title: Retinoblastoma pathway defects show differential ability to activate the constitutive DNA damage response in human tumorigenesis.
abstract: Loss of G(1)-S control and aberrations of the p16(Ink4a)-cyclin D1/cyclin-dependent kinase (CDK) 4(6)-pRb-E2F-cyclin E/CDK2 pathway are common in human cancer. Previous studies showed that oncogene-induced aberrant proliferation, such as on cyclin E overexpression, causes DNA damage and checkpoint activation. Here, we show that, in a series of human colorectal adenomas, those with deregulation of cyclin D1 and/or p16(Ink4a) showed little evidence of constitutive DNA damage response (DDR), contrary to cyclin E-overexpressing higher-grade cases. These observations were consistent with diverse cell culture models with differential defects of retinoblastoma pathway components, as overexpression of cyclin D1 or lack of p16(Ink4a), either alone or combined, did not elicit detectable DDR. In contrast, inactivation of pRb, the key component of the pathway, activated the DDR in cultured human or mouse cells, analogous to elevated cyclin E. These results highlight differential effect of diverse oncogenic events on driving the 'cancer cell cycles' and their ability to deregulate the replication-driving CDK2 kinase and to alarm the DDR as a potential anticancer barrier in accordance with their hierarchical positions along the retinoblastoma pathway. Our data provide new insights into oncogene-evoked DDR in human tumorigenesis, with potential implications for individualized management of tumors with elevated cyclin D1 versus cyclin E, due to their distinct clinical variables and biological behavior.
authors.affiliation: Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Copenhagen, Denmark.
authors.forename: Frederic
authors.initials: F
authors.lastname: Tort
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.forename: Maxwell
authors.initials: M
authors.lastname: Sehested
authors.forename: Torben
authors.initials: T
authors.lastname: Orntoft
authors.forename: Jiri
authors.initials: J
authors.lastname: Lukas
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
mesh_terms: D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000502:physiology; D019927:Cyclin E / Q000502:physiology; D051357:Cyclin-Dependent Kinase 2 / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D004249:DNA Damage; D050687:E2F1 Transcription Factor / Q000502:physiology; D016158:Genes, p53; D006801:Humans; D009369:Neoplasms / Q000209:etiology / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000502:physiology*
chemical_list: D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D051357:Cyclin-Dependent Kinase 2