Translational control of gene expression and disease

In the past decade, translational control has been shown to be crucial in the regulation of gene expression. Research in this field has progressed rapidly, revealing new control mechanisms and adding constantly to the list of translationally regulated genes. There is accumulating evidence that translational control plays a primary role in cell-cycle progression and cell differentiation, as well as in the induction of specific cellular functions. Recently, the aetiologies of several human diseases have been linked with mutations in genes of the translational control machinery, highlighting the significance of this regulatory mechanism. In addition, deregulation of translation is associated with a wide range of cancers. Current research focuses on novel therapeutic strategies that target translational control, a promising concept in the treatment of human diseases

The CCAAT enhancer-binding protein alpha (C/EBPalpha) requires a SWI/SNF complex for proliferation arrest

The transcription factor CCAAT enhancer-binding protein α (C/EBPα) is a tumor suppressor in myeloid cells and inhibits proliferation in all cell types examined. C/EBPα interacts with the SWI/SNF chromatin-remodeling complex during the regulation of differentiation-specific genes. Here we show that C/EBPα fails to suppress proliferation in SWI/SNF defective cell lines after lmock-down of SWI/SNF core components or after deletion of the SWI/SNF interaction domain in C/EBPα, respectively. Reconstitution of SWI/SNF function restores C/EBPα-dependent proliferation arrest. Our results show that the anti-proliferation activity of C/EBPα critically depends on components of the SWI/SNF core complex and suggest that the functional interaction between SWI/SNF and C/EBPα is a prerequisite for proliferation arrest

Roquin suppresses the PI3K-mTOR signaling pathway to inhibit T helper cell differentiation and conversion of treg to Tfr cells.

Roquin proteins preclude spontaneous T cell activation and aberrant differentiation of T follicular helper (Tfh) or T helper 17 (Th17) cells. Here we showed that deletion of Roquin-encoding alleles specifically in regulatory T (Treg) cells also caused the activation of conventional T cells. Roquin-deficient Treg cells downregulated CD25, acquired a follicular Treg (Tfr) cell phenotype, and suppressed germinal center reactions but could not protect from colitis. Roquin inhibited the PI3K-mTOR signaling pathway by upregulation of Pten through interfering with miR-17 92 binding to an overlapping cis-element in the Pten 3' UTR, and downregulated the Foxo1-specific E3 ubiquitin ligase Itch. Loss of Roquin enhan ced Akt-mTOR signaling and protein synthesis, whereas inhibition of PI3K or mTOR in Roquin-deficient T cells corrected enhanced Tfh and Th17 or reduced iTreg cell differentiation. Thereby, Roquin-mediated control of PI3K-mTOR signaling prevents autoimmunity by restraining activation and differentiation of conventional T cells and specialization of Treg cells. Essig et al. show that spontaneous activation and aberrant differentiation of Roquin-deficient T cells involves cell-intrinsic causes in not only conventional T cells but also impaired Treg cell function. In both cell types, Roquin inhibits the PI3K-mTOR signaling pathway at several levels, thereby controlling protein biosynthesis and limiting differentiation toward Th17 and Tfh cells as well as preventing the conversion and functional specialization of Treg into Tfr cells