Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153).
The gene encoding C/EBP-homologous protein (CHOP), also known as growth arrest and DNA-damage-inducible gene 153 (GADD153), is activated by agents that adversely affect the function of the endoplasmic reticulum (ER). Because of the pleiotropic effects of such agents on other cellular processes, the role of ER stress in inducing CHOP gene expression has remained unclear. We find that cells with conditional (temperature-sensitive) defects in protein glycosylation (CHO K12 and BHK tsBN7) induce CHOP when cultured at the nonpermissive temperature. In addition, cells that are defective in initiating the ER stress response, because of overexpression of an exogenous ER chaperone, BiP/GRP78, exhibit attenuated inducibility of CHOP. Surprisingly, attenuated induction of CHOP was also noted in BiP-overexpressing cells treated with methyl methanesulfonate, an agent thought to activate CHOP by causing DNA damage. The roles of DNA damage and growth arrest in the induction of CHOP were therefore reexamined. Induction of growth arrest by culture to confluence or treatment with the enzymatic inhibitor N-(phosphonacetyl)-L-aspartate did not induce CHOP. Furthermore, both a DNA-damage-causing nucleoside analog (5-hydroxymethyl-2'-deoxyuridine) and UV light alone did not induce CHOP. These results suggest that CHOP is more responsive to ER stress than to growth arrest or DNA damage and indicate a potential role for CHOP in linking stress in the ER to alterations in gene expression.
Wang
X Z
XZ
Department of Medicine, NYU Medical Center, New York 10016, USA.
Lawson
B
B
Brewer
J W
JW
Zinszner
H
H
Sanjay
A
A
Mi
L J
LJ
Boorstein
R
R
Kreibich
G
G
Hendershot
L M
LM
Ron
D
D
D016475:3T3 Cells; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D016466:CHO Cells; D002352:Carrier Proteins / Q000502:physiology; D002455:Cell Division; D002478:Cells, Cultured; D006224:Cricetinae; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D015870:Gene Expression; D006360:Heat-Shock Proteins; D006801:Humans; D008297:Male; D051379:Mice; D018832:Molecular Chaperones / Q000502:physiology; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics*
D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D012333:RNA, Messenger; D014157:Transcription Factors; D051742:Transcription Factor CHOP