Deregulation of the p14ARF/MDM2/p53 Pathway Is a Prerequisite for Human Astrocytic Gliomas with G1-S Transition Control Gene Abnormalities

摘要: Deregulation of G1-S transition control in cell cycle is one the important mechanisms development human tumors including astrocytic gliomas. We have previously reported that approximately two-thirds glioblastomas (GBs) had abnormalities either by mutation/homozygous deletion RB1 or CDKN2A p16INK4A), amplification CDK4 (K. Ichimura et al., Oncogene, 13: 1065-1072, 1996). However, genes may induce p53-dependent apoptosis cells. Recent investigations suggest p14ARF induced response to abnormal entry and results p53 accumulation inhibiting MDM2-mediated transactivational silencing degradation p53. To investigate roles system p14ARF/MDM2/p53 pathway gliomas, we examined involved these regulatory pathways a total 190 primary gliomas different malignancy grades [136 GBs, 39 anaplastic astrocytomas (AAs) 15 (As)]. Sixty-seven percent GBs (91/136) 21% AAs (8/39) RB1, CDKN2B, CDK4. Seventy-six (103 136), 72% (28 39), 67% As (10 15) deregulated mutation TP53, MDM2, homozygous deletion/mutation p14ARF. When all data were combined compared, 96% (87 91) 88% (7 8) with also pathway. Thus, demonstrate deregulation was almost always accompanied inactivation pathway, clearly illustrating cooperative two systems development/progression