CREB1 and ATF1 Negatively Regulate Glutathione Biosynthesis Sensitizing Cells to Oxidative Stress

Abstract

The cAMP response element binding protein (CREB) family activating transcription factor 1 (ATF1) and cAMP response element binding protein 1 (CREB1) have been reported in a diverse group of tumors, however, the mechanistic basis for this remains unclear. Here we found that CREB1 and ATF1 unexpectedly regulate glutathione (GSH) biosynthesis by suppressing the expression of glutamate-cysteine ligase modifier subunit (GCLM) and glutathione synthase (GSS), two key enzymes of GSH biosynthesis pathway. Mechanistic studies reveal that GCLM and GSS are direct transcriptional targets of CREB1 and ATF1. Through repressing the expression of these two enzymes, CREB1 and ATF1 reduce the GSH biosynthesis and the capability of cells to detoxicate reactive oxygen species (ROS), thereby increasing cellular susceptibility to oxidative stress. Therefore, our findings link CREB1 family to cellular metabolism, and uncover a potential therapeutic approach by targeting GCLM or oxidative stress for the treatment of tumors with relatively high expression of CREB1 family proteins.

Citrus flavanone metabolites protect pancreatic β-cells against cholesterol stress through a multi-proteomic mechanism

“…The overexpression of CREB1 reduces glutathione synthesis, leaving the cell more susceptible to oxidative stress. 52 Thus, the downregulation of this protein by PA may reduce the impact of oxidative stress on pancreatic β-cells. Furthermore, H7G positively modulated the NRF-2-ARE pathway, presenting high protein–protein interaction within the differentially expressed protein, such as Mapt protein (Fig.…”

“…This is an endogenous antioxidant fundamental to mitigate oxidative stress. 52 The mechanism by which cholesterol induces oxidative stress in pancreatic β-cells is unclear, but a high level of reactive oxygen species is generated, leading to the impairment of cell function. Previously, our group showed that flavanone metabolites attenuated oxidative stress, reducing the concentration of reactive species, such as hydrogen peroxide, and superoxide anions, and also modulating the activity of superoxide dismutase and glutathione peroxidase, conferring a protective effect on pancreatic β-cells.…”

Metabolites and Genes behind Cardiac Metabolic Remodeling in Mice with Type 1 Diabetes Mellitus

“…Metabolic pathways are regulated both at the genomic and metabolomic level. Transcription factors such as p63, Sp1, Srebp-1c, Jun, and Creb1, affect a variety of intracellular mechanisms in addition to regulating glucose, fatty acid, and carbohydrate metabolism [40][41][42][43][44]. Other transcription factors, such as FoxO1, specifically target genes associated with fatty acid metabolism and gluconeogenesis [45].…”

CREB1 and PPAR-α/γ Pathways in Hepatic Ischemia/Reperfusion: Route for Curcumin to Hepatoprotection

“…Another target for inflammation and oxidative stress is the transcription factor of CREB1, which inhibits RelA and activates PPARs (20,21). The PPAR activation is mediated by peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) (21,47,48), which also intercedes for the induction of synthesis of endogenous antioxidants to counteract oxidative stress (21), although Zhao et al (49) reported that CREB1 attenuated glutathione synthesis and, therefore, weakened the antioxidant capacity. Confusingly, Pregi et al (50) found an oxidative stress-induced upregulation in CREB1; however, they also reported an actuated DNA repair accompanying the increase of CREB1, which implies a time-and survivabilitydependent expression pattern.…”