The promyelocytic leukemia protein PML is ascribed roles in growth control, transformation suppression and cell death but its mechanism of action remains enigmatic. These actions are closely tied to the subcellular localization of the protein. In normal cells, the majority of PML forms nuclear bodies, which are modulated by stress. PML nuclear bodies are heterogeneous multiprotein complexes that are found in all normal cell types studies suggesting that they play a basic role in mammalian cells. The t(15;17) disrupts PML in acute promyelocytic leukemia (APL) resulting in loss of PML nuclear bodies. Subsequent disruptions of PML's growth control and apoptotic action are thought to contribute to leukemogenesis. PML is disrupted in other pathogenic conditions such as spinocerebellar ataxia, and by several viruses including papilloma and Herpes. To determine a molecular function for PML, Dr. Borden identified nuclear body components likely to be of physiological relevance. These components include eukaryotic translation initiation factor (4E (eKF-4E) and the proline-rich homeodomain protein PRH. In addition, PRH and eIF-4E interact. Her data suggest that PML acts in the regulation of transport of selected mRNAs. This action is modulated through an interaction between PML and eIF-4E, a protein with established functions in RNA transport. She has shown that transport of cyclin D1 mRNA is preferentially suppressed by PML presenting a possible mechanism for PML's growth suppression activity. EIF-4E is mitrogenic and induces oncogenic transformation suggesting that association of this protein with PML in the nucleus may be related to PML's growth control functions. PRH is required for myeloid development. Thus, the PRH-PML interaction may represent a link between growth control and differentiation. She hypothesizes that PML executes its growth suppression actions through association with other cellular partners, e.g. eIF-4E and PRH, by regulating RNA transport selectively. She proposes to: (1) Investigate the RNA transport activities of PML, and ascertain whether this function is related to its growth suppression action, (2) Determine whether PRH modulates RNA transport actions mediated by PML and PML's growth suppression action, and (3) Investigate the PML/PRH interaction using high-resolution NMR method to elucidate the basis of this interaction.
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