期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 23, 期 24, 页码 8992-9002出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.23.24.8992-9002.2003
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资金
- NATIONAL CANCER INSTITUTE [R01CA088991, R01CA090446, R01CA080728] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR009145] Funding Source: NIH RePORTER
- NCI NIH HHS [R01 CA090446, CA 90446, R01 CA080728, R01 CA088991, CA 88991, CA 80728] Funding Source: Medline
- NCRR NIH HHS [1S10 RR 09145-01] Funding Source: Medline
The eukaryotic translation initiation factor 4E (eIF4E) acts as both a key translation factor and as a promoter of nucleocytoplasmic transport of specific transcripts. Traditionally, its transformation capacity in vivo is attributed to its role in translation initiation in the cytoplasm. Here, we demonstrate that elevated eIF4E impedes granulocytic and monocytic differentiation. Our subsequent mutagenesis studies indicate that this block is a result of dysregulated eIF4E-dependent mRNA transport. These studies indicate that the RNA transport function of eIF4E could contribute to leukemogenesis. We extended our studies to provide the first evidence that the nuclear transport function of eIF4E contributes to human malignancy, specifically in a subset of acute and chronic myelogenous leukemia patients. We observe an increase in eIF4E-dependent cyclin D1 mRNA transport and a concomitant increase in cyclin D1 protein levels. The aberrant nuclear function of eIF4E is due to abnormally large eIF4E bodies and the loss of regulation by the proline-rich homeodomain PRH. We developed a novel tool to modulate this transport activity. The introduction of IkappaB, the repressor of NF-kappaB, leads to suppression of eIF4E, elevation of PRH, reorganization of eIF4E nuclear bodies, and subsequent downregulation of eIF4E-dependent mRNA transport. Thus, our findings indicate that this nuclear function of eIF4E can contribute to leukemogenesis by promoting growth and by impeding differentiation.
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