Unique integrated stress response sensors regulate cancer cell susceptibility when Hsp70 activity is compromised

AMPK, AMP-activated protein Kinase; AKT, AK strain Transforming serine/threonine kinase; ASNS, asparagine synthetase; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; BiP, Immunoglobulin Binding Protein; CHOP, C/EBP homologous protein; CQ, chloroquine; DTT, 1,4-Dithiothreitol; EBSS, Earle's balanced salt solution; eIF2α, eukaryotic initiation factor 2 alpha; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum associated degradation; FBS, fetal bovine serum; GCN2, general control non-derepressible 2 factor; GFP, green fluorescent protein; HER2, epidermal growth factor receptor 2; HIF1α, Hypoxia Inducible Factor 1 Subunit Alpha; HRI, heme-regulated inhibitor kinase; Hsp70, heat shock protein 70; IRE1, inositol-required enzyme 1; ISR, integrated stress response; MAL3-101, phenylmethyl 4-[1,1'-biphenyl]-4-yl-1-[6-[[2-(butylamino)-1-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]-2-oxoethyl]hexylamino]-6-oxohexyl]-1,2,3,4-tetrahydro-6-methyl-2-oxo-5-pyrimidinecarboxylate; mTOR, mechanistic Target Of Rapamycin; PBS, phosphate buffered saline; PERK, PKR-like endoplasmic reticulum resident kinase; PI, propidium iodide; PKR, Protein Kinase RNA-activated; RFP, red fluorescent protein; RPPA, Reverse Phase Protein Array; S6K, 70‐kDa ribosomal protein S6 kinase; TNBC, triple negative breast cancer; UPR, unfolded protein response; XbpI, X-box binding protein 1.

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Activation of NADPH Oxidase 4 in the Endoplasmic Reticulum Promotes Cardiomyocyte Autophagy and Survival During Energy Stress Through the Protein Kinase RNA-Activated-Like Endoplasmic Reticulum Kinase/Eukaryotic Initiation Factor 2α/Activating Transcription Factor 4 Pathway

Circulation Research ◽

10.1161/circresaha.113.301787 ◽

2013 ◽

Vol 113 (11) ◽

pp. 1253-1264 ◽

Cited By ~ 104

Author(s):

Sebastiano Sciarretta ◽

Peiyong Zhai ◽

Dan Shao ◽

Daniela Zablocki ◽

Narayani Nagarajan ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Transcription Factor ◽

Initiation Factor ◽

Eukaryotic Initiation Factor ◽

Nadph Oxidase 4 ◽

Energy Stress ◽

Activating Transcription Factor 4 ◽

Cardiomyocyte Autophagy ◽

Activating Transcription Factor ◽

Transcription Factor 4

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Activating Transcription Factor 3 Is Integral to the Eukaryotic Initiation Factor 2 Kinase Stress Response

Molecular and Cellular Biology ◽

10.1128/mcb.24.3.1365-1377.2004 ◽

2004 ◽

Vol 24 (3) ◽

pp. 1365-1377 ◽

Cited By ~ 328

Author(s):

Hao-Yuan Jiang ◽

Sheree A. Wek ◽

Barbara C. McGrath ◽

Dan Lu ◽

Tsonwin Hai ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Amino Acid ◽

Stress Response ◽

Amino Acid Starvation ◽

Initiation Factor ◽

Activating Transcription Factor 3 ◽

Eukaryotic Initiation Factor ◽

Initiation Factor 2 ◽

Activating Transcription Factor

ABSTRACT In response to environmental stress, cells induce a program of gene expression designed to remedy cellular damage or, alternatively, induce apoptosis. In this report, we explore the role of a family of protein kinases that phosphorylate eukaryotic initiation factor 2 (eIF2) in coordinating stress gene responses. We find that expression of activating transcription factor 3 (ATF3), a member of the ATF/CREB subfamily of basic-region leucine zipper (bZIP) proteins, is induced in response to endoplasmic reticulum (ER) stress or amino acid starvation by a mechanism requiring eIF2 kinases PEK (Perk or EIF2AK3) and GCN2 (EIF2AK4), respectively. Increased expression of ATF3 protein occurs early in response to stress by a mechanism requiring the related bZIP transcriptional regulator ATF4. ATF3 contributes to induction of the CHOP transcriptional factor in response to amino acid starvation, and loss of ATF3 function significantly lowers stress-induced expression of GADD34, an eIF2 protein phosphatase regulatory subunit implicated in feedback control of the eIF2 kinase stress response. Overexpression of ATF3 in mouse embryo fibroblasts partially bypasses the requirement for PEK for induction of GADD34 in response to ER stress, further supporting the idea that ATF3 functions directly or indirectly as a transcriptional activator of genes targeted by the eIF2 kinase stress pathway. These results indicate that ATF3 has an integral role in the coordinate gene expression induced by eIF2 kinases. Given that ATF3 is induced by a very large number of environmental insults, this study supports involvement of eIF2 kinases in the coordination of gene expression in response to a more diverse set of stress conditions than previously proposed.

