title: Deletion and altered regulation of p16INK4a and p15INK4b in undifferentiated mouse skin tumors.
abstract: p16INK4a and p15INK4b are cell cycle regulators that specifically bind to and inhibit the cyclin D-dependent kinases, cdk4 and cdk6. Because these genes undergo frequent deletions and/or mutations in various human cancers, we examined the status and expression of the cognate mouse cdk inhibitors in a panel of 29 cell lines, as well as in 12 primary tumors, representing different stages of mouse skin carcinogenesis. Deletion of p16INK4a and/or p15INK4b was seen in 8 of 10 cell lines derived from spindle carcinomas, the most advanced stage of skin carcinogenesis. Five showed deletion of both genes, and three had independent deletions of p16INK4a or p15INK4b, but in those retaining p16INK4a, expression of the protein was not detected. By contrast, none of 19 more differentiated squamous cell lines exhibited such deletions. In several cases, primary tumor DNA was available, and two spindle tumors showed the same deletion pattern as observed in the corresponding cell lines. In apparent contrast, comparison of two clonally related squamous and spindle cell lines derived from a single carcinoma showed unusually high levels of p16INK4a and p15INK4b only in the invasive spindle cells. Therefore, deletion or altered regulation of p16INK4a and p15INK4b occur concomitantly with the loss of differentiation associated with the late spindle stage of tumor progression in mouse skin.
authors.affiliation: Cancer Research Campaign Beatson Laboratories, University of Glasgow, Department of Medical Oncology, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Linardopoulos
authors.forename: A J
authors.initials: AJ
authors.lastname: Street
authors.forename: D E
authors.initials: DE
authors.lastname: Quelle
authors.forename: D
authors.initials: D
authors.lastname: Parry
authors.forename: G
authors.initials: G
authors.lastname: Peters
authors.forename: C J
authors.initials: CJ
authors.lastname: Sherr
authors.forename: A
authors.initials: A
authors.lastname: Balmain
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D047428:Protein Kinase Inhibitors; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: C493966:CDKN2B protein, human; D002352:Carrier Proteins; C493968:Cdkn2b protein, mouse; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D047428:Protein Kinase Inhibitors; D025521:Tumor Suppressor Proteins