Cardinal role of eukaryotic initiation factor 2 (eIF2α) in progressive dopaminergic neuronal death & DNA fragmentation: Implication of PERK:IRE1α:ATF6 axis in Parkinson's pathology

2021 ◽  
Vol 81 ◽  
pp. 109922
Author(s):  
Sonam Gupta ◽  
Amit Mishra ◽  
Sarika Singh
Keyword(s):  
Dna Fragmentation ◽  
Neuronal Death ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Eukaryotic Initiation Factor 2 ◽  
Initiation Factor 2

scholarly journals Defects in Translational Regulation Mediated by the α Subunit of Eukaryotic Initiation Factor 2 Inhibit Antiviral Activity and Facilitate the Malignant Transformation of Human Fibroblasts

2004 ◽  
Vol 24 (5) ◽  
pp. 2025-2040 ◽  
Author(s):  
Darren J. Perkins ◽  
Glen N. Barber
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
T Antigen ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Α Subunit ◽  
Eukaryotic Initiation Factor 2 ◽  
Initiation Factor 2

ABSTRACT Suppression of protein synthesis through phosphorylation of the translation initiation factor α subunit of eukaryotic initiation factor 2 (eIF2α) is known to occur in response to many forms of cellular stress. To further study this, we have developed novel cell lines that inducibly express FLAG-tagged versions of either the phosphomimetic eIF2α variant, eIF2α-S51D, or the phosphorylation-insensitive eIF2α-S51A. These variants showed authentic subcellular localization, were incorporated into endogenous ternary complexes, and were able to modulate overall rates of protein synthesis as well as influence cell division. However, phosphorylation of eIF2α failed to induce cell death or sensitize cells to killing by proapoptotic stimuli, though it was able to inhibit viral replication, confirming the role of eIF2α in host defense. Further, although the eIF2α-S51A variant has been shown to transform NIH 3T3 cells, it was unable to transform the murine fibroblast 3T3 L1 cell line. To therefore clarify this issue, we explored the role of eIF2α in growth control and demonstrated that the eIF2α-S51A variant is capable of collaborating with hTERT and the simian virus 40 large T antigen in the transformation of primary human kidney cells. Thus, dysregulation of translation initiation is indeed sufficient to cooperate with defined oncogenic elements and participate in the tumorigenesis of human tissue.

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