TOPs and their regulation

Abstract

Upon cell-cycle arrest or nutrient deprivation, the cellular rate of ribosome production is reduced significantly. In mammalian cells, this effect is achieved in part through a co-ordinated inhibition of RP (ribosomal protein) synthesis. More specifically, translation initiation on RP mRNAs is inhibited. Translational regulation of RP synthesis is dependent on cis-elements within the 5'-UTRs (5'-untranslated regions) of the RP mRNAs. In particular, a highly conserved 5'-TOP (5'-terminal oligopyrimidine tract) appears to play a key role in the regulation of RP mRNA translation. This article explores recent developments in our understanding of the mechanism of TOP mRNA regulation, focusing on upstream signalling pathways and trans-acting factors, and highlighting some interesting observations which have come to light following the recent development of cDNA microarray technology coupled with polysome analysis.

miR-10 in development and cancer

“…2 Interestingly, the binding site for miR-10 was mapped biochemically and genetically to the 5 0 -UTR, just downstream from the 5 0 -terminal oligo-pyrimidine (TOP) motif found in many RPs and translational regulators. Where most mRNAs have an A residue immediately after the cap structure, TOP mRNAs initiate with a C followed by a stretch of 4-14 uninterrupted pyrimidines (reviewed in Hamilton et al 45 and Meyuhas et al 46 ). TOP mRNAs comprise of RPs, elongation factors and other proteins associated with the translational apparatus and they form part of a cellular sensory mechanism by responding to a range of physiological stimuli.…”

“…In the event of stresses, such as amino acid starvation, TOP mRNAs are selectively repressed at the level of translation. 45,46 The upstream regulatory pathways regulating TOP translation involves the phosphatidylinositol 3-kinase (PI3K) and mTOR pathways, 47,48 and several RNA-binding proteins have been proposed to regulate the translation of TOP mRNAs. [49][50][51] However, the exact mechanism and wiring of upstream pathways is still largely unresolved.…”

Translational coregulation of 5′TOP mRNAs by TIA-1 and TIAR

“…59TOP elements are predominant in mammalian mRNAs encoding ribosomal proteins and translation factors (Meyuhas 2000;Hamilton et al 2006;Iadevaia et al 2008). Transcription of 59TOP mRNAs invariantly initiates at a cytosine, which is followed by an uninterrupted 4-to 15-nucleotide (nt) pyrimidine tract (Hamilton et al 2006), and many are produced from genes containing the recently described TCT promoter motif, which overlaps, at the DNA level, with the sequence encoding the 59TOP (Parry et al 2010).…”

“…59TOP elements are predominant in mammalian mRNAs encoding ribosomal proteins and translation factors (Meyuhas 2000;Hamilton et al 2006;Iadevaia et al 2008). Transcription of 59TOP mRNAs invariantly initiates at a cytosine, which is followed by an uninterrupted 4-to 15-nucleotide (nt) pyrimidine tract (Hamilton et al 2006), and many are produced from genes containing the recently described TCT promoter motif, which overlaps, at the DNA level, with the sequence encoding the 59TOP (Parry et al 2010). The 59TOP element is, along with a short downstream sequence, necessary and sufficient for selective repression of translation during cell cycle arrest or nutrient starvation, and is thought to be important for inhibiting the energetically demanding process of ribosome biogenesis during poor growth conditions (Meyuhas 2000;Hamilton et al 2006).…”

La Autoantigen Mediates Oxidant Induced De Novo Nrf2 Protein Translation

“…When interacting with IRES, ITAFs appear to recruit eIFs and ribosomes to initiate translation (6,7). Several RNA binding proteins have been characterized as functional ITAFs, including the polypyrimidine tract binding protein (PTB), poly r(C) binding protein 1/2 (PCBP1/2), La autoantigen, Upstream of N-ras (unr), heterogeneous nuclear ribonucleoproteins C1 and C2 (hnRNPC1/C2), death associated protein 5 (DAP5), embryonic lethal abnormal vision/pro- tein HuR (ELAV/HuR), and nucleolin (8,9). One or several ITAFs can bind to an IRES to regulate protein translation.…”