The c-myc proto-oncogene is a transcription-activating protein which has been linked to malignancies including B cell leukemia and lymphomas, breast tumors, small cell lung carcinomas and brain tumors. We recently identified two genes whose expression increases in response to growth induction by c-myc; they include the mRNA cap binding protein (translation initiation factor elF-2alpha). In preliminary studies, elF-4E and elF-2alpha mRNA increased in parallel with c-myc in serum-stimulated cells. In addition, myc-transfected fibroblasts overexpressed both elF-4E and elF-2alpha. Finally, both elF- 4E and elF-2alpha were transcriptionally regulated in response to estradiol activation of an estrogen-regulated c-myc allele. This induction of elF-4E and elF-2alpha expression may be a uniquely important function for c-myc because both elF-4E and elF-2alpha can act individually as transforming genes. Although we found a correlation between c-myc and expression of elF-4E and elF-2alpha, the mechanism by which c-myc regulates these factors remains unclear. To examine myc regulation of elF-4E, we will clone and characterize promoter sequences of elF-4E. Our preliminary studies identified a DNA-binding site in the elF-2alpha promoter [TCCGCATGCG-NRF- 1] as a potential site of interaction with c-myc. Consequently, we will further characterize the response of this or other conserved sequences in the elF-4E and elF-2alpha promoters to c-myc using hypersensitivity site mapping, methylation interference, gel-shift assay and reporter gene-co-transfection.
The aim of these studies is to identify sequences that may directly interact with c-myc. In addition, the potential significance of myc interactions with elF-4E and elF-2alpha will be examined in correlative and functional studies. Breast cancers often carry amplified c-myc sequences; thus, we will examine breast cancers for correlations between increased elF-4E and elF- 2alpha mRNA and increased c-myc. Furthermore, one mechanism by which interferon inhibits cell growth is to increase the elF-2alpha kinase protein which inactivates elF-2alpha. Consequently, we will examine the potential for the elF-2alpha kinase to suppress cellular transformation by myc. These correlative and functional studies should assess the significance of the upregulation of elF-4E and elF-2alpha by c-myc as a potential target for therapeutic manipulations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA063117-05
Application #
2683555
Study Section
Pathology B Study Section (PTHB)
Program Officer
Marks, Cheryl L
Project Start
1994-06-01
Project End
2000-03-31
Budget Start
1998-04-01
Budget End
2000-03-31
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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Lynch, Mary; Chen, Li; Ravitz, Michael J et al. (2005) hnRNP K binds a core polypyrimidine element in the eukaryotic translation initiation factor 4E (eIF4E) promoter, and its regulation of eIF4E contributes to neoplastic transformation. Mol Cell Biol 25:6436-53
Lynch, Mary; Fitzgerald, Chris; Johnston, Kelly A et al. (2004) Activated eIF4E-binding protein slows G1 progression and blocks transformation by c-myc without inhibiting cell growth. J Biol Chem 279:3327-39
Schmidt, Emmett V (2004) The role of c-myc in regulation of translation initiation. Oncogene 23:3217-21
Wrobel, C; Schmidt, E V; Polymenis, M (1999) CDC64 encodes cytoplasmic alanyl-tRNA synthetase, Ala1p, of Saccharomyces cerevisiae. J Bacteriol 181:7618-20
Schmidt, E V (1999) The role of c-myc in cellular growth control. Oncogene 18:2988-96
Polymenis, M; Schmidt, E V (1999) Coordination of cell growth with cell division. Curr Opin Genet Dev 9:76-80

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