p16 proteins from melanoma-prone families are deficient in binding to Cdk4.
The tumor suppressor candidate p16INK4 is a cyclin-dependent kinase inhibitor that inhibits cell proliferation. The p16 coding gene is often mutated in glioblastomas, pancreatic adenocarcinomas and melanoma-prone pedigrees, but, until recently, the significance of these allelic variants has remained unclear. Here, we used interaction mating and coprecipitation to measure interaction of seven p16 allelic variants detected in melanoma-prone pedigrees with Cyclin-dependent kinases (Cdks). We found that most variants were deficient in interaction with Cdk4 and Cdk6. One defective variant was found both in cancer prone families and in the control population and therefore previously defined as a common polymorphism. Another variant, which is weakly linked to familial cancer, is only slightly affected in interaction with Cdks. These results are consistent with the idea that p16 allelic variants that decrease Cdk interaction predispose individuals who carry them to an increased risk of cancer. Moreover, they suggest that determination of affinity between p16 mutants and partner proteins may help identify functionally-significant allelic variants not detected by classical human genetic techniques.
Reymond
A
A
Department of Molecular Biology, Massachusetts General Hospital, Boston 02114, USA.
Brent
R
R
D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D009154:Mutation; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins
D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases