title: p16(INK4a) and p53 deficiency cooperate in tumorigenesis.
abstract: The combined impact of mutations in p16(INK4a) and p53 was examined in cellular growth,transformation, and tumor formation. In cultured cells, p16(INK4a) loss enhanced growth at high density and conferred susceptibility to oncogene-induced transformation. In vivo, mice doubly deficient for p16(INK4a) and p53 showed an increased rate of tumor formation with particular susceptibility to aggressive angiosarcomas. Furthermore, p16(INK4a) silencing by promoter methylation was detected in tumors derived from p16(INK4a+/-) and (+/+) mice, independent of p53 status. These data suggest at least one general feature of malignancy, resistance to density-mediated growth arrest depends on p16(INK4a) rather than p53. This cooperation between p16(INK4a) and p53 loss in tumorigenesis is consistent with the view that these genes function in distinct anticancer pathways.
authors.affiliation: Department of Adult Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street (M413), Boston, MA 02115, USA.
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
authors.forename: Scott
authors.initials: S
authors.lastname: Alson
authors.forename: Suzanne
authors.initials: S
authors.lastname: Chan
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Silver
authors.forename: Diego H
authors.initials: DH
authors.lastname: Castrillon
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: D000818:Animals; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency* / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53