PMID: 9635589Jul 4, 1998Paper

Disruption of the cyclin D/cyclin-dependent kinase/INK4/retinoblastoma protein regulatory pathway in human neuroblastoma

Cancer Research
J EastonV J Kidd

Abstract

The p16INK4a (MTS1) and pl8INK4c gene products are normal, and highly expressed, in human neuroblastoma cell lines. The retinoblastoma protein (pRb) was, nonetheless, phosphorylated and functional in these cells. Such high levels of p16INK4a/p18INK4c should normally inhibit cyclin-dependent kinase (CDK) 4 and 6 activities in cells containing functional pRb, delaying cell cycle progression and growth. These neuroblastoma cell lines express both CDK4 and CDK6 mRNA and protein, but only significant CDK6 protein kinase activity was detected in this study. In addition, CDK6 was not present in p16INK4a immune complexes in cells with significant kinase activity, although p16INK4a levels were high. Others have shown that a specific mutation in the NH2-terminal region of the CDK4 gene product can disrupt p16INK4a binding, thereby bypassing its inhibitory activity. To determine whether mutation of the CDK6 gene, or some other mechanism, is responsible for the CDK6 kinase activity in these cell lines, several complementary analyses were performed. The CDK6 gene from each cell line was examined for mutations that might affect p16INK4a binding, whereas p16INKa add-back experiments were performed with CDK6 immune complexes to assess p16INK4a...Continue Reading

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