Multiple abnormalities of the p16INK4a-pRb regulatory pathway in cultured melanoma cells.
The retinoblastoma protein (pRb) pathway is critical in regulating the G1 phase of the cell cycle and it is frequently disrupted in human cancers. Components of the pRb pathway which are often altered in tumour progression include the INK4 cyclin-dependent kinase (CDK) inhibitors p16INK4a/ CDKN2A and p15INK4b/CDKN2B, CDK4, D-type cyclins and pRb. Several of these components were studied in a series of cultured melanoma cell lines in order to determine the frequency and spectrum of genetic alterations and to define targets for potential gene transfer studies. Also studied were the p16INK4a alternate transcript (p14ARF) and the p21(waf1) CDK inhibitor. The majority of the melanoma cell lines tested (13 out of 17; 76%) carried mutated (two), deleted (nine) or silenced (two) p16(INK4a). CDK4 was mutated or overexpressed in two melanoma cell lines with homozygously deleted CDKN2A and CDKN2B genes. This suggests that the selective growth advantages afforded by CDKN2A inactivation and CDK4 insensitivity are distinct and may involve the mediation of other CDK inhibitors or CDKs.
Rizos
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H
Westmead Institute for Cancer Research, University of Sydney Westmead Hospital, NSW, Australia. hrizos@hemonc.wh.su.edu.au
Darmanian
A P
AP
Indsto
J O
JO
Shannon
J A
JA
Kefford
R F
RF
Mann
G J
GJ
D015152:Blotting, Northern; D002453:Cell Cycle; D002455:Cell Division; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D004252:DNA Mutational Analysis; D005786:Gene Expression Regulation; D006801:Humans; D015151:Immunoblotting; D008545:Melanoma / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D019941:Cyclin-Dependent Kinase Inhibitor p16; D016160:Retinoblastoma Protein; D018844:Cyclin-Dependent Kinases