Repression of GADD153/CHOP by NF-kappa B: a possible cellular defense against endoplasmic reticulum stress-induced cell death

Exposure of mammalian cells to ultraviolet light, nutrient deprived culture media, hypoxia, environmental toxicants such as methyl mercury, methyl met hanesulfonate, crocodilite asbestos or the agents that disrupt the function of endoplasmic reticulum (ER) leads to activation of the pro-apoptotic tra nscription factor GADD153/CHOP. Paradoxically, several of these agents also induce the anti-apoptotic transcription factor NF-kappaB. In this report, we demonstrate that NF-kappaB inhibits GADD153 activation in breast cancer cells exposed to nutrient deprived media, tunicamycin (which blocks protein folding in ER) or calcium ionopore (which depletes calcium stores in ER), Basal and calcium ionopore-induced GADD153 expression was more pronounced i n fibroblasts obtained from mouse embryos lacking in p65 subunit of NF-kapp aB compared to fibroblasts from wild type Littermate embryos. Moreover, p65 -/-fibroblasts were killed more efficiently by calcium ionopore and tunicam ycin but not hydrogen peroxide compared to wild type fibroblasts, We also s how that parthenolide, a NF-kappaB inhibitor, sensitizes breast cancer tell s to tunicamycin, Transient transfection assay revealed that the p65 subuni t but not the p50 subunit of NF-kappaB represses GADD153 promoter activity, These results establish a correlation between repression of proapoptotic g enes by NF-kappaB and increased cell survival during ER stress as well as i dentify a distinct NF-kappaB regulated cell survival pathway.