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Thesis Advisor: Shengkan Jin, Ph.D.
Graduate Program in Cellular and Molecular Pharmacology
RWJMS Research Tower
4th floor Conference Room
Wednesday, July 30, 2008
Autophagy is an evolutionarily conserved membrane trafficking process leading to lysosomal degradation; it plays an essential role in recycling internal cellular components to sustain cell survival in response to metabolic and other stress. Genetic studies by targeted inactivation of autophagy genes in various organisms helped to define many functions of autophagy in neurodegeneration diseases, aging and cancer. In humans, monoallelic deletions of beclin 1, a major gene involved in autophagy, are identified in 75% of ovarian cancers, 50% of breast cancers and 40% of prostate cancers. The autophagy deficient mice suffer from a high incidence of spontaneous tumors. However, the mechanism by which autophagy suppresses cancer development is not clear. In this thesis, the role of autophagy in cancer biology has been studied. It is expected that the contribution of this thesis falls in the following three parts.
First, we clarified the genetic regulation and functional interactions of p53, mTOR and autophagy. We demonstrated that the two important cellular signaling pathways, p53 and mTOR, communicate directly with each other. Activation of p53 inhibits mTOR activity and regulates its downstream targets, including autophagy. Moreover, the mechanism by which p53 regulates mTOR involves AMP kinase activation and requires the tuberous sclerosis complex (TSC) 1/TSC2, both of which respond to energy deprivation in cells. Thus, p53 and mTOR signaling machineries can cross-talk and coordinately regulate cell growth, proliferation and death.
Second, we investigated the relationship between autophagy and vaccinia virus replication and maturation. Morphological analysis by electron microscopy showed no apparent difference in terms of vaccinia viral maturation between the autophagy deficient cells and their wild type counterpart cells. Further viral growth analysis indicated that the kinetics of viral replication and infection in the autophagy deficient cells is similar to that in the wild type cells. Our results demonstrated that although there is morphological resemblance between maturation of the autophagic vacuole and the formation of vaccinia immature virions, the cellular autophagy machinery is not required for the vaccinia virus replication and maturation, and the membrane of the vaccinian virus does not originate from autophagic membrane.
Third, we identified a novel mechanism of autophagy in genome instability and tumorigenesis. Our results demonstrated that metabolic stress increases centrosome amplification and aberrant mitosis in autophagy deficient cells, which is associated with increased chromosome instability in these cells. Autophagy can suppress tumorigenesis by alleviating metabolic stress, reducing chromosome instability, and thereby limiting tumor progression.