Functional evidence for a role of combined CDKN2A (p16-p14ARF)/CDKN2B (p15) gene inactivation in malignant gliomas

摘要: Homozygous chromosome 9p deletions in gliomas commonly include the CDKN2A and CDKN2B genes, which code for structurally highly homologous cdk inhibitors/tumor suppressors p16 p15, respectively. Alternative splicing of gene results expression p14ARF. Interestingly, not only but also unrelated p14ARF appear to function as negative cell cycle regulators. Concerted inactivation p16, p15 could be demonstrated seven nine glioblastoma lines. Strong suppression tumorigenicity after transfection with alone or combination was seen lines containing neither endogenous nor functional pRB. Significantly weaker growth observed tumors either retaining both only. proved a potent tumor suppressor presence wild-type p53, while mutant p53 substantially reduced inhibition by No differences between effects observed, suggesting largely overlapping p15. To facilitate further research into p16/p15 effects, three conditional, tetracycline-controlled were established. Reversible mediated these models. Combined CDKN2B, i.e., loss well p14ARF, disruption two major control pathways involving pRB malignant gliomas. Therefore, homozygous co-deletions rather than mutations targeting individual transcripts are frequently selected tumors.