title: CDK2 transcriptional repression is an essential effector in p53-dependent cellular senescence-implications for therapeutic intervention.
abstract: Cellular senescence, a form of cell-cycle arrest, is a tumor-suppressor mechanism triggered by multiple tumor-promoting insults, including oncogenic stress and DNA damage. The role of cyclin-dependent kinase 2 (CDK2) regulation has been evaluated in models of replicative senescence, but little is known regarding its role in other senescence settings. Using in vitro and in vivo models of DNA damage-and oncogene-induced cellular senescence, it was determined that activation of the tumor-suppressor protein p53 (TP53) resulted in repression of the CDK2 transcript that was dependent on intact RB. Ectopic CDK2 expression was sufficient to bypass p53-dependent senescence, and CDK2-specific inhibition, either pharmacologically (CVT313) or by use of a dominant-negative CDK2, was sufficient to induce early senescence. Pharmacologic inhibition of CDK2 in an in vivo model of pineal tumor decreased proliferation and promoted early senescence, and it also decreased tumor penetrance and prolonged time to tumor formation in animals lacking p53. In conclusion, for both oncogene- and DNA damage-induced cellular senescence, CDK2 transcript and protein are decreased in a p53- and RB-dependent manner, and this repression is necessary for cell-cycle exit during senescence.
  
  
  CONCLUSIONS
  These data show that CDK2 inhibition may be useful for cancer prevention in premalignant hyperproliferative lesions, as well as established tumors.
authors.affiliation: Department of Pediatric and Adolescent Medicine, American University of Beirut, Beirut, Lebanon. hz13@aub.edu.lb rs88@aub.edu.lb.
authors.forename: Hasan
authors.initials: H
authors.lastname: Zalzali
authors.affiliation: Department of Pediatric and Adolescent Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Bilal
authors.initials: B
authors.lastname: Nasr
authors.affiliation: Department of Pediatric and Adolescent Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Harajly
authors.affiliation: Department of Pediatric and Adolescent Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Hussein
authors.initials: H
authors.lastname: Basma
authors.affiliation: Department of Pediatric and Adolescent Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Farah
authors.initials: F
authors.lastname: Ghamloush
authors.affiliation: Department of Pediatric and Adolescent Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ghayad
authors.affiliation: Department of Biology, American University of Beirut, Beirut, Lebanon.
authors.forename: Noël
authors.initials: N
authors.lastname: Ghanem
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Gerard I
authors.initials: GI
authors.lastname: Evan
authors.affiliation: Department of Pediatric and Adolescent Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Raya
authors.initials: R
authors.lastname: Saab
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2