Molecular Biology Select

The successful survival and proliferation of a cell is contingent upon its ability to produce the correct proteins in the correct amounts at the correct times. Myriad regulatory processes have evolved to orchestrate the intricate steps that ensure expression of the appropriate genes when they are needed. This issue's Molecular Biology Select discusses recent reports that uncover or characterize new roles for regulatory mechanisms in translation. Many steps lie between the genesis of an mRNA transcript and its translation into protein. Mounting evidence suggests that the events surrounding mRNA synthesis—splicing, export, and translation—are tightly coupled rather than distinct enterprises. Indeed, the human protein SF2/ASF, a member of the serine/arginine-rich (SR) protein family involved in RNA processing , has been suggested to function not only in mRNA splicing but also in mRNA export and translation. Recently, Michlewski et al. (2008) confirmed and elucidated the mechanism for SF2/ASF regulation of translation in cultured human cells. Their in vitro translation studies indicated that SF2/ASF stimulates the translation of mRNAs containing both SF2/ASF binding sites and a 5 0 m7GpppX cap structure (which must be bound by the cap binding protein eIF4E before translation can begin). Activation of translation by SF2/ ASF is dependent on its ability to promote inactivation of the translational inhibitor 4E-BP1 (eIF4E binding protein 1). SF2/ASF does this by promoting the hyperphosphorylation of 4E-BP1 by the kinase mTOR. SF2/ASF also interacts with the catalytic subunit of the 4E-BP1 phosphotase PP2A, possibly inhibiting its activity. Once hyperphosphorylated, 4E-BP1 loses its binding affinity for eIF4E, allowing the initiation of translation. Indeed, in the absence of SF2/ASF, 4E-BP1 remains in a hypophosphorylated form that has high binding affinity for eIF4E. This elucidation of SF2/ASF regulatory function sheds more light on the coupling of posttranscriptional mRNA processing and translation events. Furthermore, it suggests a possible common mode of using mRNA processing proteins to specifically regulate the expression of a subset of transcripts and ties these regulatory signals to the multifaceted mTOR signaling pathway. In the process of cap-independent mRNA translation, the ribosome is recruited to the mRNA at a position close to the initiating codon independently of the 5 0 m7GpppX cap structure. This process—requiring an element known as an internal ribosomal entry site (IRES) in the 5 0 untranslated region (UTR) of the mRNA—usually occurs during cell stress when cap-dependent translation is inhibited. In new work, Marash et al. (2008) identify a role …