Cellular senescence as a tumor suppressor mechanism is mediated by sequential activation of the p53 and RB pathways

Abstract

Background and Objectives: Oncogene induced senescence is a tumor suppressor mechanism that limits progression of pre-malignant lesions. Identifying the molecular mechanisms by which cells can escape senescence may provide novel cancer therapeutic and preventive targets. Two tumor suppressors, p53 and Rb, are involved in senescence, but their specific roles are still unclear. Our aim is to investigate the role of the Rb and p53 pathways in cellular senescence, to identify mechanisms of cellular escape from senescence, and to evaluate human tumor samples for disruption of the identified pathways. Methods: We are using a transgenic mouse with pineal-cell specific cyclin D1 expression (Irbp-Cyclin D1 mouse). These mice develop premalignant pineal hyperplasia with features of cellular senescence, and tumors progress only when the p53 or the RB pathway is disrupted. Results: We found that p53 was activated early in the senescence response, and led to cell cycle exit. RB activation occurred days later, and coincided with the senescence phenotype that included formation of heterochromatin foci. Disruption of either pathway alone was sufficient for pineal tumor progression. Using genetically engineered mice with regulatable expression of p53, we are now investigating the specific role of p53 in the induction versus maintenance of cell cycle exit. In addition, we are using primary cultures of Irbp-Cyclin D1 pineal cells to examine the effects of turning the p53 and RB pathways "on" and "off" during cellular senescence, to dissect their roles during induction and maintenance of senescence. We are also analyzing premalignant versus malignant tumors from these transgenic mice, to identify recurring genetic lesions that may be important targets for tumor prevention. Finally, we are evaluating human tumor samples for genetic lesions that overlap with the identified pathways. Conclusion: Our preliminary results suggest that the p53 and RB pathways have distinct and complementary effects in the senescence response, where the p53 pathway is important for induction of senescence, while the RB pathway may be responsible for its maintenance. Studies are currently ongoing to verify these observations. These findings will have direct implications on novel approaches to cancer therapy and prevention, by activating cellular senescence and tumor suppression.