The prototypic oncogene c-MYC encodes a transcription factor that can drive proliferation by promoting cell-cycle reentry. However, the mechanisms through which c-MYC achieves these effects have been unclear. Using serial analysis of gene expression, we have identified the cyclin-dependent kinase 4 (CDK4) gene as a transcriptional target of c-MYC. c-MYC induced a rapid increase in CDK4 mRNA levels through four highly conserved c-MYC binding sites within the CDK4 promoter. Cell-cycle progression is delayed in c-MYC-deficient RAT1 cells, and this delay was associated with a defect in CDK4 induction. Ectopic expression of CDK4 in these cells partially alleviated the growth defect. Thus, CDK4 provides a direct link between the oncogenic effects of c-MYC and cell-cycle regulation.

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Eukaryotic translation elongation factor 1A (eEF1A) is one of the most abundant protein synthesis factors. eEF1A is responsible for the delivery of all aminoacyl-tRNAs to the ribosome, aside from initiator and selenocysteine tRNAs. In addition to its roles in polypeptide chain elongation, unique cellular and viral activities have been attributed to eEF1A in eukaryotes from yeast to plants and mammals. From preliminary, speculative associations to well characterized biochemical and biological interactions, it is clear that eEF1A, of all the translation factors, has been ascribed the most functions outside of protein synthesis. A mechanistic understanding of these non-canonical functions of eEF1A will shed light on many important biological questions, including viral-host interaction, subcellular organization, and the integration of key cellular pathways.Protein synthesis can be divided into three fundamental stages: initiation, elongation, and termination. Translation elongation requires several soluble proteins called eEFs. 2 During elongation, cognate aa-tRNA are delivered to the A site of the ribosome by eEF1A. Once a codon/anticodon match is detected, eEF1A deposits the aa-tRNA and is itself released from the ribosome. A peptide bond can now be made, thereby elongating the growing polypeptide. eEF2 then catalyzes the movement of the peptidyl-tRNA⅐mRNA complex from the A site to the P site of the ribosome, positioning the next codon in the A site and allowing the process to repeat. This minireview focuses on eEF1A, briefly discussing its canonical function in translation elongation and then describing other cellular activities of this highly abundant protein. Although there are many examples where components of the translational apparatus have been linked to a process distinct from protein synthesis (1), eEF1A provides perhaps the most examples. Our goal is to bring together the work from many different laboratories that support the hypothesis that eEF1A is a central regulator involved in the coordination of many different cellular and viral processes. Special Delivery: The Canonical Role of eEF1A in TranslationeEF1A is a GTP-binding protein and the homolog of the bacterial protein EF-Tu. The GTP-dependent binding of aa-tRNA to eEF1A, binding of the complex to the ribosome, and decoding are essential steps for both efficient and accurate gene expression (reviewed in Ref. 2). In addition, eEF1A requires the activity of a GEF, eEF1B␣␥, to promote GDP release and reactivate the protein for aa-tRNA delivery (3). A combination of kinetic, genetic, and structural information has provided a rich understanding of this canonical role of eEF1A and EF-Tu (3-5). High resolution crystal structures of Saccharomyces cerevisiae eEF1A (3, 6) and bacterial EF-Tu in multiple functional conformations (5) and bound to the ribosome (7) provide detailed information for the interpretation of the function of the protein in translation. As shown in Fig. 1A, the crystal structure of eEF1A forms three well defined domains involved in spe...