title: Mammalian cells resistant to tumor suppressor genes.
abstract: Expression of p53 causes growth arrest or apoptosis in many normal and neoplastic cell types, but the relationship between these two effects has remained obscure. To begin to dissect the underlying mechanisms at a genetic level, we have generated mutant cells resistant to the action of wild-type p53. Rat embryo fibroblasts transformed with ras and a temperature-sensitive p53 (tsp53(135val)) gene were chemically mutagenized and selected for growth at a temperature at which p53 adopts a wild-type conformation (31.5 degrees C). Clones that grew exponentially at 31.5 degrees C were selected. Cell fusion experiments demonstrated that the mutations conferring resistance to p53-mediated growth arrest were dominant. The mutagenized clones were resistant not only to p53-mediated growth arrest, but also to the apoptosis induced by E1A in conjunction with p53, and partially resistant to the retinoblastoma tumor suppressor, pRB. The results suggest that a single downstream pathway can control the induction of growth arrest and apoptosis, and that both p53 and RB function through this pathway.
authors.affiliation: Howard Hughes Medical Institute, Johns Hopkins Oncology Center, Baltimore, MD 21231, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Pietenpol
authors.forename: C
authors.initials: C
authors.lastname: Lengauer
authors.forename: J
authors.initials: J
authors.lastname: Jordan
authors.forename: K W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: B
authors.initials: B
authors.lastname: Vogelstein
mesh_terms: D017500:Adenovirus E1A Proteins / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004249:DNA Damage; D005799:Genes, Dominant; D016147:Genes, Tumor Suppressor; D009154:Mutation; D051381:Rats; D016160:Retinoblastoma Protein / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D017500:Adenovirus E1A Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53