Cytoplasmic polyadenylation plays a key role in the translational control of mRNAs driving biological processes such as gametogenesis, cell-cycle progression, and synaptic plasticity. What determines the distinct time of polyadenylation and extent of translational control of a given mRNA, however, is poorly understood. The polyadenylation-regulated translation is controlled by the cytoplasmic polyadenylation element (CPE) and its binding protein, CPEB, which can assemble both translational repression or activation complexes. Using a combination of mutagenesis and experimental validation of genome-wide computational predictions, we show that the number and relative position of two elements, the CPE and the Pumilio-binding element, with respect to the polyadenylation signal define a combinatorial code that determines whether an mRNA will be translationally repressed by CPEB, as well as the extent and time of cytoplasmic polyadenylation-dependent translational activation.

Beyond the well-known function of poly(A) tail length in mRNA stability, recent years have witnessed an explosion of information about how changes in tail length and the selection of alternative polyadenylation sites contribute to the translational regulation of a large portion of the genome. The mechanisms and factors mediating nuclear and cytoplasmic changes in poly(A) tail length have been studied in great detail, the targets of these mechanisms have been identified--in some cases by genome-wide screenings--and changes in poly(A) tail length are now implicated in a number of physiological and pathological processes. However, in very few cases have all three levels--mechanisms, targets and functions--been studied together.

Protein synthesis is regulated in response to environmental stimuli by covalent modification, primarily phosphorylation, of components of the tranelational machinery. Phosphorylation of the α subunit of eIF‐2 is one of the best‐characterized mechanisms for down‐regulating protein synthesis in higher eukaryotes in response to various stress conditions. Three distinct protein kinases regulate protein synthesis in eukaryotic cells by phosphorylating the α subunit of eIF‐2 at serine‐51. There are two mammalian eIF‐2α kinases: the double‐stranded RNA‐dependent kinase (PKR) and heme‐regulated inhibitor kinase (HRI), and the yeast GCN2. The regulatory mechanisms and the molecular sizes of these eIF‐2α kinases are different. The expression of PKR is induced by interferon, and the kinase activity is stimulated by low concentrations of double‐stranded RNA. HRI is activated under heme‐defi‐cient conditions. Yeast GCN2 is activated by amino acid starvation. The phosphorylation of eIF‐2α results in the shutdown of protein synthesis. Nevertheless, the eIF‐2α kinases can regulate both global as well as specific mRNA translation. Inhibition of protein synthesis correlates with eIF‐2α phosphorylation in response to a wide variety of different stimuli, including heat shock, serum deprivation, glucose starvation, amino acid starvation, exposure to heavy metal ions, and viral infection. Finally, recent studies suggest a role for eIF‐2α phosphorylation in the control of cell growth and differentiation.—de Haro, C., Méndez, R., Santoyo, J. The eIF‐2α kinases and the control of protein synthesis. FASEB J. 10, 1378‐1387(1996)

Blocking mitotic progression has been proposed as an attractive therapeutic strategy to impair proliferation of tumour cells. However, how cells survive during prolonged mitotic arrest is not well understood. We show here that survival during mitotic arrest is affected by the special energetic requirements of mitotic cells. Prolonged mitotic arrest results in mitophagy-dependent loss of mitochondria, accompanied by reduced ATP levels and the activation of AMPK. Oxidative respiration is replaced by glycolysis owing to AMPK-dependent phosphorylation of PFKFB3 and increased production of this protein as a consequence of mitotic-specific translational activation of its mRNA. Induction of autophagy or inhibition of AMPK or PFKFB3 results in enhanced cell death in mitosis and improves the anti-tumoral efficiency of microtubule poisons in breast cancer cells. Thus, survival of mitotic-arrested cells is limited by their metabolic requirements, a feature with potential implications in cancer therapies aimed to impair mitosis or metabolism in tumour cells.