Protein synthesis inhibition promotes nitric oxide generation and activation of CGKII-dependent downstream signaling pathways in the retina

Cossenza, Marcelo; Socodato, Renato; Mejía-García, Telmo A.; Domith, Ivan; Portugal, Camila C.; Gladulich, Luis Felipe Homem; Duarte-Silva, Aline T.; Khatri, Latika; Antoine, Shannon O.; Hofmann, Franz; Ziff, Edward B.; Paes‐de‐Carvalho, Roberto

doi:10.1016/j.bbamcr.2020.118732

Cited by 7 publications

(6 citation statements)

References 55 publications

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“…To inhibit the abnormal activation of mTORC1‐mediated protein synthesis in leukemia cells and recover from transplant‐induced stress, we used CHX and the mTORC1 inhibitors Torin 1 and rapamycin [34,35]. We found that CHX, Torin 1, and rapamycin could reduce the apoptosis of cells under serum treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

mTORC1‐mediated amino acid signaling is critical for cell fate determination under transplant‐induced stress

Cheng

Zhu

et al. 2020

FEBS Letters

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Transplantation of in vitro-manipulated cells is widely used in hematology. While transplantation is well recognized to impose severe stress on transplanted cells, the nature of transplant-induced stress remains elusive. Here, we propose that the lack of amino acids in serum is the major cause of transplant-induced stress. Mechanistically, amino acid deficiency decreases protein synthesis and nutrient consummation. However, in cells with overactive AKT and ERK, mTORC1 is not inhibited and protein synthesis remains relatively high. This impaired signaling causes nutrient depletion, cell cycle block, and eventually autophagy and cell death, which can be inhibited by cycloheximide or mTORC1 inhibitors. Thus, mTORC1-mediated amino acid signaling is critical in cell fate determination under transplant-induced stress, and protein synthesis inhibition can improve transplantation efficiency.

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Section: Resultsmentioning

confidence: 99%

mTORC1‐mediated amino acid signaling is critical for cell fate determination under transplant‐induced stress

Cheng

Zhu

et al. 2020

FEBS Letters

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“…eEF2K activity and inhibition of protein synthesis have previously been linked with correct synaptic maintenance and survival, especially during events related to neuronal plasticity (Cossenza et al., 2020; Gladulich, Peixoto‐Rodrigues, Campello‐Costa, Paes‐de‐Carvalho, & Cossenza, 2020; Heise et al., 2014; Proud, 2015). The expression of a specific set of proteins is, paradoxically, increased upon eEF2K activation; these include the α‐subunit of CaMKII; BDNF; Arc/Arg3.1 and MAPB1 (Davidkova & Carroll, 2007; Park et al., 2008; Scheetz et al., 2000; Verpelli et al., 2010).…”

Section: Discussionmentioning

confidence: 99%

Bicuculline regulated protein synthesis is dependent on Homer1 and promotes its interaction with eEF2K through mTORC1‐dependent phosphorylation

Gladulich

Xie

Jensen

et al. 2020

Journal of Neurochemistry

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The regulation of protein synthesis is a vital and finely tuned process in cellular physiology. In neurons, this process is very precisely regulated, as which mRNAs undergo translation is highly dependent on context. One of the most prominent regulators of protein synthesis is the enzyme eukaryotic elongation factor kinase 2 (eEF2K) that regulates the elongation stage of protein synthesis. This kinase and its substrate, eukaryotic elongation factor 2 (eEF2) are important in processes such as neuronal development and synaptic plasticity. eEF2K is regulated by multiple mechanisms including Ca 2+ -ions and the mTORC1 signaling pathway, both of which play key roles in neurological processes such as learning and memory. In such settings, the localized control of protein synthesis is of crucial importance. In this work, we sought to investigate how the localization of eEF2K is controlled and the impact of this on protein synthesis in neuronal cells. In this study, we used both SH-SY5Y neuroblastoma cells and mouse cortical neurons, and pharmacologically and/or genetic approaches to modify eEF2K function. We show that eEF2K activity and localization can be regulated by its binding partner Homer1b/c, a scaffolding protein known for its participation in calcium-regulated signaling pathways. Furthermore, our results indicate that this interaction is regulated by the mTORC1 pathway, through a known phosphorylation site in eEF2K (S396), and that it affects rates of localized protein synthesis at synapses depending on the presence or absence of this scaffolding protein.

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“…Furthermore, eEF2 phosphorylation mediated by NMDAR activation was clearly associated with CREB activation in the retina, an event that appears to depend on the increase in free L-arginine and the activation of nNOS [37]. Increased L-arginine has also been described during pharmacological treatments with cycloheximide or anisomycin (CHX or ANISO, respectively), where the PKG-dependent NO signaling pathway (a canonical pathway) was shown to activate ERK and AKT [36,48]. It is known that CREB, AKT, and ERK are widely associated with promoting survival, neuronal growth, synaptic plasticity, response to stress, and learning and memory [49][50][51].…”

Section: Glutamatementioning

confidence: 98%

The Healthy and Diseased Retina Seen through Neuron–Glia Interactions

Tempone,

Borges-Martins,

César

et al. 2024

IJMS

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The retina is the sensory tissue responsible for the first stages of visual processing, with a conserved anatomy and functional architecture among vertebrates. To date, retinal eye diseases, such as diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, glaucoma, and others, affect nearly 170 million people worldwide, resulting in vision loss and blindness. To tackle retinal disorders, the developing retina has been explored as a versatile model to study intercellular signaling, as it presents a broad neurochemical repertoire that has been approached in the last decades in terms of signaling and diseases. Retina, dissociated and arranged as typical cultures, as mixed or neuron- and glia-enriched, and/or organized as neurospheres and/or as organoids, are valuable to understand both neuronal and glial compartments, which have contributed to revealing roles and mechanisms between transmitter systems as well as antioxidants, trophic factors, and extracellular matrix proteins. Overall, contributions in understanding neurogenesis, tissue development, differentiation, connectivity, plasticity, and cell death are widely described. A complete access to the genome of several vertebrates, as well as the recent transcriptome at the single cell level at different stages of development, also anticipates future advances in providing cues to target blinding diseases or retinal dysfunctions.

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Protein synthesis inhibition promotes nitric oxide generation and activation of CGKII-dependent downstream signaling pathways in the retina

Cited by 7 publications

References 55 publications

mTORC1‐mediated amino acid signaling is critical for cell fate determination under transplant‐induced stress

mTORC1‐mediated amino acid signaling is critical for cell fate determination under transplant‐induced stress

Bicuculline regulated protein synthesis is dependent on Homer1 and promotes its interaction with eEF2K through mTORC1‐dependent phosphorylation

The Healthy and Diseased Retina Seen through Neuron–Glia Interactions

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