Mechanisms governing the control of mRNA translation

Livingstone, Mark; Atas, Evrim; Meller, A.; Sonenberg, Nahum

doi:10.1088/1478-3975/7/2/021001

Cited by 68 publications

(66 citation statements)

References 64 publications

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“…It is also known that protein synthesis is primarily regulated at the translation initiation step (rather than during elongation or termination), allowing rapid, reversible, and spatial control of gene expression. This regulation occurs by means of both the cis-regulatory elements, such as the 5′ and 3′ UTRs, and the transacting factors (54). Thus, the highly structured UTRs with GC-rich sequences, upstream ORFs, and internal ribosome entry site could all significantly influence the rate of translation.…”

Section: Discussionmentioning

confidence: 99%

Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic β cells

Liew

Assmann

Templin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Insulin resistance, hyperinsulinemia, and hyperproinsulinemia occur early in the pathogenesis of type 2 diabetes (T2D). Elevated levels of proinsulin and proinsulin intermediates are markers of β-cell dysfunction and are strongly associated with development of T2D in humans. However, the mechanism(s) underlying β-cell dysfunction leading to hyperproinsulinemia is poorly understood. Here, we show that disruption of insulin receptor (IR) expression in β cells has a direct impact on the expression of the convertase enzyme carboxypeptidase E (CPE) by inhibition of the eukaryotic translation initiation factor 4 gamma 1 translation initiation complex scaffolding protein that is mediated by the key transcription factors pancreatic and duodenal homeobox 1 and sterol regulatory element-binding protein 1, together leading to poor proinsulin processing. Reexpression of IR or restoring CPE expression each independently reverses the phenotype. Our results reveal the identity of key players that establish a previously unknown link between insulin signaling, translation initiation, and proinsulin processing, and provide previously unidentified mechanistic insight into the development of hyperproinsulinemia in insulinresistant states.ER stress | prohormone | bIRKO | GWAS

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Section: Discussionmentioning

confidence: 99%

Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic β cells

Liew

Assmann

Templin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…After fertilization, endogenous nanos1 is translated, strongly suggesting the presence of a developmentally regulated activator. In eukaryotes, the known mechanisms for mRNA-specific translational repression require trans-acting factors that interact with cis-regulatory regions (TCEs), which are most commonly found in the 3ЈUTR (reviewed by Livingstone et al, 2010). TCEs for which structure is a critical feature are not common, but have been described for nanos repression in Drosophila and C. elegans (D'Agostino et al, 2006;Gavis et al, 1996;Kalifa et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Xenopusgermlinenanos1is translationally repressed by a novel structure-based mechanism

Luo

Nerlick

et al. 2011

Development

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SUMMARYThe translational repressor Nanos is expressed in the germline and stem cell populations of jellyfish as well as humans. Surprisingly, we observed that unlike other mRNAs, synthetic nanos1 RNA translates very poorly if at all after injection into Xenopus oocytes. The current model of simple sequestration of nanos1 within germinal granules is insufficient to explain this observation and suggests that a second level of repression must be operating. We find that an RNA secondary structural element immediately downstream of the AUG start site is both necessary and sufficient to prevent ribosome scanning in the absence of a repressor. Accordingly, repression is relieved by small in-frame insertions before this secondary structure, or translational control element (TCE), that provide the 15 nucleotides required for ribosome entry. nanos1 is translated shortly after fertilization, pointing to the existence of a developmentally regulated activator. Oocyte extracts were rendered fully competent for nanos1 translation after the addition of a small amount of embryo extract, confirming the presence of an activator. Misexpression of Nanos1 in oocytes from unlocalized RNA results in abnormal development, highlighting the importance of TCE-mediated translational repression. Although found in prokaryotes, steric hindrance as a mechanism for negatively regulating translation is novel for a eukaryotic RNA. These observations unravel a new mode of nanos1 regulation at the post-transcriptional level that is essential for normal development.

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“…Of Ͼ600 queried pathways, the top three (p ϭ 10 Ϫ13 -10 Ϫ37 ) involved signaling by eukaryotic initiation factors (eIFs), p70S6K, and the mammalian target of rapamycin (mTOR) (32,33). These included transcripts encoding 74 of 86 ribosomal proteins (RPs) comprising the 40S and 60S ribosomal subunits, nearly all of which were up-regulated in HBs ( Fig.…”

Section: Tumor Growth But Not Initiation Is Myc-dependent-sleep-mentioning

confidence: 99%

Coordinated Activities of Multiple Myc-dependent and Myc-independent Biosynthetic Pathways in Hepatoblastoma

Wang

Edmunds

et al. 2016

Journal of Biological Chemistry

244

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Edited by Eric FearonHepatoblastoma (HB) is associated with aberrant activation of the ␤-catenin and Hippo/YAP signaling pathways. Overexpression of mutant ␤-catenin and YAP in mice induces HBs that express high levels of c-Myc (Myc). In light of recent observations that Myc is unnecessary for long-term hepatocyte proliferation, we have now examined its role in HB pathogenesis using the above model. Although Myc was found to be dispensable for in vivo HB initiation, it was necessary to sustain rapid tumor growth. Gene expression profiling identified key molecular differences between myc ؉/؉ (WT) and myc ؊/؊ (KO) hepatocytes and HBs that explain these behaviors. In HBs, these included both Myc-dependent and Myc-independent increases in families of transcripts encoding ribosomal proteins, non-structural factors affecting ribosome assembly and function, and enzymes catalyzing glycolysis and lipid bio-synthesis. In contrast, transcripts encoding enzymes involved in fatty acid ␤-oxidation were mostly down-regulated. Myc-independent metabolic changes associated with HBs included dramatic reductions in mitochondrial mass and oxidative function, increases in ATP content and pyruvate dehydrogenase activity, and marked inhibition of fatty acid ␤-oxidation (FAO). Myc-dependent metabolic changes included higher levels of neutral lipid and acetylCoA in WT tumors. The latter correlated with higher histone H3 acetylation. Collectively, our results indicate that the role of Myc in HB pathogenesis is to impose mutually dependent changes in gene expression and metabolic reprogramming that are unattainable in non-transformed cells and that cooperate to maximize tumor growth.

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Mechanisms governing the control of mRNA translation

Cited by 68 publications

References 64 publications

Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic β cells

Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic β cells

Xenopusgermlinenanos1is translationally repressed by a novel structure-based mechanism

Coordinated Activities of Multiple Myc-dependent and Myc-independent Biosynthetic Pathways in Hepatoblastoma

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