In Vivo Discoveries in MDM2-Mediated p53 Regulation

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  • March 20, 2019
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  • Tackmann, Nicole
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • The transcription factor p53 is a stress sensor and tumor suppressor. Its many target genes contribute to tumor suppression through regulation of cell cycle arrest, senescence, apoptosis, and metabolism. Ubiquitously transcribed and translated, p53 regulation is primarily mediated through mouse double minute 2 (MDM2). MDM2 binds to p53, inhibits its transcriptional activation capabilities, and harbors E3 ubiquitin ligase activity to facilitate p53 degradation. Upon cellular stress, upstream signaling transducers modify or bind MDM2 to prevent its inhibition of p53. Ribosomal proteins (RPs) bind to MDM2 either in the response to ribosomal biogenesis stress or oncogenic overproduction of RPs, which occurs in cancer due to increased proliferation. p19ARF also transduces hyperproliferative signals, inhibiting MDM2 to stabilize p53. Both p19ARF- and RP-MDM2 binding are important for p53 activation following oncogenic c-MYC overexpression, but whether these interactions are interdependent was unknown. We utilized mice bearing the MDM2C305F mutation, which disrupts RPL11- and RPL5-MDM2 binding, crossed them with mice containing deletion of p19ARF, and examined c-MYC-induced tumorigenesis. We found that concomitant disruption of these signals enhanced tumorigenesis, indicating that RP-MDM2 and p19ARF-MDM2 binding are two distinct mechanisms causing c-MYC-induced p53 activation. Further, we examined whether RP-MDM2 interaction could transduce proliferative signals in cancers driven by other oncogenes. We crossed MDM2C305F mice to mice bearing an HrasG12V transgene or an ApcMin allele, which promote melanoma and colorectal tumor formation, respectively. We found that in response to RAS stimulation, RPL11 and RPL5 do not participate in MDM2 inhibition. In response to APC deletion, RPL11 and RPL5 expression and MDM2 binding are increased in a colon-specific manner. As a result, MDM2C305F mice experience increased colorectal tumorigenesis and decreased p53 activation. Collectively, these results suggest that RP-MDM2 interaction is important for transducing individual oncogenic stress signals in a p19ARF-independent manner. We have also examined the role of MDM2 E3 ligase activity in controlling p53 following the overexpression of c-MYC. Using mice bearing the MDM2Y487A mutation, which disrupts MDM2 E3 ligase activity, we found that MDM2 E3 ligase activity is dispensable for regulating p53 following oncogenic c-MYC overexpression and surprisingly that its disruption may provide a survival advantage.
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  • In Copyright
Advisor
  • Zhang, Yanping
  • Mohlke, Karen
  • Zhang, Qing
  • MacDonald, Jeffrey
  • Cox, Adrienne
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017
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