Nucleolar Protein Function in Cell Growth and Stress

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Intellectual merit. The overall goal of this project is to test the hypotheses that 1) a block in nucleolar function in Drosophila melanogaster (fruit fly) induces cell stress leading to programmed cell death (apoptosis) via p53 activation, and that 2) certain nucleolar proteins participate in ribosome assembly under normal growth conditions, but then regulate cell stress response upon their release to the nucleoplasm when cells are stressed. The nucleolus is the sub-compartment within the cell nucleus that is responsible for the biosynthesis of ribosomes, elaborate protein and RNA complexes that catalyze protein synthesis once they are exported to the cytoplasm. Nopp140 is a nucleolar protein considered to be a chaperone for ribosome assembly. Loss of Nopp140 could result in the under-production of ribosomes, or in the production of ribosomes that are defective in structure and function. One specific aim will test the hypothesis that the loss of Nopp140 and thus nucleolar function induces p53-mediated apoptosis. This basic research in Drosophila has direct implications to the human Treacher Collins Syndrome (TCS) which is characterized by craniofacial birth defects. A second specific aim examines Drosophila nucleostemin (NS1), a nucleolar GTP-binding protein. This aim will test if NS1 plays an active role in the maturation and nuclear export of the large ribosomal subunit in non-stressed cells. This aim will also test the hypothesis that nucleoli act as cell stress sensors; specifically, the studies will determine if Drosophila NS1 regulates either p53, the nuclear transcription factor known to induce apoptosis in both human and Drosophila cells, or negative regulators of the TOR signaling pathway that normally suppresses a second form of programmed cell death called autophagy. Broader impacts. This award will maintain the strong support provided to women and minorities in past years of funding. For example, an African-American female research associate has been supported through this project. Several undergraduate minority students have also been supported in this laboratory by the Louisiana Alliance for Minority Participation (LAMP) which is a Louisiana Board of Regents/NSF Program grant awarded to the LSU College of Basic Sciences. Other minority students in the laboratory have been supported by the Louisiana State University Ronald E. McNair Post-Baccalaureate Achievement Program that targets first-generation college students of low-income groups that are under-represented at the post-graduate level. The current award will also support a minority graduate student, who provided important preliminary data for part of this project. The current award will also maintain strong undergraduate research in the laboratory. In the last two years, nine undergraduates and two high school students (as part of an out-reach program) participated in aspects of this project. As one example of the impact of this effort, one minority undergraduate researcher completed an LSU Honors thesis, recently graduated with a perfect 4.00 GPA with a major in Biological Sciences, and starts medical school at LSU-New Orleans in August, 2009.