TRNT-1 Deficiency Is Associated with Loss of tRNA Integrity and Imbalance of Distinct Proteins.

Mitochondrial diseases are a group of heterogeneous disorders caused by dysfunctional mitochondria. Interestingly, a large proportion of mitochondrial diseases are caused by defects in genes associated with tRNA metabolism. We recently discovered that partial loss-of-function mutations in tRNA Nucleotidyl Transferase 1 (), the nuclear gene encoding the CCA-adding enzyme essential for modifying both nuclear and mitochondrial tRNAs, causes a multisystemic and clinically heterogenous disease termed SIFD (sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay; SIFD).

Loss of PDCD4 contributes to enhanced chemoresistance in Glioblastoma multiforme through de-repression of Bcl-xL translation.

Glioblastoma multiforme (GBM) is the most common and aggressive form of tumor of the central nervous system. Despite significant efforts to improve treatments, patient survival rarely exceeds 18 months largely due to the highly chemoresistant nature of these tumors. Importantly, misregulation of the apoptotic machinery plays a key role in the development of drug resistance.

Translation control in apoptosis.

Regulation of protein synthesis, although known for many decades, has only recently begun to be recognized as a critical control mechanism for the maintenance of cellular homeostasis and cellular stress response. One of the key advantages of translational control is the ability of cells to rapidly reprogram the protein output in response to internal or external triggers. This is particularly important during cellular response to stress that may lead to apoptosis by providing cells with a fine tuning mechanism that tips the balance between cell survival or apoptosis.

Tumor suppressor PDCD4 represses internal ribosome entry site-mediated translation of antiapoptotic proteins and is regulated by S6 kinase 2.

Apoptosis can be regulated by extracellular signals that are communicated by peptides such as fibroblast growth factor 2 (FGF-2) that have important roles in tumor cell proliferation. The prosurvival effects of FGF-2 are transduced by the activation of the ribosomal protein S6 kinase 2 (S6K2), which increases the expression of the antiapoptotic proteins X chromosome-linked Inhibitor of Apoptosis (XIAP) and Bcl-x(L). We now show that the FGF-2-S6K2 prosurvival signaling is mediated by the tumor suppressor programmed cell death 4 (PDCD4).

RNA-binding protein HuR mediates cytoprotection through stimulation of XIAP translation.

Expression of the intrinsic cellular caspase inhibitor XIAP is regulated primarily at the level of protein synthesis. The 5' untranslated region harbours an Internal Ribosome Entry Site (IRES) motif that supports cap-independent translation of XIAP mRNA during conditions of cellular stress. In this study, we show that the RNA-binding protein HuR, which is known to orchestrate an antiapoptotic cellular program, stimulates translation of XIAP mRNA through XIAP IRES.