MODULATION OF P53 SIGNALING IN an APT121 INDUCED PROSTATE CANCER MODEL Public Deposited

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  • March 20, 2019
Creator
  • Pan, Wenqi
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Recently, an APT121-induced prostate cancer mouse model was generated, in which Rb and its family members, p107 and p130, are inhibited, therefore leading to initiation and progression of prostate cancer. In the APT121 prostate cancer model, germline deletion of p53 has been shown to accelerate epithelial tumors as well as stromal tumors induced by paracrine stress signals from epithelial cells. However, given that human cancer is often the result of a somatic mutation rather than a germline mutation, the model described above cannot fully mimic the human situation. To address this issue, we have generated a mouse model harboring a somatic deletion of p53 in prostate epithelial cells. Through the development of a pre-clinical mouse model that more closely recapitulates the human disease, we are able to further explore the function of p53 signaling in response to Rb inhibition. Moreover, to investigate the potential therapeutic effects of p53 on prostate cancer, we utilized a p53 knock-in mouse model, p53ER, in which inactive p53 can be restored to its active state by tamoxifen treatment. Our study shows that somatic deletion of p53 accelerates tumor progression and confirms that the stromal tumors observed in the previous report are indeed caused by paracrine signaling from epithelial cells. In the second part of our study, we focused on novel p53 signaling which has been reported to play a critical role in maintaining cell homeostasis after ribosomal stress. Disruption of the binding of ribosomal proteins (RP) and Mdm2 (a primary inhibitor of p53) in the Mdm2 point-mutation mouse model Mdm2C305F, has been shown to attenuate p53 signaling in Myc-induced lymphoma. This suggests that RP-Mdm2-p53 signaling could be a general tumor suppressor pathway activated in response to a variety of oncogenic stresses. To investigate this possibility, we crossed Mdm2C305F mice with APT121 mice. Our results showed that disruption of the RP-Mdm2-p53 pathway does not accelerate prostate tumorigenesis induced by APT121. Instead, the p19Arf-Mdm2-p53 pathway is the major player in response to Rb inhibition. All these studies have revealed the importance of p53 in the APT121 mouse model of prostate cancer.
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  • In Copyright
Advisor
  • Zhang, Yanping
  • Cox, Adrienne
  • Sharpless, Norman
  • Koller, Beverly H.
  • Cook, Jean
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2011
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