Lack of mutation in the cyclin-dependent kinase inhibitor, p19INK4d, in tumor-derived cell lines and primary tumors.
Inhibitors of cyclin-dependent kinases provide a major mechanism of negative regulation on cell cycle progression. Defects in the function of the CDK inhibitors may lead to uncontrolled cell proliferation and potentially facilitate tumorigenesis. The p16INK4 family of CDK inhibitors specifically prevent the phosphorylation of the retinoblastoma susceptibility gene product, pRb, by inhibiting the kinase activity of CDK4 and CDK6, thereby keeping pRb in its active form as a growth suppressor. The loss of p16INK4 inhibitory activity would, therefore, have the same consequence as the loss of pRb growth suppressing activity. The p16INK4 family currently includes four members, p15INK4b, pl6INK4a, pl8INK4c and p19INK4d. Two members, p15INK4b and pl6INK4a have been found to be deleted and mutated in a variety of human tumor-derived cell lines and primary tumors. In the present study we have examined the genomic status of the newly isolated p19INK4d gene in 75 tumor-derived cell lines; 13 immortalized, transformed or normal cell lines; 19 ovarian tumors and 18 acute myelogenous leukemias. No deletions or point mutations were observed in the pl9INK4d gene. A genetic polymorphism at codon 30 (CGC-->CGG) in exon 1 of the pl9INK4d gene was observed in 10% of the samples under investigation. In the same set of samples, p16INK4a was found to be homozygously deleted in 32% of the tumor derived cell lines. These results together with our previous data that showed a 22% deletion frequency in p15INK4b and rare alterations in the pl8INK4c gene, indicating that the p16INK4a and pl5INK4b, but not the p18INK4c and pl9INK4d genes, are frequently mutated in human tumors. Hence, members of the p16INK4 CDK inhibitor family, while evolutionary related and biochemically indistinguishable, carry out distinct biological functions.
Zariwala
M
M
Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, 27599-3280, USA.
Xiong
Y
Y
D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D002460:Cell Line; D002461:Cell Line, Transformed; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D050764:Cyclin-Dependent Kinase Inhibitor p19; D004791:Enzyme Inhibitors; D005260:Female; D005347:Fibroblasts; D017353:Gene Deletion; D006720:Homozygote; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
C493966:CDKN2B protein, human; C493971:CDKN2C protein, human; C493974:CDKN2D protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D050764:Cyclin-Dependent Kinase Inhibitor p19; D004791:Enzyme Inhibitors; D025521:Tumor Suppressor Proteins