Signals from the Stressed Endoplasmic Reticulum Induce C/EBP-Homologous Protein (CHOP/GADD153)

Abstract

The gene encoding C/EBP-homologous protein (CHOP), also known as growth arrest and DNA-damageinducible 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.

Roles of CHOP/GADD153 in endoplasmic reticulum stress

“…23,27,28,56,57. Overexpression of BiP attenuates the induction of CHOP in ER stress and reduces ER stressinduced apoptosis. 31 CHOP À/À mice exhibit reduced apoptosis in response to ER stress. 56,58,59 Thus, CHOP plays an important role in ER stress-induced apoptosis.…”

“…Subsequent studies revealed that a DNAdamaging nucleoside analogue or UV light alone does not induce CHOP. 31 Glucose deprivation is known to induce ER stress, presumably by inhibiting N-linked protein glycosylation Figure 1 Proposed profile of ER stress response. In an early phase, translational attenuation occurs to reduce the load of ER.…”

Rottlerin induces pro-apoptotic endoplasmic reticulum stress through the protein kinase C-δ-independent pathway in human colon cancer cells

“…The key players of the unfolded protein response (UPR) are three chronologically activated ER resident signaling proteins: protein kinaselike ER-resident kinase (PERK), inositol requiring 1 (Ire1) and activating transcription factor-6(ATF-6) [3][4][5][6]. Several pro-apoptotic factors and signaling pathways, including C/EBP homologous protein/growth arrest and DNA damage-inducible gene 153 (CHOP/GADD153), pro-apoptotic Bcl-2 family members, and caspase-12, have been shown to be involved in ER stress-induced cell death [7][8][9]. CHOP is a key pro-apoptotic transcription factor induced during ER stress [10,11].…”

The C/EBP homologous protein CHOP (GADD153) is an inhibitor of Wnt/TCF signals

“…CHOP is a member of the CCAAT/enhancer binding protein (C/EBP) family of transcription factors (reviewed in Ron and Habener, 1992;Leckstrom-Himes and Xanthopoulos, 1998;Ramji and Foka, 2002) and is ubiquitously expressed at low levels in proliferating cells, but strikingly upregulated by oxidative stress, endoplasmatic reticulum (ER) stress and DNA damage in different adult tissues (Ubeda et al, 1996;Wang et al, 1996;Talukder et al, 2002). CHOP induces cell cycle arrest and apoptosis in response to cellular stress factors (Zinszner et al, 1998;Maytin et al, 2001), and was therefore also termed 'growth arrest and DNA damageinducible gene' (GADD153).…”