Nuclear protein 1 induced by ATF4 in response to various stressors acts as a positive regulator on the transcriptional activation of ATF4

Jin, Hyeon‐Ok; Seo, Sung‐Keum; Woo, Sang-Hyeok; Choe, Taeboo; Hong, Seok‐Il; Kim, Jong‐il; Park, In-Chul

doi:10.1002/iub.271

Cited by 41 publications

(24 citation statements)

References 27 publications

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“…Furthermore, silencing ATF4 using siRNA reduced transcription of CHOP, NUPR1 and PUMA, resulting in diminished apoptosis following treatment with encorafenib plus binimetinib. This is consistent with two reports showing that siRNA against ATF4 reduces NUPR1 expression and that ATF4-CHOP-mediated ER-stress causes neuronal apoptosis via PUMA induction (28,33). …”

Section: Discussionsupporting

confidence: 93%

BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

Niessner¹,

Sinnberg²,

Kosnopfel³

et al. 2017

Clinical Cancer Research

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Purpose NRAS mutations in malignant melanoma are associated with aggressive disease requiring rapid antitumor intervention, but there is no approved targeted therapy for this subset of patients. In clinical trials, the MEK inhibitor (MEKi) binimetinib displayed modest antitumor activity, making combinations a requisite. In a previous study, the BRAF inhibitor (BRAFi) vemurafenib was shown to induce endoplasmic reticulum (ER) stress that together with inhibition of the RAF-MEK-ERK (MAPK) pathway amplified its pro-apoptotic activity in BRAF-mutant melanoma. The present study investigated whether this effect might extent to NRAS-mutant melanoma, in which MAPK activation would be expected. Experimental design and results BRAFi increased pERK, but also significantly increased growth inhibition and apoptosis induced by the MEKi in monolayer, spheroids, organotypic and patient-derived tissue slice cultures of NRAS-mutant melanoma. BRAFi such as encorafenib induced an ER stress response via the PERK pathway, as detected by phosphorylation of eIF2α and upregulation of the ER stress-related factors ATF4, CHOP and NUPR1 and the pro-apoptotic protein PUMA. MEKi such as binimetinib induced the expression of the pro-apoptotic protein BIM and activation of the mitochondrial pathway of apoptosis, the latter of which was enhanced by combination with encorafenib. The increased apoptotic rates caused by the combination treatment were significantly reduced through siRNA knockdown of ATF4 and BIM, confirming its critical roles in this process. Conclusion The data presented herein encourage further advanced in vivo and clinical studies to evaluate MEKi in combination with ER stress inducing BRAFi as a strategy to treat rapidly progressing NRAS-mutant melanoma.

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Section: Discussionsupporting

confidence: 93%

BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

Niessner¹,

Sinnberg²,

Kosnopfel³

et al. 2017

Clinical Cancer Research

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“…Three of the highest expressed genes in terms of dominance from the data of this study (with significant up-regulation ) were identified as activating transcription factor 4 (Atf4) m RNA and two genes that are controlled by Atf4 which include 1) nuclear protein 1 (Nupr1) and 2) CHAC1 (cation transport regulator-like protein 1). Nuclear protein 1 is highly up-regulated in response to various stressors (Jin et al, 2009), playing a role in metastasis, progression of cancer and chemo-resistance in various types of malignancies. (Chowdhury et al, 2009) Nupr1 forms a complex with p53 and up-regulates p21, Bcl-x (L), allowing for cells to progress through cell cycle in presence of chemotherapy drugs.…”

Section: 0 Discussionmentioning

confidence: 99%

Whole genome expression profile in neuroblastoma cells exposed to 1-methyl-4-phenylpyridine

