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Research Interests:
Research Synopsis:The tumor suppressors encoded by the p53 and ARF gene loci are the most frequently mutated in human cancers. The function of p53 is controlled by the proto-oncoprotein Mdm2, which is in turn controlled by ARF. Together, ARF, Mdm2 and p53 constitute a network that safeguards normal cells from developing into cancers. The broad goal of our lab is to uncover the complex regulatory network surrounding ARF-Mdm2-p53 tumor suppression pathway, thereby providing a possible means to manipulate p53 function. Postdoctoral fellows and graduate students will receive supervision in a multi-disciplinary program based on (but not limited to) the research outlined below that seeks to maximize trainees’ abilities to successfully perform novel and speculative experiments. We are currently focusing on three related areas. 1. Role of ribosomal protein-Mdm2-p53 pathway in growth control The first area of research interest in the lab is to understand how cell growth and cell division are coordinated. We recently discovered physical and functional interaction between Mdm2 and several ribosomal proteins. On the basis of this discovery, we have proposed a model suggesting that the ribosomal protein-Mdm2 interaction represents a signaling pathway coupling cell proliferation with ribosomal biogenesis—a means ensuring coordinated regulation of cell growth and cell division. Our study has raised some critical questions. First, whether and how the ribosomal protein-Mdm2 interaction functions in tumor suppression? Second, besides coordinating cell growth and proliferation, what else might be controlled by the ribosomal protein-Mdm2 interaction? Third, what specific roles are associated with each of the Mdm2-interacting ribosomal proteins? Fourth, can this pathway offer an effective and tumor-specific general therapeutic strategy for treating cancer? Recent work in our laboratory uses both biochemical tools and mouse models to address these questions. 2. In vivo function of Mdm2 E3 ubiquitin ligase The second area of research interest is to understand the function and mechanism of Mdm2 E3 ubiquitin ligase. For more than a decade, Mdm2 has been believed to regulate p53 primarily through two mechanisms: by masking p53’s access to transcriptional machinery, and by ubiquitinating p53, targeting it for proteasomal degradation. This dogma was recently challenged by our data generated from knockin mice in which Mdm2’s RING E3 ubiquitin ligase activity was abrogated by a single point mutation. The RING mutant Mdm2 is fully capable of binding with p53, yet cannot suppress p53 activity, suggesting that Mdm2 cannot block p53 by binding alone without ubiquitination. Data from the RING knockin mice also revealed that endogenous Mdm2 does not, as previously thought, regulate its own stability by self-ubiquitination. Using the animal model, we are currently exploring the control mechanism of p53-induced cell cycle arrest vs. apoptosis. In addition, we are investigating the role of Mdm2 RING E3 in regulation of Mdm4—a homologue of Mdm2 also critical in p53 regulation. 3. Function and mechanism of tumor suppressor ARF The third area of our research interest is to delineate the broad tumor suppression role of ARF. Previously, we identified the ARF-Mdm2 interaction and established the ARF-Mdm2-p53 pathway in control cell division. We then demonstrated the ARF-B23/NPM interaction and uncovered a function for ARF in regulating cell growth. We recently discovered that ARF physically and functionally interacts with a mitochondrial protein known as p32, and through this interaction ARF helps to coordinate inhibitions of cell division with apoptosis—the same functions that are essential to restrain and to eliminate unwanted cancerous cells and are often perturbed in cancer development. Based on our findings, we propose an integrated role for ARF in concurrently controlling cell growth, division and apoptosis through interactions with B23, Mdm2 and p32, respectively. Several projects are currently ongoing aimed at understanding this integrated role of ARF in tumor suppression. Recent Publications:
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