title: DNA replication licensing and cell cycle kinetics of oligodendroglial tumours.
abstract: The convergence point of growth-signalling pathways that control cell proliferation is the initiation of genome replication, the core of which is the assembly of pre-replicative complexes (pre-RCs), resulting in chromatin being 'licensed' for DNA replication in the subsequent S phase. The Mcm2-7 complex is a core constituent of the pre-RC, whose recruitment to replication origins is dependent on the Cdt1 loading factor. Geminin is a potent inhibitor of the initiation of DNA replication by preventing Mcm2-7 assembly at origins via its interaction with Cdt1, ensuring genomic integrity through suppression of re-initiation events in S phase. Here we investigate the regulation of Ki67, Mcm2, p21, caspase 3 and Geminin in a series of 55 oligodendrogliomas to provide an integrated picture of how cellular proliferation and programmed cell death are dysregulated in these tumours. Geminin does not behave as an inhibitor of cell proliferation, its labelling index rising with increasing growth fraction as defined by Ki67 or Mcm2 expression. Geminin is expressed in a higher proportion of cells in higher grade tumours (P<0.001) and shows a strong correlation to proliferation and replication licensing (P<0.01), but not apoptosis. Increasing tumour anaplasia is not associated with loss of Geminin. Importantly, the G1 phase of the proliferative cell cycle, as assessed by the Geminin/Ki67 ratio, shortens with increasing anaplasia, providing new potential algorithms for prognostic assessment. Origin licensing proteins thus provide powerful novel tools for assessment of tumour cell cycle kinetics in routinely processed surgical biopsy material.
authors.affiliation: 1Academic Unit of Pathology, University of Sheffield, UK.
authors.forename: S B
authors.initials: SB
authors.lastname: Wharton
authors.forename: S
authors.initials: S
authors.lastname: Hibberd
authors.forename: K L
authors.initials: KL
authors.lastname: Eward
authors.forename: D
authors.initials: D
authors.lastname: Crimmins
authors.forename: D A
authors.initials: DA
authors.lastname: Jellinek
authors.forename: D
authors.initials: D
authors.lastname: Levy
authors.forename: K
authors.initials: K
authors.lastname: Stoeber
authors.forename: G H
authors.initials: GH
authors.lastname: Williams
mesh_terms: D000328:Adult; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000276:immunology / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D004261:DNA Replication; D005260:Female; D064248:Geminin; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D019394:Ki-67 Antigen / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D064111:Minichromosome Maintenance Complex Component 2; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D009837:Oligodendroglioma / Q000378:metabolism* / Q000473:pathology; D011817:Rabbits
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C577995:GMNN protein, human; D064248:Geminin; D007074:Immunoglobulin G; D019394:Ki-67 Antigen; D009687:Nuclear Proteins; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2