Role of p70S6K1-mediated Phosphorylation of eIF4B and PDCD4 Proteins in the Regulation of Protein Synthesis

Dennis, Michael D.; Jefferson, Leonard S.; Kimball, Scot R.

doi:10.1074/jbc.m112.404822

Cited by 114 publications

(94 citation statements)

References 35 publications

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“…Phosphorylation of 4E-BP1 liberates eIF4E allowing progression in the formation of the functional ribosome. Furthermore, mTORC1 directly phosphorylates the 70-kDa ribosomal protein S6 kinase 1 (p70S6K1), which subsequently phosphorylates components required in the formation/maintenance of the ribosome (21,31) (Fig. 3, left).…”

Section: Mv-induced Decreases In Protein Diaphragmatic Synthesismentioning

confidence: 99%

Ventilator-induced diaphragm dysfunction: cause and effect

Powers

Wiggs

Sollanek

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

139

156

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Powers SK, Wiggs MP, Sollanek KJ, Smuder AJ. Ventilator-induced diaphragm dysfunction: cause and effect. Am J Physiol Regul Integr Comp Physiol 305: R464 -R477, 2013. First published July 10, 2013 doi:10.1152/ajpregu.00231.2013 is used clinically to maintain gas exchange in patients that require assistance in maintaining adequate alveolar ventilation. Common indications for MV include respiratory failure, heart failure, drug overdose, and surgery. Although MV can be a life-saving intervention for patients suffering from respiratory failure, prolonged MV can promote diaphragmatic atrophy and contractile dysfunction, which is referred to as ventilator-induced diaphragm dysfunction (VIDD). This is significant because VIDD is thought to contribute to problems in weaning patients from the ventilator. Extended time on the ventilator increases health care costs and greatly increases patient morbidity and mortality. Research reveals that only 18 -24 h of MV is sufficient to develop VIDD in both laboratory animals and humans. Studies using animal models reveal that MV-induced diaphragmatic atrophy occurs due to increased diaphragmatic protein breakdown and decreased protein synthesis. Recent investigations have identified calpain, caspase-3, autophagy, and the ubiquitin-proteasome system as key proteases that participate in MV-induced diaphragmatic proteolysis. The challenge for the future is to define the MV-induced signaling pathways that promote the loss of diaphragm protein and depress diaphragm contractility. Indeed, forthcoming studies that delineate the signaling mechanisms responsible for VIDD will provide the knowledge necessary for the development of a pharmacological approach that can prevent VIDD and reduce the incidence of weaning problems. respiratory muscle; atrophy; mechanical ventilation; weaning; muscle wasting MECHANICAL VENTILATION (MV) is used clinically to achieve sufficient pulmonary gas exchange in patients unable to sustain adequate alveolar ventilation on their own. Common indications for MV include respiratory failure due to chronic obstructive pulmonary disease, status asthmaticus, and/or heart failure. In addition, MV is often an essential intervention in patients suffering from acute drug overdose, neuromuscular diseases, sepsis, and during surgery along with postsurgical recovery.The number of patients receiving prolonged MV in the United States exceeds more than 300,000 each year in the intensive care unit (ICU) (20). Although MV can be a lifesaving measure, prolonged MV results in the rapid development of diaphragmatic weakness due to both atrophy and contractile dysfunction. This detrimental impact of prolonged MV on the diaphragm has been termed ventilator-induced diaphragmatic dysfunction (VIDD) and VIDD is predicted to be a major contributor to problems in weaning patients from the ventilator (26, 114). Although previous reports describing the impact of prolonged MV on the diaphragm have appeared in the literature, advances in our understanding of the mechanisms responsible for VIDD h...

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Section: Mv-induced Decreases In Protein Diaphragmatic Synthesismentioning

confidence: 99%

Ventilator-induced diaphragm dysfunction: cause and effect

Powers

Wiggs

Sollanek

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

139

156

View full text Add to dashboard Cite

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“…11 Another substrate of MTORC1 is p70s6K, which enhances the RNA helicase activity of eIF4A by phosphorylating EIF4B, allowing it to subsequently bind eIF4A. [12][13][14] p70s6K also phosphorylates the eIF4A inhibitor PDCD4, 15 which results in its bTRCP-mediated ubiquitination and degradation, freeing eIF4A for mRNA binding and cap-complex formation. 16 Significantly, 86% of PDCD4 2/2 mice succumb to B-cell lymphomas.…”

Section: Introductionmentioning

confidence: 99%

Inhibiting CARD11 translation during BCR activation by targeting the eIF4A RNA helicase

