Differential Phosphorylation of Translation Initiation Regulators 4EBP1, S6k1, and Erk 1/2 Following Inhibition of Alcohol Metabolism in Mouse Heart

Vary, Thomas C.; Lang, Charles H.

doi:10.1007/s12012-008-9012-4

Cited by 10 publications

(9 citation statements)

References 57 publications

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“…Hypophosphorylated EIF4EBP acts as a repressor of eIF4E whereas its phosphorylation releases eIF4E, thereby up-regulating protein translation in response to signaling by diverse cell-surface receptors, including insulin, EGF, PDGF, and other ligands (13). In heart, EIF4EBP has been implicated in ischemia-reperfusion stress, cardiomyocyte survival, cardiac hypertrophy, and oxidative and nutritional stress responses (13).…”

Section: Resultsmentioning

confidence: 99%

Global phosphoproteomic profiling reveals perturbed signaling in a mouse model of dilated cardiomyopathy

Kuzmanov

Guo

Buchsbaum

et al. 2016

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

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Phospholamban (PLN) plays a central role in Ca2+ homeostasis in cardiac myocytes through regulation of the sarco(endo)plasmic reticulum Ca 2+ -ATPase 2A (SERCA2A) Ca 2+ pump. An inherited mutation converting arginine residue 9 in PLN to cysteine (R9C) results in dilated cardiomyopathy (DCM) in humans and transgenic mice, but the downstream signaling defects leading to decompensation and heart failure are poorly understood. Here we used precision mass spectrometry to study the global phosphorylation dynamics of 1,887 cardiac phosphoproteins in early affected heart tissue in a transgenic R9C mouse model of DCM compared with wild-type littermates. Dysregulated phosphorylation sites were quantified after affinity capture and identification of 3,908 phosphopeptides from fractionated whole-heart homogenates. Global statistical enrichment analysis of the differential phosphoprotein patterns revealed selective perturbation of signaling pathways regulating cardiovascular activity in early stages of DCM. Strikingly, dysregulated signaling through the Notch-1 receptor, recently linked to cardiomyogenesis and embryonic cardiac stem cell development and differentiation but never directly implicated in DCM before, was a prominently perturbed pathway. We verified alterations in Notch-1 downstream components in early symptomatic R9C transgenic mouse cardiomyocytes compared with wild type by immunoblot analysis and confocal immunofluorescence microscopy. These data reveal unexpected connections between stress-regulated cell signaling networks, specific protein kinases, and downstream effectors essential for proper cardiac function.phospholamban | proteomic | bioinformatics | heart disease | signaling C ardiovascular diseases (CVDs) leading to systolic/diastolic heart failure (HF), such as hypertensive/diabetic heart disease, stroke, and vascular atherosclerosis, are leading causes of death in the developed world (1). Many CVDs are associated with genetic predispositions. For example, in humans, the arginine to cysteine (R9C) substitution in phospholamban (PLN) has been shown to result in dilated cardiomyopathy (DCM) presenting in adolescence, leading to rapid deterioration of heart function and premature death (2). However, the etiology and molecular mechanisms of progression of DCM and other CVDs leading to HF are complex and still poorly understood, further complicating clinical assessment and management. From a biological and clinical perspective, the identification and characterization of clinically relevant, potentially druggable, pathways driving the maladaptive response in affected heart tissue are key challenges to improved diagnostic and therapeutic tools for earlier detection and preventative treatment of both inherited and chronic CVDs.Cardiac muscle contraction is controlled by Ca 2+ flux and signaling relays, which are perturbed in HF. Internal stores of Ca 2+ required for the proper functioning of cardiomyocytes (CMs) are normally maintained through the function of the sarco(endo)plasmic reticulum Ca 2+ -ATPase 2 ...

