Aberrant Eukaryotic Translation Initiation Factor 4E-Dependent mRNA Transport Impedes Hematopoietic Differentiation and Contributes to Leukemogenesis

Abstract

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 IB, the repressor of NF-B, 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.The eukaryotic translation initiation factor 4E (eIF4E) promotes cellular growth and transformation. In fact, eIF4E levels are used as prognostic indicators of clinical outcome in human cancers, including breast cancer and head and neck squamous cell carcinomas (6,28,29,45). Even moderate overexpression of eIF4E leads to dysregulated cellular proliferation and malignant transformation in immortalized cell lines (21-23). Biochemically, eIF4E acts at the rate-limiting step of cap-dependent translation initiation where it binds the methyl 7 guanosine (m 7 G) cap present on the 5Ј end of mRNAs and recruits the given transcript to the ribosome (36). The traditional view is that eIF4E transforms cells by promoting inappropriate translation of mRNAs important to growth (36).Recent findings suggest that eIF4E has functions in addition to its well-defined role in translation. Up to 68% of eIF4E is found in multiprotein nuclear structures referred to as eIF4E nuclear bodies (15,20,24,37). In the nucleus, eIF4E promotes the selective transport of specific mRNAs, such as cyclin D1, from the nucleus to the cytoplasm without affecting housekeeping mRNAs such as GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and actin or altering levels of cyclin D1 transcripts (20,35,43,44). This activity of eIF4E responds to physiological stresses such as interferon (43). Similar to its cytoplasmic function, eIF4E requires its m 7 G cap-binding activity for its mRNA transport function (4). The molecular mechanism of how eIF4E-sensitive transcripts are transported, what the featu...

Effects of protein phosphorylation on ubiquitination and stability of the translational inhibitor protein 4E-BP1

“…Likewise, the inactivation or loss of 4E-BP1 releases active eIF4E, which stimulates post-transcriptionally the expression of antiapoptotic or oncogenic proteins (Rosenwald et al, 1995;Rousseau et al, 1996; Hoover et al, 1997; Carter Nimmanapalli et al, 2003;Othumpangat et al, 2005b). Since the overactivity or overexpression of either NF-kB or eIF4E inhibits apoptosis and promotes malignant transformation (Topisirovic et al, 2003;Clemens, 2004;Ren et al, 2006), the eIF4E/4E-BP1 system and its regulatory mechanisms can be viewed as a translational parallel to the NF-kB/IkB system.…”

PRH/HHex inhibits the migration of breast and prostate epithelial cells through direct transcriptional regulation of Endoglin

“…Moreover, in human T-cell leukaemias associated with the aberrant expression of the LMO2 oncogene, elevated PRH expression is necessary for development of the disease (7,8). However, more generally, it is the disruption of PRH activity that is associated with a variety of diseases states (9)(10)(11)(12).…”

“…Aberrant subcellular localisation of PRH with loss of nuclear PRH is associated with blast crisis chronic myeloid leukaemia (CML) and some subtypes of acute myeloid leukaemia (AML) (12). Furthermore in one human AML the only characterised genetic change is a fusion of the prh gene with the nucleoporin gene Nup98 and this is thought to decrease the activity of endogenous PRH (11).…”

The Cap-Dependent Translation Apparatus Integrates and Amplifies Cancer Pathways

“…[20][21][22][23] Environmental signals can alter the nuclear set point of eIF4E-mediated translational control by modulating the interaction of eIF4E with nuclear eIF4E-binding proteins. 24,25 Two known tissue-specific nuclear eIF4E-binding proteins, the promyelocytic leukemia (PML) protein and the proline-rich homeodomain (PRH) protein, inhibit the mRNA-transport function of eIF4E by binding to its dorsal surface. [24][25][26] However, major challenges remain in linking this distal step to proximal signals and their receptors.…”