Dose-dependent differential response of mammalian cells to cytoplasmic stress is mediated through the heme-regulated eIF2α kinase

Mittal, Smriti; Kulkarni, Abhijeet; Mathai, Jinumary; Chattopadhyay, Samit; Pal, Jayanta K.

doi:10.1016/j.biocel.2014.07.016

Cited by 9 publications

(4 citation statements)

References 44 publications

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“…Our results implicating HRI in BZ-induced eIF2α phosphorylation and cytoprotection are consistent with the work of Lu, et al ( 48 ), who concluded that HRI controlled translational attenuation in response to a variety of cytosolic stressors such as arsenite, heat shock, and osmotic stress, but not ER-stress or nutrient starvation. Similarly, HRI was also implicated in the stress response following lead exposure in mammalian cells ( 49 ). Like the other eIF2α kinases, HRI activation is accompanied by extensive autophosphorylation, with the Thr485 residue being most critical for kinase activity ( 50 ).…”

Section: Discussionmentioning

confidence: 99%

HRI-mediated translational repression reduces proteotoxicity and sensitivity to bortezomib in human pancreatic cancer cells

White

Schroeder²,

Zhu

et al. 2018

Oncogene

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Human cancer cells display extensive heterogeneity in their sensitivities to the proteasome inhibitor bortezomib (Velcade). The molecular mechanisms underlying this heterogeneity remain unclear, and strategies to overcome resistance are limited. Here, we discover that inherent differences in eIF2α phosphorylation among a panel of 10 human pancreatic cancer cell lines significantly impacts bortezomib sensitivity, and implicate the HRI (heme-regulated inhibitor) eIF2α kinase as a novel therapeutic target. Within our panel, we identified a subset of cell lines with defective induction of eIF2α phosphorylation, conferring a high degree of sensitivity to bortezomib. These bortezomib-sensitive cells exhibited impaired translation attenuation followed by toxic accumulation of protein aggregates and reactive oxygen species (ROS), whereas the bortezomib-resistant cell lines displayed increased phosphorylation of eIF2α, decreased translation, few protein aggregates, and minimal ROS production. Importantly, we identified HRI as the primary bortezomib-activated eIF2α kinase, and demonstrated that HRI knockdown promoted cell death in the bortezomib-resistant cells. Overall, our data implicate inducible HRI-mediated phosphorylation of eIF2α as a central cytoprotective mechanism following exposure to bortezomib and provide proof-of-concept for the development of HRI inhibitors to overcome proteasome inhibitor resistance.

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Section: Discussionmentioning

confidence: 99%

HRI-mediated translational repression reduces proteotoxicity and sensitivity to bortezomib in human pancreatic cancer cells

White

Schroeder²,

Zhu

et al. 2018

Oncogene

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“…Control and treated cells were washed with 1× phosphate buffered saline (1× PBS) (137 mM NaCl, 2.7 mM KCl, 10 mM Na 2 HPO 4 , 2 mM KH 2 PO 4 ) and fixed at 4°C for 2 hrs using 70% ethanol. The single cell suspension was then treated with RNase A (100 mg/ml) at 37°C for 30 mins followed by staining with 50 mg/ml propidium iodide ( 22 ). Stained cells were analyzed with FACSCanto, using cell quest software (BD, USA).…”

Section: Methodsmentioning

confidence: 99%

Cytoprotective effect exerted by geraniin in HepG2 cells is through microRNA mediated regulation of BACH-1 and HO-1

Aayadi

Mittal

Deshpande³

et al. 2017

BMB Rep.

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Geraniin, a hydrolysable tannin, used in traditional medicine in Southeast Asia, is known to exhibit various biological activities. As an antioxidant it is known to up-regulate phase II enzyme Heme oxygenase-1 (HO-1). However its mechanism is not clearly understood. Nuclear factor erythroid-derived 2 related factor 2 (Nrf-2) is transcriptionally up-regulated by Extracellular signal-regulated kinase (ERK) 1/2 and retained in nucleus due to inactivated Glycogen synthase kinase 3 beta (GSK-3β). Geraniin additionally down-regulates expression of microRNA 217 and 377 (miR-217 and miR-377) which target HO-1 mRNA. Expression of BTB and CNC homolog 1 (BACH-1), another regulator of HO-1, is also down-regulated by up-regulating microRNA 98 (miR-98), a negative regulator of BACH-1. Thus, geraniin up-regulates HO-1 expression both through activating its positive regulator Nrf-2 and by down-regulating its negative regulator BACH-1. Up-regulation of HO-1 also confers protection to HepG2 cells from tertiary butyl hydroperoxide (TBH) induced cytotoxicity.

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“…Salubrinal, a treatment alternative method, selectively suppresses eIF2α dephosphorylation by inhibiting PP1 activity, sustaining the phosphorylated eIF2α status, while ISRIB inhibits the eIF2α phosphorylation [15][16][17]. In addition, DnaJC3 is an ER stress-regulated chaperone and can inhibit eIF2α kinases including PERK, protein kinase R (PKR), general control nonderepressible 2 (GCN2), and heme-regulated inhibitor (HRI) [18,19]. Taken together, PERK, ATF6, and IRE1α can impede protein synthesis, upregulate an ER response protein, activate ER-related degradation, and promote cell survival [20].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of eIF2α Dephosphorylation Protects Hepatocytes from Apoptosis by Alleviating ER Stress in Acute Liver Injury

Tang

Chen

et al. 2020

BioMed Research International

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Objectives. Protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α) is an important factor along the main pathways for endoplasmic reticulum (ER) stress-mediated apoptosis. In this study, we investigated the effects of eIF2α phosphorylation on hepatocyte apoptosis and the ER stress mechanisms in acute liver injury. Methods. eIF2α phosphorylation and apoptosis under ER stress were monitored and measured in male BALB/c mice with acute liver injury and human hepatocyte line LO2 cells. Results. Carbon tetrachloride (CCl4) administration triggered ER stress and hepatocyte apoptosis, as well as eIF2α phosphorylation in mice. Inhibition of eIF2α dephosphorylation, as the pretreatment with 4-phenylbutyric acid (chemical chaperone, ER stress inhibitor), mitigated CCl4-induced intrahepatic ER stress, apoptosis, and liver injury. In an ER stress model of LO2 cells induced by thapsigargin (disrupting ER calcium balance), inhibition of eIF2α dephosphorylation reduced ER stress and apoptosis, while PERK knockdown reduced eIF2α phosphorylation and exacerbated ER stress and apoptosis. Conclusions. eIF2α phosphorylation is one of the mechanisms employed by ER stress for restoring cellular homeostasis. Inhibition of eIF2α dephosphorylation mitigates hepatocyte apoptosis by alleviating ER stress in acute liver injuries.

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Dose-dependent differential response of mammalian cells to cytoplasmic stress is mediated through the heme-regulated eIF2α kinase

Cited by 9 publications

References 44 publications

HRI-mediated translational repression reduces proteotoxicity and sensitivity to bortezomib in human pancreatic cancer cells

HRI-mediated translational repression reduces proteotoxicity and sensitivity to bortezomib in human pancreatic cancer cells

Cytoprotective effect exerted by geraniin in HepG2 cells is through microRNA mediated regulation of BACH-1 and HO-1

Inhibition of eIF2α Dephosphorylation Protects Hepatocytes from Apoptosis by Alleviating ER Stress in Acute Liver Injury

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