A CDKN2A mutation in familial melanoma that abrogates binding of p16INK4a to CDK4 but not CDK6.
The CDKN2A locus encodes two distinct proteins, p16INK4a and p14ARF, both of which are implicated in replicative senescence and tumor suppression in different contexts. Here, we describe the characterization of a novel strain of human diploid fibroblasts (designated Milan HDFs) from an individual who is homozygous for the R24P mutation in p16INK4a. As this mutation occurs in the first exon of INK4a (exon 1alpha), it has no effect on the primary sequence of p14(ARF). Based on both in vitro and in vivo analyses, the R24P variant is specifically defective for binding to CDK4 but remains able to associate with CDK6. Nevertheless, Milan HDFs behave as if they are p16INK4a deficient, in terms of sensitivity to spontaneous and oncogene-induced senescence, and the R24P variant has little effect on proliferation when ectopically expressed in normal fibroblasts. It can, however, impair the proliferation of U20S cells, presumably because they express more CDK6 than primary fibroblasts. These observations suggest that CDK4 and CDK6 are not functionally redundant and underscore the importance of CDK4 in the development of melanoma.
Jones
Rebecca
R
Molecular Oncology Laboratory, Cancer Research UK London Research Institute, Lincolns Inn Field London, WC2A 3PX, United Kingdom
Ruas
Margarida
M
Gregory
Fiona
F
Moulin
Stephanie
S
Delia
Domenico
D
Manoukian
Siranoush
S
Rowe
Janice
J
Brookes
Sharon
S
Peters
Gordon
G
D048708:Cell Growth Processes / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D004171:Diploidy; D005347:Fibroblasts / Q000473:pathology / Q000502:physiology; D019942:Genes, p16; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D011485:Protein Binding
D019941:Cyclin-Dependent Kinase Inhibitor p16; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6