The promyelocytic leukemia protein PML has been ascribed roles in growth control, transformation suppression and cell death but its mechanism of action is unknown. These functions are closely tied to the subcellular localization of the protein. In normal cells, the majority of PML forms nuclear bodies which are disrupted when the cell undergoes stress. A chromosomal translocation disrupts PML in acute promyelocytic leukemia (APL) patients resulting in loss of PML nuclear bodies. Disruption of PML's growth control and apoptotic action is thought to contribute to leukemogenesis. Most viruses have evolved mechanisms to bypass host cell defenses such as apoptosis in order to survive. Several viruses target PML bodies during infection. The investigator has studied the effect of a single stranded RNA virus on PML to better understand its physiological function. This virus, lymphocytic choriomeningitis virus (LCMV), is able to establish chronic infection in tissue culture: thus, LCMV must disrupt host cell mediates apoptosis. This establishes a system for the study of PML and its role in apoptosis. A single viral protein, Z, can translocate PML nuclear bodies to the cytoplasm. This translocation may cause the decreased propensity of infected cells to undergo cell death when serum deprived. The investigator has identified a previously unknown component of PML nuclear bodies, the ribosomal protein PO. This protein has a nuclear role in DNA repair, endonuclease activities and a cytoplasmic role in translation. PO is upregulated in colon polyps and tumors suggesting that its association with PML in the nucleus may be related to PML's apoptotic action. The investigator are involved in studying several novel aspects of PML function, in particular interactions with Z, PO and a novel proline rich homeodomain protein PRH and the function of PML in translation. The investigator hypothesizes that PML executes its pro-apoptotic actions through association with other cellular partners and that LCMV proteins block this activity. Because of the association with PML with ribosomal proteins like PO, they predict that PML is involved in translational control and that this action is linked to its pro-apoptotic function. They propose to: (1) determine other cellular partners of PML and assess whether these new partners affect PML's apoptotic action; (2) investigate the PML/Z interaction using high resolution NMR methods to elucidate that basis of this proline interaction motif; (3) determine whether PML is involved in translational control perhaps through interaction with PO and whether this action could be linked to PML's apoptotic action. Elucidating the molecular mechanism of action of PML has important implications for understanding the progression of APL and certain viral infections.
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