title: Alterations of INK4a(p16-p14ARF)/INK4b(p15) expression and telomerase activation in meningioma progression.
abstract: Dysregulation of cell cycle progression and telomerase activation have been implicated in malignant tumor progression as well as in the evasion of senescence and immortalization. We have investigated expression of the cell cycle control and tumor suppressor genes INK4a(p16-p14ARF), INK4b(p15-p10) and RB, and their relation to telomerase activation during malignant meningioma progression. 7/26 (27%) benign, 3/12 (25%) atypical but 4/7 (57%) anaplastic tumors lacked both, p16 and p15 protein expression. 14/39 (36%) benign and atypical but 5/7 (71%) anaplastic meningiomas contained no p14ARF mRNA. 2/46 (4%) tumors failed to express pRB. We observed frequent differential loss of expression of the alternatively spliced INK4a tumor suppressors p16 and p14ARF. Exclusive expression of the alternative INK4b transcript p10 possibly at the expense of p15 and therefore resulting in loss of p15 tumor suppressor activity was noted in two meningiomas. We have previously described telomerase activity or expression of the telomerase catalytic subunit hTERT in this meningioma series. Telomerase activation was detected in 10/27 (37%) benign, but 18/19 (95%) non-benign meningiomas. We observed no significant overall correlation between loss of INK4a/INK4b expression and telomerase activation. In conclusion, our results suggest a greater role for losses of INK4a/INK4b gene products in meningioma formation and malignant progression than previously thought. Inactivation of p16/p15- and pl4ARF-dependent pathways possibly in conjunction with telomerase activation might be critical steps for a meningioma cell towards escape from senescence, that is, immortalization.
authors.affiliation: Neurochirurgische Universitätsklinik, Bonn, Germany. Matthias.Simon@ukb.uni-bonn.de
authors.forename: M
authors.initials: M
authors.lastname: Simon
authors.forename: T W
authors.initials: TW
authors.lastname: Park
authors.forename: G
authors.initials: G
authors.lastname: Köster
authors.forename: R
authors.initials: R
authors.lastname: Mahlberg
authors.forename: M
authors.initials: M
authors.lastname: Hackenbroch
authors.forename: J
authors.initials: J
authors.lastname: Boström
authors.forename: T
authors.initials: T
authors.lastname: Löning
authors.forename: J
authors.initials: J
authors.lastname: Schramm
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation; D016922:Cellular Senescence; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins; D018450:Disease Progression; D005260:Female; D016161:Genes, Retinoblastoma; D016147:Genes, Tumor Suppressor; D019942:Genes, p16; D006801:Humans; D008297:Male; D008577:Meningeal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008579:Meningioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000378:metabolism*; D025803:Tumor Suppressor Protein p14ARF / Q000096:biosynthesis* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: C493966:CDKN2B protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016160:Retinoblastoma Protein; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D019098:Telomerase