Steinhardt¹,

Peroutka²,

Mazan-Mamczarz³

et al. 2014

Blood

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Key Points• BCR activation enhances eIF4A m7GTP cap-binding.• The 59UTR of CARD11 suppresses protein translation.Human diffuse large B-cell lymphomas (DLBCLs) often aberrantly express oncogenes that generally contain complex secondary structures in their 59 untranslated region (UTR). Oncogenes with complex 59UTRs require enhanced eIF4A RNA helicase activity for translation. PDCD4 inhibits eIF4A, and PDCD4 knockout mice have a high penetrance for B-cell lymphomas. Here, we show that on B-cell receptor (BCR)-mediated p70s6K activation, PDCD4 is degraded, and eIF4A activity is greatly enhanced. We identified a subset of genes involved in BCR signaling, including CARD11, BCL10, and MALT1, that have complex 59UTRs and encode proteins with short half-lives. Expression of these known oncogenic proteins is enhanced on BCR activation and is attenuated by the eIF4A inhibitor Silvestrol. Antigen-experienced immunoglobulin (Ig)G 1 splenic B cells, from which most DLBCLs are derived, have higher levels of eIF4A cap-binding activity and protein translation than IgM 1 B cells. Our results suggest that eIF4A-mediated enhancement of oncogene translation may be a critical component for lymphoma progression, and specific targeting of eIF4A may be an attractive therapeutic approach in the management of human B-cell lymphomas. (Blood. 2014;124(25):3758-3767)

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“…The cellular factor eIF4B is an accessory factor to the eukaryotic translation initiation factor eIF4A (also known as DDX2) which possesses helicase activity to unwind secondary structure in the 5= untranslated region (5= UTR) of mRNA (12). Phosphorylation of eIF4B is thought to enhance RNA scanning of the 40S ribosomal subunit, enhance eIF4A-mediated melting of secondary structure, or facilitate the translation of a specific subset of cellular RNAs (13,14).…”

mentioning

confidence: 99%

West Nile Virus-Induced Activation of Mammalian Target of Rapamycin Complex 1 Supports Viral Growth and Viral Protein Expression

Shives

Beatman

Chamanian

et al. 2014

J Virol

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Since its introduction in New York City, NY, in 1999, West Nile virus (WNV) has spread to all 48 contiguous states of the United States and is now the leading cause of epidemic encephalitis in North America. As a member of the family Flaviviridae, WNV is part of a group of clinically important human pathogens, including dengue virus and Japanese encephalitis virus. The members of this family of positive-sense, single-stranded RNA viruses have limited coding capacity and are therefore obligated to co-opt a significant amount of cellular factors to translate their genomes effectively. Our previous work has shown that WNV growth was independent of macroautophagy activation, but the role of the evolutionarily conserved mammalian target of rapamycin (mTOR) pathway during WNV infection was not well understood. mTOR is a serine/threonine kinase that acts as a central cellular censor of nutrient status and exercises control of vital anabolic and catabolic cellular responses such as protein synthesis and autophagy, respectively. We now show that WNV activates mTOR and cognate downstream activators of cap-dependent protein synthesis at early time points postinfection and that pharmacologic inhibition of mTOR (KU0063794) significantly reduced WNV growth. We used an inducible Raptor and Rictor knockout mouse embryonic fibroblast (MEF) system to further define the role of mTOR complexes 1 and 2 in WNV growth and viral protein synthesis. Following inducible genetic knockout of the major mTOR cofactors raptor (TOR complex 1 [TORC1]) and rictor (TORC2), we now show that TORC1 supports flavivirus protein synthesis via cap-dependent protein synthesis pathways and supports subsequent WNV growth. IMPORTANCE Since its introduction in New York West Nile virus (WNV) is an enveloped, single-stranded, positive-sense RNA virus in the genus Flavivirus, which includes multiple clinically important viral species such as dengue virus, yellow fever virus, and Japanese encephalitis virus. Since the first North American outbreak in New York City, NY, in 1999 (1), WNV has spread across the continent to become the leading cause of epidemic encephalitis (2). To date, there have been more than 37,000 confirmed cases of WNV disease, 16,000 cases of neuroinvasive disease, and 1,500 fatalities (www.cdc.gov/westnile). Currently, there is no licensed human vaccine or pharmacologic therapy for WNV. Owing to difficulties in predicting the location and timing of WNV outbreaks, insufficient enrollment of WNV-infected patients has complicated human clinical trial design for candidate vaccines and therapeutic interventions. A better understanding of the molecular pathogenesis of flaviviruses and the mechanisms behind how they successfully compete with host messages for access to translational components may reveal broad-spectrum antiflaviviral targets that can be evaluated and licensed for treatment of acute flaviviral infections.Due to the high mutation rates of RNA viral genomes and their subsequent ability to rapidly generate escape mutations, we ...

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Role of p70S6K1-mediated Phosphorylation of eIF4B and PDCD4 Proteins in the Regulation of Protein Synthesis

Cited by 114 publications

References 35 publications

Ventilator-induced diaphragm dysfunction: cause and effect

Ventilator-induced diaphragm dysfunction: cause and effect

Inhibiting CARD11 translation during BCR activation by targeting the eIF4A RNA helicase

West Nile Virus-Induced Activation of Mammalian Target of Rapamycin Complex 1 Supports Viral Growth and Viral Protein Expression

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