Mazzio

Soliman

2012

NeuroToxicology

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Mitochondrial dysfunction and subsequent energy failure is a contributing factor to degeneration of the substantia nigra pars compacta associated with Parkinson’s disease (PD). In this study, we investigate molecular events trigger by 1-methyl-4-phenylpyridine (MPP+) using whole genome-expression microarray, western blot and HPLC quantification of metabolites. The data show that MPP+ (500μM) evokes obstruction of mitochondrial respiration/oxidative phosphorylation (OXPHOS) in mouse neuroblastoma Neuro-2a cells, juxtapose to accelerated glucose consumption and production of lactic acid. While additional glucose concentrations restored viability at MPP+ (500μM), loss of OXPHOS was sustained suggesting that compensatory anaerobic metabolic systems were fulfilling required energy needs. Under these conditions, MPP+ initiated significant changes to the transcription of 799 genes (596 up-regulated and 203 down-regulated) of which 612 David IDS were applied and 136 functional annotation clusters were identified. Prominent changes were as follows; MPP+ initiated loss of mRNA for mitochondrial encoded NADH dehydrogenase 4, 5 genes, cytochrome b and NADH dehydrogenase (ubiquinone) flavoprotein 3, concomitant to rise in a mitochondrial fission gene; ganglioside-induced differentiation-associated-protein 1 (GDAP1). These negative changes to OXPHOS components were accompanied by a number of protective forces to the mitochondria including elevated ratio of mitochondrial anti/pro-apoptotic processes including a loss of apoptotic Bcl-2/adenovirus E1B 19-kDa-interacting protein (BNIP3) and family with sequence similarity 162, member A (FAM162a) and rise of heat shock protein 1 and Lon peptidase 1. There were no changes indicative of free radical damage (e.g. SOD, GSH-Px), rather MPP+ initiated a large number of significant G protein signaling components (which trigger catabolic processes) and anaerobic metabolic systems involving carboxylic acid/ transamination reactions (e.g. glutamate oxaloacetate transaminase 1 (GOT1), glutamic pyruvate-alanine transaminase 2 (GPT2), cystathionase and redox proteins such as cytochrome b5 reductase 1 and ferredoxin reductase. Counter-intuitively, the data show reduction of mRNA in glycolytic processes [DAVID enrichment score 9.96 p value 1.90E-19], some corroborated by western blot, bringing in to question the sources of lactate observed in the presence of MPP+. Examining this aspect, the data show that diverse carboxylic acids (succinate, oxaloacetate and a-ketoglutarate) are capable of contributing to the lactate pool in addition to phosph(enolpyruvate) or pyruvate in the absence of glucose by this cell line. In conclusion, these findings show that MPP+ negatively affects the transcriptome involved with complex I, but evoked elevation in G protein signaling and anaerobic metabolic systems involved with nitrogen/carboxylic acid metabolism and redox reactions. Anaerobic survival systems appear to be far more complex than previously believed, and future research will be required to elucidate th...

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“…Real-time PCR assays were conducted using QuantiTect SYBR Green PCR Kit (Qiagen, Valencia, CA, USA) on a Roche LightCycler 96 real-time PCR machine (Roche Diagnostics GmbH, Roche Applied Science, Penzberg, Germany). Primer sequences for real-time PCR were as follows: Bnip3 (5′-TTCAGCAATAATGGGAACGG-3′ and 5′-TGTT TCAGAAGCCCTGTTGG-3′; 180 bp product) and β-actin (5′-GGATTCCT ATGTGGGCGACGA-3′ and 5′-GAGTCCATCACGATGCCAGTG-3′; 315 bp product) (Jin et al, 2009). The protocol involved an initial 10-min denaturing step at 95°C, followed by 45 cycles of 95°C for 15 sec, 55°C for 30 sec, and 72°C for 30 sec.…”

Section: Methodsmentioning

confidence: 99%

“…cDNA primed with oligo dT was prepared from 2 μg of total RNA using M-MLV reverse transcriptase (Invitrogen). The following specific primers were used for PCR: Bnip3 (5'-GATACCAACAGGGCTTCTGAAA CAG-3' and 5'-CAGAGAATATGCCCCCTTTCTTCA-3'; 253 bp product), Hif-1α (5′-CTCAAAGTCGGACAGCCTC-3′ and 5′-CCCTGCAGTAGGTTTC TGC-3′; 460 bp) (Leonard et al, 2003) and β-actin (5'-GGATTCCTATGT GGGCGACAG-3' and 5'-CGCTCGGTGAGGATCTTCATG-3'; 438 bp product) (Jin et al, 2009). PCR products were subjected to electrophoresis on 1.5% agarose gels and visualized with ethidium bromide.…”

Section: Methodsmentioning

confidence: 99%

Combined effects of EGFR tyrosine kinase inhibitors and vATPase inhibitors in NSCLC cells

Jin

Hong

Kim

et al. 2015

Toxicology and Applied Pharmacology

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Nuclear protein 1 induced by ATF4 in response to various stressors acts as a positive regulator on the transcriptional activation of ATF4

Cited by 41 publications

References 27 publications

BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

Whole genome expression profile in neuroblastoma cells exposed to 1-methyl-4-phenylpyridine

Combined effects of EGFR tyrosine kinase inhibitors and vATPase inhibitors in NSCLC cells

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