title: Allele specific gain-of-function activity of p53 mutants in lung cancer cells.
abstract: p53 mutations are mostly single amino acid changes resulting in expression of a stable mutant protein with "gain of function" (GOF) activity having a dominant oncogenic role rather than simple loss of function of wild-type p53. Knock-down of mutant p53 in human lung cancer cell lines with different endogenous p53 mutants results in loss of GOF activity as shown by lowering of cell growth rate. Two lung cancer cell lines, ABC1 and H1437, carrying endogenous mutants p53-P278S and -R267P, show reduction in growth rate on knock-down on p53 levels. However, whereas reduction of the p53 level induces loss of tumorigenicity in nude mice for ABC1 cells, it escalates tumorigenicity for H1437 cells. We have tested their transactivation potential on p53 target gene promoters by performing transient transcriptional assays in the p53-null H1299 lung cancer cell line. Interestingly, while the mutant p53 target promoter Axl was activated by both the mutants, the p21 promoter was activated by p53-R267P and wild-type p53 but not by p53-P278S; showing a clear difference in transcriptional activity between the two mutants. Our results demonstrate allele specificity between GOF p53 mutants and attempt to show that the specificity is dependent on the transactivation property of GOF p53; it also suggests importance of p21 activation in tumor suppression by p53.
authors.affiliation: Department of Biochemistry & Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Vaughan
authors.forename: Rebecca
authors.initials: R
authors.lastname: Frum
authors.forename: Isabella
authors.initials: I
authors.lastname: Pearsall
authors.forename: Shilpa
authors.initials: S
authors.lastname: Singh
authors.forename: Brad
authors.initials: B
authors.lastname: Windle
authors.forename: Andrew
authors.initials: A
authors.lastname: Yeudall
authors.forename: Swati P
authors.initials: SP
authors.lastname: Deb
authors.forename: Sumitra
authors.initials: S
authors.lastname: Deb
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D016158:Genes, p53 / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D013489:Suppression, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology*; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D000094963:Axl Receptor Tyrosine Kinase