GSK3β-cyclin D3-CUGBP1-eIF2 pathway in aging and in myotonic dystrophy

Epigenetic silencing of the cell cycle proteins is one of the major pathways of the inhibition of liver proliferation in old mice. We recently identified glycogen synthase 3β, GSK3β, as an enzyme which controls the epigenetic regulation of the liver proliferation via reduction of cyclin D3-cdk4. The elevation of cyclin D3 in livers of old mice leads to the accumulation of a transcriptional C/EBPα-HDAC1-Brm complex and translational CUGBP1-eIF2 complex. The accumulation of the CUGBP1-eIF2 increases translation of HDAC1 and C/EBPβ in livers of old mice leading to formation of C/EBPβ-HDAC1 complex which represses C/EBPβ-dependent genes by interacting with their promoters. The translational CUGBP1-eIF2 complex also plays critical role in the regulation of biological processes in young livers and needs to be tightly regulated. Our recent paper showed that this complex is un-appropriately upregulated in skeletal muscle precursors of patients affected with multisystemic disease, Myotonic Dystrophy 2 (DM2) leading to translational elevation of several proteins. These data suggest that the age-specific translational dysfunctions might be involved in DM2 pathogenesis. Our data also suggest that the regulation of translation is conserved in liver and skeletal muscle. In this review, we discuss biological consequences of the age-associated alterations of translation in the liver and a possible role of the elevation of the CUGBP1-eIF2 complex in development of DM2 pathology.