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Section: Resultsmentioning

confidence: 99%

Global phosphoproteomic profiling reveals perturbed signaling in a mouse model of dilated cardiomyopathy

Kuzmanov

Guo

Buchsbaum

et al. 2016

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

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“…Although glycosylation of intracellular proteins is not always associated with heart failure, it has been suggested that glycogen stores are considered cardiac protective because partitioning of free glucose into glycogen reduces this posttranslational modification [28]. Phosphorylation and activation of the eukaryotic translation initiation factor 4E-binding protein (4EBP1) are markers for translation initiation [29]. The data depicted in Fig.…”

Section: Assessment Of Mitochondrial Dysfunction In the Hearts Of Idhmentioning

confidence: 99%

IDH2 deficiency promotes mitochondrial dysfunction and cardiac hypertrophy in mice

Ahn

Lee

et al. 2015

Free Radical Biology and Medicine

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“…Addition of 4-MP partially prevents the inhibition of protein synthesis and completely restores the polysome distribution in rat hepatocytes in culture, suggesting that ethanol inhibition of protein synthesis is partly linked to ethanol metabolism (14). In heart and skeletal muscle, the effect of pretreatment with 4-MP or cyanamide, an inhibitor of ALDH, before ethanol administration suggests that both alcohol itself and its metabolite acetaldehyde are inhibitory agents (40,55).…”

Section: Inhibitor Studiesmentioning

confidence: 99%

Acute and chronic ethanol consumption differentially impact pathways limiting hepatic protein synthesis

Karinch¹,

Martin²,

Vary³

2008

American Journal of Physiology-Endocrinology and Metabolism

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This review identifies the various pathways responsible for modulating hepatic protein synthesis following acute and chronic alcohol intoxication and describes the mechanism(s) responsible for these changes. Alcohol intoxication induces a defect in global protein synthetic rates that is localized to impaired translation of mRNA at the level of peptide-chain initiation. Translation initiation is regulated at two steps: formation of the 43S preinitiation complex [controlled by eukaryotic initiation factors 2 (eIF2) and 2B (eIF2B)] and the binding of mRNA to the 40S ribosome (controlled by the eIF4F complex). To date, alcohol-induced alterations in eIF2 and eIF2B content and activity are best investigated. Ethanol decreases eIF2B activity when ingested either acutely or chronically. The reduced eIF2B activity most likely is a consequence of twofold increased phosphorylation of the alpha-subunit of eIF2 on Ser(51) following acute intoxication. The increase in eIF2alpha phosphorylation after chronic alcohol consumption is the same as that induced by acute ethanol intoxication, and protein synthesis is not further reduced by long-term alcohol ingestion despite additional reduced expression of initiation factors and elongation factors. eIF2alpha phosphorylation alone appears sufficient to maximally inhibit hepatic protein synthesis. Indeed, pretreatment with Salubrinal, an inhibitor of eIF2alpha(P) phosphatase, before ethanol treatment does not further inhibit protein synthesis or increase eIF2alpha phosphorylation, suggesting that acute ethanol intoxication causes maximal eIF2alpha phosphorylation elevation and hepatic protein synthesis inhibition. Ethanol-induced inhibition of hepatic protein synthesis is not rapidly reversed by cessation of ethanol consumption. In conclusion, sustained eIF2alpha phosphorylation is a hallmark of excessive alcohol intake leading to inhibition of protein synthesis. Enhanced phosphorylation of eIF2alpha represents a unique response of liver to alcohol intoxication, because the ethanol-induced elevation of eIF2alpha(P) is not observed in skeletal muscle or heart.

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Differential Phosphorylation of Translation Initiation Regulators 4EBP1, S6k1, and Erk 1/2 Following Inhibition of Alcohol Metabolism in Mouse Heart

Cited by 10 publications

References 57 publications

Global phosphoproteomic profiling reveals perturbed signaling in a mouse model of dilated cardiomyopathy

Global phosphoproteomic profiling reveals perturbed signaling in a mouse model of dilated cardiomyopathy

IDH2 deficiency promotes mitochondrial dysfunction and cardiac hypertrophy in mice

Acute and chronic ethanol consumption differentially impact pathways limiting hepatic protein synthesis

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