Showing papers on "Integrated stress response published in 2010"

Growing Rats Respond to a Sulfur Amino Acid–Deficient Diet by Phosphorylation of the α Subunit of Eukaryotic Initiation Factor 2 Heterotrimeric Complex and Induction of Adaptive Components of the Integrated Stress Response

Abstract: Mammalian cells respond to various kinds of stress, including nutritional stress, via pathways that are initiated by phosphorylation of the α subunit of the eukaryotic initiation factor 2 complex (eIF2α). Because the models used to study eIF2α-kinase–mediated responses to amino acid deficiency have commonly used media or diets devoid of 1 or more essential amino acids, we asked whether eIF2α-kinase–mediated responses would be induced in animals fed a more typical diet that was not as imbalanced as one in which 1 essential amino acid is totally absent. To answer this question, we fed rats soy protein-based diets that were either adequate or limiting in sulfur-containing amino acids (SAA). Rats fed a SAA-deficient diet (3.4 g methionine equivalents/kg diet) grew more slowly than rats fed the control diet (5.86 g methionine equivalents/kg diet). Analysis of liver from rats fed these diets for 7 d showed that the SAA-deficient rats had higher levels of eIF2α phosphorylation and higher levels of activating transcription factor (ATF) 4, ATF3, asparagine synthetase, solute carrier 7A11, cysteinyl-tRNA synthetase, and cystathionine γ-lyase. On the other hand, components of the integrated stress response (ISR) known to promote apoptosis or translational recovery were not induced. Taken together, our results indicate that rats fed the SAA-deficient diet had a prolonged activation of an eIF2α kinase that leads to upregulation of adaptive components of the ISR.

Impaired tissue growth is mediated by checkpoint kinase 1 (CHK1) in the integrated stress response.

Abstract: The integrated stress response (ISR) protects cells from numerous forms of stress and is involved in the growth of solid tumours; however, it is unclear how the ISR acts on cellular proliferation. We have developed a model of ISR signalling with which to study its effects on tissue growth. Overexpression of the ISR kinase PERK resulted in a striking atrophic eye phenotype in Drosophila melanogaster that could be rescued by co-expressing the eIF2α phosphatase GADD34. A genetic screen of 3000 transposon insertions identified grapes, the gene that encodes the Drosophila orthologue of checkpoint kinase 1 (CHK1). Knockdown of grapes by RNAi rescued eye development despite ongoing PERK activation. In mammalian cells, CHK1 was activated by agents that induce ER stress, which resulted in a G2 cell cycle delay. PERK was both necessary and sufficient for CHK1 activation. These findings indicate that non-genotoxic misfolded protein stress accesses DNA-damage-induced cell cycle checkpoints to couple the ISR to cell cycle arrest.

The integrated stress response-associated signals modulates intestinal tumor cell growth by NSAID-activated gene 1 (NAG-1/MIC-1/PTGF-β)

Abstract: Phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2alpha) is a critical convergence point of the integrated stress response (ISR), which supports eukaryotic cellular adaptation to diverse stressful conditions, including the endoplasmic reticulum (ER) stress by global protein translational arrest and induction of numerous stress-triggered cytoprotective genes. Challenge with non-steroidal anti-inflammatory drug (NSAID) leads to ER perturbation that may sensitize cancer cells to drug-induced apoptosis. Here, we examined the ER stress signals in the context of NSAID exposure and the induction of the critical tumor suppressor, NSAID-activated gene 1 (NAG-1), in the epithelial cancer cells. Sulindac sulfide, the active sulindac metabolite, was shown to trigger the ISRs via eIF2alpha kinase such as RNA-dependent protein kinase-related endoplasmic reticulum kinase (PERK) and RNA-dependent protein kinase (PKR). ER stress markers such as glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and activating transcription factor (ATF)-3 were enhanced by sulindac sulfide in colon cancer cells. In these cells, the PERK-activated ATF3-CHOP signaling pathway mediated the gene expression of pro-apoptotic NAG-1- and NSAID-induced apoptosis. In contrast, PKR protein was not involved in the signaling cascade for the gene expression of CHOP-linked NAG-1. Instead, PKR mediated activation of pro-survival extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway, which was enhanced by NAG-1 suppression in response to cytotoxic sulindac sulfide exposure. PKR-ERK1/2 activation may thus contribute to the defensive cellular response to cytotoxic NSAIDs while drug-mediated ER stress triggers the pro-apoptotic NAG-1 production in human colon cancer cells.

The Role of IFRD1 during the Integrated Stress Response

Abstract: 5

Abstract LB-333: A CREBZF/Zhangfei isoform activates CHOP and promotes apoptosis during prolonged endoplasmic reticulum stress

Abstract: The basic leucine zipper transcription factor CREBZF (Zhangfei or ZF) was identified through its interaction with Herpes Simplex Virus-1 related cellular protein HCF-1, and has been implicated in cellular stress responses through its interaction with other proteins, such as CREB3/Luman and ATF4. Here we investigated the production of four CREBZF isoforms, which arise from translational initiation of a downstream AUG at codon 83 and mRNA alternative splicing that adds an IFFFR pentapeptidyl tail to the C-terminus. We found that in addition to transcriptional induction, the short-tailed CREBZF (stZF) isoform was specifically induced by prolonged ER stress treatment and amino acid deprivation. This stZF isoform is a potent transcriptional activator of the pro-apoptotic protein CHOP. Overexpression of stZF activates transcription of CHOP through a CCAAT enhancer binding protein (C/EBP)-ATF site, and promotes apoptosis. We propose that 1) CREBZF is a key component of the integrated stress response; 2) stZF is tightly regulated and induced primarily under prolonged cellular stress, and is essential for the role of CREBZF in inducing CHOP and promoting cell death. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-333.

Activation of the integrated stress response in HIV-associated neurocognitive disorder

Abstract: HIV-associated neurocognitive disorders (HAND) are comprised of a host of behavioral, cognitive, and motor disabilities and can range from more minor disorders that largely allow basic daily functioning to severe disorders, such as HIV-associated dementia. The mechanisms that ultimately result in neuronal death in HAND are not known. Presented here are data demonstrating activation of the Integrated Stress Response (ISR) in cortical autopsy tissue from HAND patients, as well as data characterizing the nature of the activation of this cellular stress response in this disease. Specifically, we have shown that there are increased levels of the molecular chaperone protein, BiP, which serves as an indicator of general ISR activation. We then present data to suggest that, of the three prongs of the ISR, the prong initiated by ATF6 appears to be active, while PERK does not appear to initiate the prong it regulates. However, intriguingly, proteins downstream of PERK, namely global pEIF2α and astrocytic ATF4 do appear to be activated, suggesting that other initiators outside of the PERK pathway may be acting on these classic components of the ISR. Finally, we show data suggesting that Nrf2, the master regulator of the endogenous antioxidant component of the ISR, may be active in the cortex of HAND patients. While the ISR is clearly a protective response, able to help individual cells protect themselves from toxic insults, it is also able to initiate cellular apoptosis, which in principle protects healthy cells from a dangerous necrotic death of neighboring cells. However, under conditions of chronic stress in the CNS, such as that seen in HAND, too many neurons may die as a result of ISR-initiated apoptosis, thereby resulting in the neurocognitive decline with which these patients are afflicted. Thus, the findings presented here provide starting points of investigation for research aimed at developing potential therapeutic targets for HAND, with some targets for which their response must be increased by therapies and other targets for which their response must be dampened by therapies. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Neuroscience First Advisor Dr. Kelly L. Jordan-Sciutto