In vivo function and mechanism of the r-protein-Mdm2-p53 pathway Mdm2 interacts with a large number of proteins and plays a critical role in regulating cell growth, proliferation and apoptosis. One of the most significant breakthroughs in the study of Mdm2 in the past several years is the demonstration of Mdm2's interaction with ribosomal proteins (r-proteins). We discovered that three r-proteins, L5, L11 and L23, bind Mdm2 and block Mdm2-mediated p53 degradation, leading to p53-dependent growth inhibition. We demonstrated that events inhibiting ribosomal biogenesis cause nucleolar stress and release nucleolar r-proteins, which interact with Mdm2 in the nucleus and trigger activation of p53. However, the physiological function of the r-protein- Mdm2 interaction has not been addressed in vivo, and the biological role of the interaction has not been established in a mouse model. A number of Mdm2 inhibiting molecules, including the three r-proteins and the tumor suppressor ARF, are known to bind Mdm2 in the central acidic domain. Mutations targeting Mdm2 the central acidic domain have been reported in human cancers. We recently found that mutations in the Mdm2'central acidic domain disrupt r-protein interaction and attenuate p53's response to nucleolar stress. However, despite implications in human cancer the role of the r-protein-Mdm2-p53 pathway in tumor suppression has not been proven in vivo, and mouse models are essential for the further study of these proteins. We have recently generated a knockin mouse model expressing a mutant Mdm2 deficient in r-protein binding and begun to dissect the biological functions of the mutant mice. During a discovery screen for novel Mdm2 binding partners we identified the mitochondrial Hep27 as a potential Mdm2 binding protein. Hep27 binds to Mdm2's central acidic region-in concert with the other Mdm2 inhibitors, and mechanistically is an inhibitor of Mdm2 function. Building upon a large amount of biochemical, biological and genetic information, we have formulated two hypotheses: 1) the r-protein-Mdm2 interaction constitutes surveillance for ribosomal biogenesis and is critical for the activation of p53 and suppression of tumorigenesis. 2) The Hep27- Mdm2 interaction represents a novel mitochondrial retrograde signaling pathway that transduces mitochondrial stress through Mdm2 to amplify p53 function.
Our Specific Aims are: 1. To determine the biological function and biochemical mechanism of Mdm2 C4 zinc finger. 2. To investigate how the r-protein-Mdm2-p53 pathway interacts with other p53 signaling pathways. 3. To define a mitochondrial stress-activated, Hep27-mediated p53 pathway.
Mutations in the tumor suppressor p53 gene that compromise p53 functions occur in 50% of human cancers, and elevated levels of a p53 inhibitor Mdm2 occur in most of the rest. This project proposes to investigate the function and mechanism of the Mdm2-p53 regulatory loop using novel mouse models. Detailed knowledge of the molecular mechanisms and regulation of the Mdm2 and p53 is critically important for the design of future p53-based anticancer strategies.
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