title: p53 promotes selection for Fas-mediated apoptotic resistance.
abstract: Although p53 inactivation is implicated as a mechanism to explain diminished apoptotic response, it is clear that tumor cells that possess transcriptionally functional p53 can also be resistant to diverse apoptotic stimuli. We hypothesize that oncogenic activation and DNA damage are sufficient stimuli to increase the p53-dependent transcription of Fas and thereby establish a situation in which cell to cell contact could be a selective pressure to either lose p53 function or inactivate components of the Fas death pathway. Examination of genetically matched tumor cell lines that possessed either wild-type or null p53 loci indicated that cells possessing functional p53 increased their surface levels of Fas and Fas ligand (FasL) in response to DNA damage. In contrast, stress induced by changes in the tumor microenvironment such as decreased oxygen did not up-regulate Fas or FasL. Cells with wild-type p53 underwent Fas-mediated killing in the presence of either FasL-expressing killer cells or activating Fas antibodies, whereas cells in which p53 was deleted or inactivated were protected from such killing. Furthermore, Fas and FasL expression and induction became transcriptionally repressed in transformed cells with wild-type p53 with increasing passage, whereas other p53 downstream targets and functions, such as p21 inducibility and cell cycle arrest, remained intact. Repression of the Fas locus could be reverted by treatment with the histone deacetylase inhibitor trichostatin A. These results support a model of tumor progression in which oncogenic transformation drives tumor cells to lose either p53 or their Fas sensitivity as a means of promoting their survival and evade immune surveillance.
authors.affiliation: Department of Radiation Oncology, Stanford University Medical Center, California 94305-5468, USA.
authors.forename: H L
authors.initials: HL
authors.lastname: Maecker
authors.forename: C
authors.initials: C
authors.lastname: Koumenis
authors.forename: A J
authors.initials: AJ
authors.lastname: Giaccia
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology / Q000528:radiation effects; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019014:fas Receptor / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; C012589:trichostatin A