Temporally distinct roles for tumor suppressor pathways in cell cycle arrest and cellular senescence in Cyclin D1-driven tumor

Molecular Cancer

Research

Mohamad Harajly¹  Lina Abdul-Latif¹  Nader El-Chaar¹  Ghassan Dbaibo¹  Raya Saab²  Hasan Zalzali²  Stephen X Skapek³ 

[1] Department of Pediatric and Adolescent Medicine, American University of Beirut, Beirut, Lebanon;Department of Pediatric and Adolescent Medicine, American University of Beirut, Beirut, Lebanon;Children’s Cancer Center of Lebanon, American University of Beirut, Beirut, Lebanon;Pediatric Hematology-Oncology, University of Chicago, Chicago, Illinois, USA;

关键词: p18Ink4c;    Cyclin D1;    Senescence;    p53;    Rb;    Cdk2;    Tumor;    Reactive oxygen species;   

DOI  :  10.1186/1476-4598-11-28

 received in 2012-01-02, accepted in 2012-04-10,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundCellular 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.ResultsSenescence 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.ConclusionOur 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.

【 授权许可】

Unknown   
© Zalzali et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.