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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA088991-05
Application #
6905379
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mufson, R Allan
Project Start
2001-01-05
Project End
2005-12-31
Budget Start
2004-09-24
Budget End
2004-12-31
Support Year
5
Fiscal Year
2004
Total Cost
$27,880
Indirect Cost
Name
University of Montreal
Department
Type
DUNS #
207622838
City
Montreal
State
PQ
Country
Canada
Zip Code
H3 3-J7
Culjkovic, Biljana; Topisirovic, Ivan; Skrabanek, Lucy et al. (2005) eIF4E promotes nuclear export of cyclin D1 mRNAs via an element in the 3'UTR. J Cell Biol 169:245-56
Capili, Allan D; Edghill, E L; Wu, Kenneth et al. (2004) Structure of the C-terminal RING finger from a RING-IBR-RING/TRIAD motif reveals a novel zinc-binding domain distinct from a RING. J Mol Biol 340:1117-29
Pan, Zhen-Qiang; Kentsis, Alex; Dias, Dora C et al. (2004) Nedd8 on cullin: building an expressway to protein destruction. Oncogene 23:1985-97
Kentsis, Alex; Topisirovic, Ivan; Culjkovic, Biljana et al. (2004) Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap. Proc Natl Acad Sci U S A 101:18105-10
Topisirovic, Ivan; Ruiz-Gutierrez, Melisa; Borden, Katherine L B (2004) Phosphorylation of the eukaryotic translation initiation factor eIF4E contributes to its transformation and mRNA transport activities. Cancer Res 64:8639-42
Topisirovic, Ivan; Culjkovic, Biljana; Cohen, Natalie et al. (2003) The proline-rich homeodomain protein, PRH, is a tissue-specific inhibitor of eIF4E-dependent cyclin D1 mRNA transport and growth. EMBO J 22:689-703
Topisirovic, Ivan; Guzman, Monica L; McConnell, Melanie J et al. (2003) Aberrant eukaryotic translation initiation factor 4E-dependent mRNA transport impedes hematopoietic differentiation and contributes to leukemogenesis. Mol Cell Biol 23:8992-9002
Strudwick, Stephen; Borden, Katherine L B (2002) The emerging roles of translation factor eIF4E in the nucleus. Differentiation 70:10-22
Topisirovic, Ivan; Capili, Allan D; Borden, Katherine L B (2002) Gamma interferon and cadmium treatments modulate eukaryotic initiation factor 4E-dependent mRNA transport of cyclin D1 in a PML-dependent manner. Mol Cell Biol 22:6183-98
Strudwick, S; Borden, K L B (2002) Finding a role for PML in APL pathogenesis: a critical assessment of potential PML activities. Leukemia 16:1906-17

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