title: Deregulation of the p14ARF/MDM2/p53 pathway is a prerequisite for human astrocytic gliomas with G1-S transition control gene abnormalities.
abstract: Deregulation of G1-S transition control in cell cycle is one of the important mechanisms in the development of human tumors including astrocytic gliomas. We have previously reported that approximately two-thirds of glioblastomas (GBs) had abnormalities of G1-S transition control either by mutation/homozygous deletion of RB1 or CDKN2A p16INK4A), or amplification of CDK4 (K. Ichimura et al., Oncogene, 13: 1065-1072, 1996). However, abnormalities of G1-S transition control genes may induce p53-dependent apoptosis in cells. Recent investigations suggest that p14ARF is induced in response to abnormal cell cycle entry and results in p53 accumulation by inhibiting MDM2-mediated transactivational silencing and degradation of p53. To investigate the roles of the G1-S transition control system and the p14ARF/MDM2/p53 pathway in the development of astrocytic gliomas, we examined abnormalities of genes involved in these regulatory pathways in a total of 190 primary human astrocytic gliomas of different malignancy grades [136 GBs, 39 anaplastic astrocytomas (AAs) and 15 astrocytomas (As)]. Sixty-seven percent of GBs (91/136) and 21% of AAs (8/39) had abnormalities of the G1-S control system either by mutation/homozygous deletion of RB1, CDKN2A or CDKN2B, or amplification of CDK4. Seventy-six percent of GBs (103 of 136), 72% of AAs (28 of 39), and 67% of As (10 of 15) had deregulated p53 pathway either by mutation of TP53, amplification of MDM2, or homozygous deletion/mutation of p14ARF. When all of the data were combined and compared, 96% of GBs (87 of 91) and 88% of AAs (7 of 8) with abnormal G1-S transition control also had deregulated p53 pathway. Thus, we demonstrate that deregulation of the G1-S transition control system was almost always accompanied by inactivation of the p53 pathway, clearly illustrating the cooperative roles of these two systems in the development/progression of primary human astrocytic gliomas.
authors.affiliation: Department of Pathology, University of Cambridge, Addenbrooke's Hospital, United Kingdom.
authors.forename: K
authors.initials: K
authors.lastname: Ichimura
authors.forename: M B
authors.initials: MB
authors.lastname: Bolin
authors.forename: H M
authors.initials: HM
authors.lastname: Goike
authors.forename: E E
authors.initials: EE
authors.lastname: Schmidt
authors.forename: A
authors.initials: A
authors.lastname: Moshref
authors.forename: V P
authors.initials: VP
authors.lastname: Collins
mesh_terms: D001254:Astrocytoma / Q000235:genetics* / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons; D016193:G1 Phase; D020868:Gene Silencing; D016158:Genes, p53; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D011519:Proto-Oncogenes; D016196:S Phase; D017384:Sequence Deletion; D015533:Transcriptional Activation; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2