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Transcriptional and post-translational regulation of mouse cation transport regulator homolog 1

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Abstract

Recently, cation transport regulator homolog 1 (Chac1) has been identified as a novel pro-apoptotic factor in cells under endoplasmic reticulum (ER) stress. Of the three major ER stress sensors, it is suggested that ATF4 participates in the transcriptional regulation of Chac1 gene expression. The precise characterization of the Chac1 promoter, however, has not yet been elucidated. In this study, we detected the induction of Chac1 mRNA expression using DNA array analysis and RT-PCR of thapsigargin (Tg)-inducible genes in Neuro2a cells. Chac1 mRNA expression was also induced immediately following treatment with tunicamycin (Tm) and brefeldin A. Characterization of the mouse Chac1 promoter activity using a luciferase reporter assay revealed that the CREB/ATF element and amino acid response element in the mouse Chac1 promoter are functional and respond to Tm stimulation and ATF4 overexpression. Mutations in either element in the Chac1 promoter did not inhibit the responsiveness of this promoter to Tm and ATF4; however, mutations in both of these elements dramatically decreased the basal activity and response to ER stress stimuli. In addition to the transcriptional regulation, we found that Chac1 protein expression was only detected in the presence of MG132, a proteasome inhibitor, even though mouse Chac1 gene was transiently overexpressed in Neuro2a cells. Taken together, we are the first to demonstrate the transcriptional and post-translational regulation of Chac1 expression in a neuronal cell line.

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Abbreviations

AARE:

Amino acid response element

AP1:

Activator protein 1

ATF:

Activating transcription factor

BFA:

Brefeldin A

bZIP:

Basic leucine zipper

Chac1:

Cation transport regulator homolog 1

C/EBP:

CCAAT-enhancer-binding protein

CHOP:

C/EBP homologous protein

CREB:

cAMP response element binding protein

CRELD2:

Cysteine-rich with EGF-like domains 2

eIF2α:

Eukaryotic translation initiation factor 2A

ER:

Endoplasmic reticulum

ERSE:

ER stress response element

GADD153:

Growth arrest and DNA-damage-inducible protein 153

GRP78:

78 kDa glucose-regulated protein

IRE1:

Inositol-requiring enzyme 1

MANF:

Mesencephalic astrocyte-derived neurotrophic factor

Nrf2:

Nuclear factor (erythroid-derived 2)-like 2

PKA:

Protein kinase A

PERK:

PRKR-like endoplasmic reticulum kinase

RT-PCR:

Reverse transcription polymerase chain reaction

Tg:

Thapsigargin

Tm:

Tunicamycin

TRIB3:

Tribbles homolog 3

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Authors and Affiliations

  1. Department of Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan

    Kentaro Oh-hashi, Yuki Nomura, Yoko Hirata & Kazutoshi Kiuchi

  2. Kazusa DNA Research Institute, 2-6-7 Kazusa-Kamatari, Kisarazu, Chiba, 292-0818, Japan

    Kiyo Shimada & Hisashi Koga

  3. United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan

    Yoko Hirata & Kazutoshi Kiuchi

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  1. Kentaro Oh-hashi
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  2. Yuki Nomura
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Correspondence to Kentaro Oh-hashi.

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Kentaro Oh-hashi, Yuki Nomura contributed equally to this study.

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Oh-hashi, K., Nomura, Y., Shimada, K. et al. Transcriptional and post-translational regulation of mouse cation transport regulator homolog 1. Mol Cell Biochem 380, 97–106 (2013). https://doi.org/10.1007/s11010-013-1663-1

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  • DOI: https://doi.org/10.1007/s11010-013-1663-1

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