wild type p53. We analyzed primary breast and colon cancers for p53 mutations and FAK expression, and showed that FAK expression was increased in tumors containing mutations of p53 compared to tumors with wild type p53. In addition, tumor-derived missense mutations in the DNA-binding domain (R282, R249, and V173) also led to increased FAK promoter activity. Thus, the present data show that p53 can regulate FAK expression during tumorigenesis.
authors.affiliation: Department of Surgery, University of Florida, Gainesville, USA.
authors.forename: Vita M
authors.initials: VM
authors.lastname: Golubovskaya
authors.forename: Richard
authors.initials: R
authors.lastname: Finch
authors.forename: Frederick
authors.initials: F
authors.lastname: Kweh
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Massoll
authors.forename: Martha
authors.initials: M
authors.lastname: Campbell-Thompson
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wallace
authors.forename: William G
authors.initials: WG
authors.lastname: Cance
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D019656:Loss of Heterozygosity; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D008156:Luciferases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005472:Fluorouracil