Disruption of the Cyclin D/Cyclin-dependent Kinase/INK4/Retinoblastoma Protein Regulatory Pathway in Human Neuroblastoma

摘要: The p16INK4a (MTS1) and pl8INK4c gene products are normal, highly expressed, in human neuroblastoma cell lines. retinoblastoma protein (pRb) was, nonetheless, phosphorylated functional these cells. Such high levels of p16INK4a/p18INK4c should normally inhibit cyclin-dependent kinase (CDK) 4 6 activities cells containing pRb, delaying cycle progression growth. These lines express both CDK4 CDK6 mRNA protein, but only significant activity was detected this study. In addition, not present immune complexes with activity, although were high. Others have shown that a specific mutation the NH2-terminal region product can disrupt binding, thereby bypassing its inhibitory activity. To determine whether gene, or some other mechanism, is responsible for lines, several complementary analyses performed. from each line examined mutations might affect whereas p16INKa add-back experiments performed to assess function. A bona fide disrupts binding prevents inhibition identified 1 17 mechanism(s) disruption remaining unknown, results suggest may bypass block imposed by constitutive expression wild-type novel ways.