Translation control of gene expression.
The bacteriophage lambda cIII gene product is an early regulator of the lysogenic pathway. The availability of a set of cIII expression mutants allowed us to establish the structure-function relationship of the cIII mRNA. We demonstrated, using defined in vitro systems, that the cIII mRNA is present in two conformations at equilibrium. Mutations that have been shown to lead to cIII overexpression were found to freeze the RNA in one conformation (structure B), and permit efficient binding to the 30S ribosomal subunit. Mutations that have been shown to prevent cIII translation cause the mRNA to assume the alternative conformation (structure A). In this structure, the translation initiation region is occluded, thereby preventing 30S ribosomal subunit binding. Translation of the cIII gene is regulated by RNaseIII. We have localized the RNaseIII responsive element (RRE) to the cIII coding region. We suggest that the regulation of the equilibrium between the two mRNA conformations provides a mechanism for the control of cIII gene expression. The way in which RNaseIII participates in this regulation is as yet unknown.
Available from: Kobi Rosenblum
- "Protein synthesis, the last step in gene expression and a key control process for its regulation, can be divided into initiation, elongation, and termination (Sonenberg et al. 2000; Richter and Klann 2009). The process of elongation, like initiation, requires nonribosomal proteins, termed eukaryotic elongation factors (eEFs). "
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ABSTRACT: Memory consolidation is defined temporally based on pharmacological interventions such as inhibitors of mRNA translation (molecular consolidation) or post-acquisition deactivation of specific brain regions (systems level consolidation). However, the relationship between molecular and systems consolidation are poorly understood. Molecular consolidation mechanisms involved in translation initiation and elongation have previously been studied in the cortex using taste-learning paradigms. For example, the levels of phosphorylation of eukaryotic elongation factor 2 (eEF2) were found to be correlated with taste learning in the gustatory cortex (GC), minutes following learning. In order to isolate the role of the eEF2 phosphorylation state at Thr-56 in both molecular and system consolidation, we analyzed cortical-dependent taste learning in eEF2K (the only known kinase for eEF2) ki mice, which exhibit reduced levels of eEF2 phosphorylation but normal levels of eEF2 and eEF2K. These mice exhibit clear attenuation of cortical-dependent associative, but not of incidental, taste learning. In order to gain a better understanding of the underlying mechanisms, we compared brain activity as measured by MEMRI (manganese-enhanced magnetic resonance imaging) between eEF2K ki mice and WT mice during conditioned taste aversion (CTA) learning and observed clear differences between the two but saw no differences under basal conditions. Our results demonstrate that adequate levels of phosphorylation of eEF2 are essential for cortical-dependent associative learning and suggest that malfunction of memory processing at the systems level underlies this associative memory impairment.
Learning & memory (Cold Spring Harbor, N.Y.) 02/2012; 19(3):116-25. DOI:10.1101/lm.023937.111 · 3.66 Impact Factor
Available from: Peter J Lukavsky
- "Eukaryotic translation initiation is usually a protein-mediated process, which requires the full complement of canonical eukaryotic initiation factors (eIFs) and a 5′-capped mRNA (Hershey and Merrick, 2000; Kapp and Lorsch, 2004; Merrick, 2004; Sachs et al., 1997). The 80S ribosome assembly starts with recognition of the 5′-cap structure by the eIF4F complex, consisting of eIF4E (cap-binding protein), eIF4A (RNA helicase) and the scaffold protein, eIF4G. "
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ABSTRACT: The HCV IRES is a highly structured RNA which mediates cap-independent translation initiation in higher eukaryotes. This function is encoded in conserved structural motifs in the two major domains of HCV and HCV-like IRESs, which play crucial and distinct roles along the initiation pathway. In this review, I discuss structural features of IRES domains and how these RNA motifs function as RNA-based initiation factors to form 48S initiation complexes and 80S ribosomes with only a subset of canonical, protein-based eukaryotic initiation factors.
Virus Research 02/2009; 139(2):166-71. DOI:10.1016/j.virusres.2008.06.004 · 2.32 Impact Factor
Available from: Johanie Charbonneau
- "Phosphorylation of the α subunit of eIF2 (eIF2-α) prevents the recycling of eIF2-GDP in eIF2-GTP, blocking translation initiation. Thapsigargin induces endoplasmic reticulum stress, which stimulates the PERK kinase that phosphorylates eIF2-α, reducing the level of functional eIF2 (55–57). Rapamycin shuts down the mammalian target of rapamycin (mTOR) pathway, which blocks the phosphorylation of the translation repressor 4E-BP, and hypophosphorylated 4E-BP sequesters the initiation factor eIF4E (58,59). "
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ABSTRACT: HIV-1 uses a programmed -1 ribosomal frameshift to synthesize the precursor of its enzymes, Gag-Pol. The frameshift efficiency that is critical for the virus replication, is controlled by an interaction between the ribosome and a specific structure on the viral mRNA, the frameshift stimulatory signal. The rate of cap-dependent translation initiation is known to be altered by the TAR RNA structure, present at the 5' and 3' end of all HIV-1 mRNAs. Depending upon its concentration, TAR activates or inhibits the double-stranded RNA-dependent protein kinase (PKR). We investigated here whether changes in translation initiation caused by TAR affect HIV-1 frameshift efficiency. CD4+ T cells and 293T cells were transfected with a dual-luciferase construct where the firefly luciferase expression depends upon the HIV-1 frameshift. Translation initiation was altered by adding TAR in cis or trans of the reporter mRNA. We show that HIV-1 frameshift efficiency correlates negatively with changes in the rate of translation initiation caused by TAR and mediated by PKR. A model is presented where changes in the rate of initiation affect the probability of frameshifting by altering the distance between elongating ribosomes on the mRNA, which influences the frequency of encounter between these ribosomes and the frameshift stimulatory signal.
Nucleic Acids Research 02/2008; 36(1):30-40. DOI:10.1093/nar/gkm906 · 9.11 Impact Factor
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