Multiple abnormalities of the p16(INK4a)-pRb regulatory pathway in cultured melanoma cells

The retinoblastoma protein (pRb) pathway is critical in regulating the G(1) phase of the cell cycle and it is frequently disrupted in human cancers. C omponents of the pRb pathway which are often altered in tumour progression include the INK4 cyclin-dependent kinase (CDK) inhibitors p16(INK4a)/CDKN2A and p15(INK4b)/CDKN2B CDK4, D-type cyclins and pRb. Several of these compo nents were studied in a series of cultured melanoma cell lines In order to determine the frequency and spectrum of genetic alterations and to define t argets for potential gene transfer studies. Also studied were the p16(INK4a ) alternate transcript (p14ARF) and the p21(waf1) CDK inhibitor. The majori ty of the melanoma cell lines tested (13 out of 17; 76%) carried mutated (t wo), deleted (nine) or silenced (two) p16(INK4a). CDK4 was mutated or overe xpressed in two melanoma cell lines with homozygously deleted CDKN2A and CD KN2B genes. This suggests that the selective growth advantages afforded by CDKN2A inactivation and CDK4 insensitivity are distinct and may involve the mediation of of her CDK inhibitors or CDKs. (C) 1999 Lippincott Williams & Wilkins.