Expression of the Pro-apoptotic Genegadd153/chop Is Elevated in Liver with Aging and Sensitizes Cells to Oxidant Injury

Abstract

Aging is generally accompanied by reduced tolerance to oxidative stress and altered responsiveness to proliferative signals. We have shown that hepatocytes derived from aged rats (24 -26 months) exhibit greater sensitivity to H 2 O 2 treatment and reduced proliferation following epidermal growth factor (EGF) treatment than cells of young adult rats (5-6 months). Here we examined the effects of aging and calorie restriction (CR) on expression of the oxidative stress-inducible and pro-apoptotic gene gadd153 (chop) in these hepatocytes, and we investigated its influence on sensitivity to oxidants. We show that aging was associated with elevated expression of gadd153, both basally and in response to H 2 O 2 treatment. CR, which attenuates age-associated declines in stress tolerance, prevented the age-related increase in gadd153 expression. EGF treatment also resulted in gadd153 induction in old cells. This effect was absent in young cells and in old cells of CR rats. gadd153 induction by EGF was reactive oxygen species-dependent and correlated with heightened sensitivity to subsequent H 2 O 2 treatment, suggesting that elevated Gadd153 contributes to the greater sensitivity of EGF-pretreated old cells to oxidative stress. Additional support for this hypothesis was provided by experiments with Rat1 fibroblasts in which conditional expression of Gadd153 conferred increased sensitivity to H 2 O 2 . We propose a model whereby the diminished ability of old hepatocytes to overcome an EGF-triggered reactive oxygen species load leads to induction of the proapoptotic gene gadd153, which, in turn, sensitizes the cells to oxidant injury. Our findings point to gadd153 expression levels as an important factor in liver aging.

HMDB and 5-AzadC Combination Reverses Tumor Suppressor CCAAT/Enhancer-Binding Protein Delta to Strengthen the Death of Liver Cancer Cells

“…Importantly, inactivation of CEBPD during cancer progression has been reported in breast cancer, cervical cancer, HCC, leukemia, and prostate cancer (16,39,40). In addition to the proapoptotic genes PPARG2 and GADD153 (41,42), our recent results suggested that CEBPD contributes to the transcriptional activation of procaspase-8 in prostate cancer (43). These observations further support the hypothesis that activation of CEBPD contributes to the induction of death signaling in cancer cells.…”

15-deoxy-Δ12,14-prostaglandin J2 up-regulates death receptor 5 gene expression in HCT116 cells: involvement of reactive oxygen species and C/EBP homologous transcription factor gene transcription

“…Indeed, previous studies reported that 15dPGJ 2 can generate ROS in cancer cells (23,30), and ROS can induce CHOP production (31,32). To confirm this suggestion, we determined intracellular levels of ROS and calcium.…”

“…Moreover, all stimulation of mRNA and protein expressions of CHOP and DR5 was almost completely abrogated by NAC (a ROS scavenger) but only partial reduced by BAPTA (a calcium chelator). In this aspect, previous studies showed that ROS is a molecular mediator inducing CHOP (31,32,46) and DR5 (10, 11, 47) expression.…”

Mitochondrial Uncoupling Protein-4 Regulates Calcium Homeostasis and Sensitivity to Store Depletion-induced Apoptosis in Neural Cells

“…Previous studies have shown that TG and ionophores induce transcriptional activation of Gadd153 by elevating [Ca 2ϩ ] i (35), and induction of Gadd153 may be required for release of cytochrome c from mitochondria and caspase activation (57). Gadd153 expression is also induced by oxidative stress (40 -42), and the age-related increase in Gadd153 expression is correlated with heightened sensitivity to oxidant injury (58). Increased Gadd153 expression also mediates dopaminergic death following intrastriatal injection of 6-hydroxydopamine (59), a hydroxylated dopamine analogue that is readily oxidized causing oxidant injury.…”