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

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 coin...