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  • Original Paper
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Involvement of c-Fos in signaling grp78 induction following ER calcium release

Oncogene volume 19, pages 5936–5943 (2000)Cite this article

Abstract

Release of calcium from the endoplasmic reticulum (ER) signals an increase in transcription of both the early response gene, c-fos, and the late response gene, grp78. We have used thapsigargin (TG), an ER calcium-ATPase pump inhibitor that induces calcium release from the ER, to investigate the possible involvement of c-Fos, a component of the AP-1 transcription factor, in grp78 induction. Two cell lines with markedly different responses to TG treatment were employed: the WEHI7.2 mouse lymphoma line in which TG fails to induce grp78, and the MDA-MB-468 mammary epithelial line in which TG induces grp78. In WEHI7.2 cells, TG-induced calcium release triggers a rapid increase in c-fos mRNA, but the level of c-Fos protein decreases due to degradation by the multicatalytic proteasome. C-FosΔC, a proteasome resistant c-Fos mutant with AP-1 activity similar to that of wild type c-Fos, restores grp78 induction in WEHI7.2 cells, detected by both Northern hybridization and a grp78 promoter-luciferase reporter assay. In MDA-MB-468 cells, TG-mediated calcium release induces a sustained elevation of c-Fos protein that precedes grp78 induction. A region of the grp78 promoter containing both ERSE and CORE regions, but missing TRE and CRE regions, is sufficient to mediate induction of reporter luciferase activity. Induction of this reporter was blocked by A-Fos, a dominant negative inhibitor of c-Fos. Also, the induction of grp78-luciferase reporter activity was inhibited by c-fos antisense mRNA. In summary, the findings indicate that c-Fos is involved in signaling grp78 induction following TG treatment, and that grp78 induction is inhibited by proteasome-mediated c-Fos degradation.

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Abbreviations

TG:

thapsigargin

ER:

endoplasmic reticulum

AP1:

activation protein-1

TRE:

TPA-responsive element

CRE:

cyclic-AMP responsive element

ATF:

activating transcription factor

ERSE:

ER stress response element

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Acknowledgements

The authors thank Amy Lee for helpful suggestions and for providing the hamster grp78 cDNA and the (−456)CAT reporter plasmid. We also thank John Nilson for suggesting the A-Fos experiments and for providing the A-Fos plasmid. We thank David Ginty for permission to use the A-Fos plasmid. We thank Colin Clay for providing the AP-1-Luc reporter plasmid. We thank Monica Montano for providing −73col-CAT reporter plasmid and for help doing CAT assays. We also thank Nancy Wang and Michael Simonson for critically reading the manuscript. This work was supported by NIH grant CA79806 to CW Distelhorst.

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  1. Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, Ohio, USA

    Huiling He, Karen McColl & Clark W Distelhorst

  2. Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, Ohio, USA

    Huiling He, Karen McColl & Clark W Distelhorst

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He, H., McColl, K. & Distelhorst, C. Involvement of c-Fos in signaling grp78 induction following ER calcium release. Oncogene 19, 5936–5943 (2000). https://doi.org/10.1038/sj.onc.1203994

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