A role of GADD153 in ER stress-induced apoptosis in recombinant Chinese hamster ovary cells

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The imbalance between the folding capacity and the folding demand imposed on the endoplasmic reticulum (ER) of therapeutic protein-producing host cells results in a stressed ER. This initiates a series of cellular signaling events termed the unfolded protein response (UPR) aimed at restoring homeostasis. In order to alleviate ER stress and ER stress-induced apoptosis in recombinant Chinese hamster ovary (rCHO) cells, silencing of the growth arrest and DNA damage 153 gene (GADD153), the main pro-apoptotic factor of UPR, was attempted. The rCHO cells were cultured under four ER stress inducing conditions, including thapsigargin, brefeldin A, glucose deprivation, glucose and glutamine deprivation. In these conditions, the functions of stably GADD153-silenced clones were investigated. It was found that under exclusive ER stress-inducing conditions of thapsigargin and brefeldin A treatments, the GADD153-silenced clones showed a less incidence of apoptosis (about 38%) and less cell viability (about 58% non-viable cells) than the control cells. However, under nutrient deprivation, the beneficial effect of GADD153 silencing was not pronounced because nutrient deprivation led to a cascade of various events including GADD153-induced cell death. GADD153-overexpressing pool cells also substantiated the findings of GADD153 downregulation. Investigation of the underlying mechanism revealed that increased GADD153 expression results in an exaggerated production of reactive oxygen species (ROS) and that GADD153 silencing promotes translational attenuation facilitating cell recovery from stress. Taken together, this study suggests that GADD153 sensitizes cells to ER stress through mechanisms that involve enhanced oxidative injury and by manipulating the ER client protein load in rCHO cells.
Publisher
KOREAN SOC BIOTECHNOLOGY BIOENGINEERING
Issue Date
2012-06
Language
English
Article Type
Article
Keywords

UNFOLDED PROTEIN RESPONSE; AMINO-ACID LIMITATION; NS0 MYELOMA CELLS; ENDOPLASMIC-RETICULUM; MAMMALIAN-CELLS; DOWN-REGULATION; OXIDATIVE STRESS; GROWTH-ARREST; CHO-CELLS; EXPRESSION

Citation

BIOTECHNOLOGY AND BIOPROCESS ENGINEERING, v.17, no.3, pp.446 - 455

ISSN
1226-8372
DOI
10.1007/s12257-011-0653-y
URI
http://hdl.handle.net/10203/104577
Appears in Collection
BS-Journal Papers(저널논문)
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