title: The p110 isoform of the CDP/Cux transcription factor accelerates entry into S phase.
abstract: The CDP/Cux transcription factor was previously found to acquire distinct DNA binding and transcriptional properties following a proteolytic processing event that takes place at the G1/S transition of the cell cycle. In the present study, we have investigated the role of the CDP/Cux processed isoform, p110, in cell cycle progression. Populations of cells stably expressing p110 CDP/Cux displayed a faster division rate and reached higher saturation density than control cells carrying the empty vector. p110 CDP/Cux cells reached the next S phase faster than control cells under various experimental conditions: following cell synchronization in G0 by growth factor deprivation, synchronization in S phase by double thymidine block treatment, or enrichment in G2 by centrifugal elutriation. In each case, duration of the G1 phase was shortened by 2 to 4 h. Gene inactivation confirmed the role of CDP/Cux as an accelerator of cell cycle progression, since mouse embryo fibroblasts obtained from Cutl1z/z mutant mice displayed a longer G1 phase and proliferated more slowly than their wild-type counterparts. The delay to enter S phase persisted following immortalization by the 3T3 protocol and transformation with H-RasV12. Moreover, CDP/Cux inactivation hindered both the formation of foci on a monolayer and tumor growth in mice. At the molecular level, expression of both cyclin E2 and A2 was increased in the presence of p110 CDP/Cux and decreased in its absence. Overall, these results establish that p110 CDP/Cux functions as a cell cycle regulator that accelerates entry into S phase.
authors.affiliation: McGill University Health Center, Molecular Oncology Group, 687 Pine Avenue West, room H5.21, Montreal, Quebec H3A 1A1, Canada.
authors.forename: Laurent
authors.initials: L
authors.lastname: Sansregret
authors.forename: Brigitte
authors.initials: B
authors.lastname: Goulet
authors.forename: Ryoko
authors.initials: R
authors.lastname: Harada
authors.forename: Brian
authors.initials: B
authors.lastname: Wilson
authors.forename: Lam
authors.initials: L
authors.lastname: Leduy
authors.forename: Jacques
authors.initials: J
authors.lastname: Bertoglio
authors.forename: Alain
authors.initials: A
authors.lastname: Nepveu
mesh_terms: D016475:3T3 Cells; D000818:Animals; D015197:Carcinogenicity Tests; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D002498:Centrifugation; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D056751:Cyclin A2; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D011905:Genes, ras; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016196:S Phase / Q000502:physiology*; D013936:Thymidine / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C508184:CCNA2 protein, mouse; C503689:Ccne2 protein, mouse; C000624101:Cux1 protein, mouse; D019925:Cyclin A; D056751:Cyclin A2; D016213:Cyclins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012097:Repressor Proteins; D014157:Transcription Factors; D013936:Thymidine