A pathway distinct from the mammalian unfolded protein response regulates expression of endoplasmic reticulum chaperones in non-stressed cells

The stress‐induced unfolded protein response (UPR) is the only signaling pathway known to regulate expression of genes encoding the resident endoplasmic reticulum (ER) molecular chaperones and folding enzymes, yet these genes are constitutively expressed in all cells. We have examined the expression...

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Bibliographic Details
Published in:The EMBO journal 1997-12, Vol.16 (23), p.7207-7216
Main Authors: Brewer, Joseph W., Cleveland, John L., Hendershot, Linda M.
Format: Article
Language:English
Subjects:
Animals
Carrier Proteins - biosynthesis
endoplasmic reticulum
Endoplasmic Reticulum - metabolism
Gene Expression Regulation
Growth Substances - pharmacology
Heat-Shock Proteins
HSP70 Heat-Shock Proteins - biosynthesis
Membrane Proteins - biosynthesis
Mitogens - pharmacology
Models, Biological
molecular chaperone
Molecular Chaperones - biosynthesis
Protein Folding
Signal Transduction
unfolded protein response
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Summary:The stress‐induced unfolded protein response (UPR) is the only signaling pathway known to regulate expression of genes encoding the resident endoplasmic reticulum (ER) molecular chaperones and folding enzymes, yet these genes are constitutively expressed in all cells. We have examined the expression of ER chaperones in several cell lines that are dependent on a variety of cytokines for growth and survival. When the various cell lines were deprived of essential growth factors, mRNA levels of the ER chaperones BiP and GRP94 decreased dramatically. Re‐stimulation of ligand‐deprived cells with the appropriate growth factor induced BiP and GRP94 as delayed‐early response genes. Cytokine induction of BiP and GRP94 biosynthesis was not preceded by a burst of glycoprotein traffic through the ER nor accompanied by expression of the CHOP transcription factor. The glycosylation inhibitor tunicamycin potently induced expression of both ER chaperones and CHOP in ligand‐deprived cells, demonstrating that the UPR pathway remains functionally intact in the absence of growth factor‐mediated signaling. Therefore, basal expression of ER chaperones is dependent upon and regulated by a mitogenic pathway distinct from the stress‐inducible UPR cascade and this probably controls expression of ER chaperones and folding enzymes needed to assist protein biogenesis in the ER of normal, non‐stressed cells.
ISSN:0261-4189
1460-2075
1460-2075
DOI:10.1093/emboj/16.23.7207