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Activating transcription factor 4 and CCAAT/enhancer-binding protein-β negatively regulate the mammalian target of rapamycin via Redd1 expression in response to oxidative and endoplasmic reticulum stress

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2009.01.015 ◽

2009 ◽

Vol 46 (8) ◽

pp. 1158-1167 ◽

Cited By ~ 70

Author(s):

Hyeon-Ok Jin ◽

Sung-Keum Seo ◽

Sang-Hyeok Woo ◽

Eun-Sung Kim ◽

Hyung-Chahn Lee ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Transcription Factor ◽

Endoplasmic Reticulum Stress ◽

Binding Protein ◽

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

Activating Transcription Factor 4 ◽

Enhancer Binding Protein ◽

Activating Transcription Factor ◽

Transcription Factor 4

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Death-associated Protein Kinase-1 Expression and Autophagy in Chronic Lymphocytic Leukemia Are Dependent on Activating Transcription Factor-6 and CCAAT/Enhancer-binding Protein-β

Journal of Biological Chemistry ◽

10.1074/jbc.m116.725796 ◽

2016 ◽

Vol 291 (42) ◽

pp. 22030-22042 ◽

Cited By ~ 11

Author(s):

Padmaja Gade ◽

Amy S. Kimball ◽

Angela C. DiNardo ◽

Priyamvada Gangwal ◽

Douglas D. Ross ◽

...

Keyword(s):

Transcription Factor ◽

Protein Kinase ◽

Chronic Lymphocytic Leukemia ◽

Binding Protein ◽

Lymphocytic Leukemia ◽

Enhancer Binding Protein ◽

Ccaat Enhancer Binding Protein ◽

Death Associated Protein Kinase ◽

Activating Transcription Factor

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Distinct roles of activating transcription factor 6 (ATF6) and double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK) in transcription during the mammalian unfolded protein response

Biochemical Journal ◽

10.1042/bj20020391 ◽

2002 ◽

Vol 366 (2) ◽

pp. 585-594 ◽

Cited By ~ 346

Author(s):

Tetsuya OKADA ◽

Hiderou YOSHIDA ◽

Rieko AKAZAWA ◽

Manabu NEGISHI ◽

Kazutoshi MORI

Keyword(s):

Endoplasmic Reticulum ◽

Transcription Factor ◽

Protein Kinase ◽

Er Stress ◽

Double Stranded Rna ◽

Unfolded Protein ◽

Genes Encoding ◽

Membrane Bound ◽

Activating Transcription Factor ◽

Protein Response

In response to accumulation of unfolded proteins in the endoplasmic reticulum (ER), a homoeostatic response, termed the unfolded protein response (UPR), is activated in all eukaryotic cells. The UPR involves only transcriptional regulation in yeast, and approx. 6% of all yeast genes, encoding not only proteins to augment the folding capacity in the ER, but also proteins working at various stages of secretion, are induced by ER stress [Travers, Patil, Wodicka, Lockhart, Weissman and Walter (2000) Cell (Cambridge, Mass.) 101, 249–258]. In the present study, we conducted microarray analysis of HeLa cells, although our analysis covered only a small fraction of the human genome. A great majority of human ER stress-inducible genes (approx. 1% of 1800 genes examined) were classified into two groups. One group consisted of genes encoding ER-resident molecular chaperones and folding enzymes, and these genes were directly regulated by the ER-membrane-bound transcription factor activating transcription factor (ATF) 6. The ER-membrane-bound protein kinase double-stranded RNA-activated protein kinase-like ER kinase (PERK)-mediated signalling pathway appeared to be responsible for induction of the remaining genes, which are not involved in secretion, but may be important after cellular recovery from ER stress. In higher eukaryotes, the PERK-mediated translational-attenuation system is known to operate in concert with the transcriptional-induction system. Thus we propose that mammalian cells have evolved a strategy to cope with ER stress different from that of yeast cells.

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