May 2012, 11:28,
Open Access This content is freely available online to anyone, anywhere at any time.
Date: 01 May 2012
Temporally distinct roles for tumor suppressor pathways in cell cycle arrest and cellular senescence in Cyclin D1-driven tumor
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.
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.
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.
Harvey M, Sands AT, Weiss RS, Hegi ME, Wiseman RW, Pantazis P, Giovanella BC, Tainsky MA, Bradley A, Donehower LA: In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice. Oncogene 1993, 8:2457–2467.PubMed
Kubo A, Nakagawa K, Varma RK, Conrad NK, Cheng JQ, Lee WC, Testa JR, Johnson BE, Kaye FJ, Kelley MJ: The p16 status of tumor cell lines identifies small molecule inhibitors specific for cyclin-dependent kinase 4. Clin Cancer Res 1999, 5:4279–4286.PubMed
Hirai H, Roussel MF, Kato JY, Ashmun RA, Sherr CJ: Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. Mol Cell Biol 1995, 15:2672–2681.PubMed
- Temporally distinct roles for tumor suppressor pathways in cell cycle arrest and cellular senescence in Cyclin D1-driven tumor
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
- Online Date
- May 2012
- Online ISSN
- BioMed Central
- Additional Links
- Cyclin D1
- Reactive oxygen species
- Author Affiliations
- 1. Department of Pediatric and Adolescent Medicine, American University of Beirut, Beirut, Lebanon
- 2. Children’s Cancer Center of Lebanon, American University of Beirut, Beirut, Lebanon
- 3. Pediatric Hematology-Oncology, University of Chicago, Chicago, Illinois, USA