Functional evidence for a role of combined CDKN2A (p16-p14(ARF))/CDKN2B (p15) gene inactivation in malignant gliomas.
Homozygous chromosome 9p deletions in gliomas commonly include the CDKN2A and CDKN2B genes, which code for the structurally highly homologous cdk inhibitors/tumor suppressors p16 and p15, respectively. Alternative splicing of the CDKN2A gene results in the expression of p14(ARF). Interestingly, not only p16 and p15, but also the structurally unrelated p14(ARF) appear to function as negative cell cycle regulators. Concerted inactivation of p16, p15 and p14(ARF) could be demonstrated in seven of nine glioblastoma cell lines. Strong suppression of tumorigenicity after transfection with p16 and p15 alone or in combination was seen in cell lines containing neither endogenous p16 nor p15 but functional pRB. Significantly weaker growth suppression was observed in tumors either retaining expression of both p16 and p15 or p15 only. p14(ARF) proved to be a potent tumor suppressor in the presence of wild-type p53, while mutant p53 substantially reduced growth inhibition by p14(ARF). No differences between p16 and p15 effects could be observed, suggesting a largely overlapping function of p16 and p15. To facilitate further research into p16/p15 effects, three cell lines with conditional, tetracycline-controlled p16 expression were established. Reversible growth suppression mediated by p16 was observed in these models. Combined inactivation of CDKN2A and CDKN2B, i.e., loss of both p16 and p15 as well as p14(ARF), results in disruption of two major growth control pathways involving pRB and p53 in malignant gliomas. Therefore, homozygous co-deletions of CDKN2A and CDKN2B rather than mutations targeting individual transcripts are frequently selected for in these tumors.
Simon
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Neurochirurgische Klinik, Universitätskliniken Bonn, Sigmund-Freud-Strasse 25, D-53105 Bonn, Germany. simonmat@mailer.meb.uni-bonn.de
Köster
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Menon
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Schramm
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J
D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics*; D004273:DNA, Neoplasm / Q000032:analysis; D020868:Gene Silencing / Q000502:physiology*; D019942:Genes, p16 / Q000235:genetics*; D005910:Glioma / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D013752:Tetracycline / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF
D004273:DNA, Neoplasm; D011506:Proteins; D025803:Tumor Suppressor Protein p14ARF; D013752:Tetracycline