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. 2013 Jul 17;18(3):398–415. doi: 10.2478/s11658-013-0096-x

Transcriptional regulation of mouse mesencephalic astrocyte-derived neurotrophic factor in Neuro2a cells

Kentaro Oh-Hashi 196,✉, Yoko Hirata 196,296, Kazutoshi Kiuchi 196,296
PMCID: PMC6275609  PMID: 23864333

Abstract

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel type of trophic factor. Recent studies indicate that the MANF gene is induced in response to endoplasmic reticulum (ER) stress through ER stress response element II (ERSE-II) in its 5′-flanking region. In this study, we evaluated the roles of six ER stress response transcription factors in the regulation of the promoter activities of the mouse MANF gene via ERSE-II using various types of mutant MANF luciferase reporter constructs. Treatment with thapsigargin (Tg) induced MANF mRNA generation in parallel with the elevation of ATF6α, sXBP and Luman mRNA levels in Neuro2a cells. Of the six transcription factors, ATF6β most strongly increased the MANF promoter activity via ERSE-II, while the effects of ATF6β and sXBP1 were moderate. However, overexpression of Luman or OASIS did not enhance ERSE-II-dependent MANF promoter activity in Neuro2a cells. To evaluate the relationships between transcription factors in the regulation of ERSE-II-dependent MANF promoter activity, we transfected two effective transcription factor constructs chosen from ATF6α, ATF6β, uXBP1 and sXBP1 into Neuro2a cells with the MANF reporter construct. The MANF promoter activity induced by co-transfection of ATF6α with ATF6β was significantly lower than that induced by ATF6α alone, while other combinations did not show any effect on the ERSE-II-dependent MANF promoter activity in Neuro2a cells. Our study is the first to show the efficiency of ER stress-related transcription factors for ERSE-II in activating the transcription of the mouse MANF gene in Neuro2a cells.

Electronic Supplementary Material

Supplementary material is available for this article at 10.2478/s11658-013-0096-x and is accessible for authorized users.

Key words: ATF6α, ATF6β, ERSE-II, ER stress, Luman, MANF, OASIS, sXBP1, uXBP1

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Abbreviations used

Armet

arginine-rich, mutated in early stage of tumor

ATF6

activating transcription factor 6

CRE

cyclic AMP-responsive element

CREB

cyclic AMP-responsive element-binding protein

CRELD2

cysteine-rich with EGF-like domains 2

ER

endoplasmic reticulum

ERSE

ER stress response element

GRP78

78-kDa glucose-regulated protein

Herp

homocysteine-induced endoplasmic reticulum protein

IRE1

inositol-requiring enzyme 1

MANF

mesencephalic astrocyte-derived neurotrophic factor

NA

nicotinamide

OASIS

old astrocyte specifically induced substance

PERK

PRKR-like endoplasmic reticulum kinase

RIP

regulated intramembrane proteolysis

Tg

thapsigargin

XBP1

X-box binding protein 1

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