title: Temporally distinct roles for tumor suppressor pathways in cell cycle arrest and cellular senescence in Cyclin D1-driven tumor.
abstract: BACKGROUND
  Cellular senescence represents a tumor suppressive response to a variety of aberrant and oncogenic insults. We have previously described a transgenic mouse model of Cyclin D1-driven senescence in pineal cells that opposes tumor progression. We now attempted to define the molecular mechanisms leading to p53 activation in this model, and to identify effectors of Cyclin D1-induced senescence.
  
  
  RESULTS
  Senescence evolved over a period of weeks, with initial hyperproliferation followed by cell cycle arrest due to ROS production leading to activation of a DNA damage response and the p53 pathway. Interestingly, cell cycle exit was associated with repression of the Cyclin-dependent kinase Cdk2. This was followed days later by formation of heterochromatin foci correlating with RB protein hypophosphorylation. In the absence of the Cdk4-inhibitor p18Ink4c, cell cycle exit was delayed but most cells eventually showed a senescent phenotype. However, tumors later arose from this premalignant, largely senescent lesion. We found that the p53 pathway was intact in tumors arising in a p18Ink4c-/- background, indicating that the two genes represent distinct tumor suppressor pathways. Upon tumor progression, both p18Ink4c-/- and p53-/- tumors showed increased Cdk2 expression. Inhibition of Cdk2 in cultured pre-tumorigenic and tumor cells of both backgrounds resulted in decreased proliferation and evidence of senescence.
  
  
  CONCLUSIONS
  Our findings indicate that the p53 and the RB pathways play temporally distinct roles in senescence induction in Cyclin D1-expressing cells, and that Cdk2 inhibition plays a role in tumor suppression, and may be a useful therapeutic target.
authors.affiliation: Department of Pediatric and Adolescent Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Hasan
authors.initials: H
authors.lastname: Zalzali
authors.forename: Mohamad
authors.initials: M
authors.lastname: Harajly
authors.forename: Lina
authors.initials: L
authors.lastname: Abdul-Latif
authors.forename: Nader
authors.initials: N
authors.lastname: El-Chaar
authors.forename: Ghassan
authors.initials: G
authors.lastname: Dbaibo
authors.forename: Stephen X
authors.initials: SX
authors.lastname: Skapek
authors.forename: Raya
authors.initials: R
authors.lastname: Saab
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D051379:Mice; D008822:Mice, Transgenic; D017382:Reactive Oxygen Species; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D050763:Cyclin-Dependent Kinase Inhibitor p18; D017382:Reactive Oxygen Species; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D051357:Cyclin-Dependent Kinase 2