No evidence of a role for activating CDK2 mutations in melanoma

Inactivation of p16(INK4a) and/or activation of cyclin-dependent kinase-4 ( CDK4) are strongly associated with both susceptibility and progression in m elanoma. Activating CDK4 mutations prevent the binding and inhibition of CD K4 by p16(INK4a). A second, more indirect role for CDK4 is in late G(1), wh ere It may sequester the inhibitors p27(KIP1) or p21(CIP1) away from CDK2, and in doing so upregulate the CDK2 activity necessary for cells to proceed completely through G(1) into S phase. As the pivotal residues around the m ost predominant R24C activating CDK4 mutation are invariant between CDK2 an d CDK4, we speculated that the pivotal arginine (position 22 in CDK2), or a nearby residue, may be mutated in some melanomas, resulting in the diminut ion of its binding and inhibition by p27(KIP1) or p21(CIP1). However, excep t for a silent polymorphism, we detected no variants within this region of the CDK2 gene in 60 melanoma cell lines. Thus, if CDK2 activity is dysregul ated in melanoma it is likely to occur by a means other than mutations caus ing loss of direct inhibition. We also examined the expression of the CDK2 gene in melanoma cell lines, to assess its possible co-regulation with the gene for the melanocyte-lineage antigen pmel17, which maps less than 1 kb a way in head to head orientation with CDK2 and may be transcribed off the sa me bidirectional promoter. However, expression of the genes is not co-regul ated. (C) 2001 Lippincott Williams & Wilkins.