Oxidative stress-induced CREB upregulation promotes DNA damage repair prior to neuronal cell death protection

Abstract

cAMP response element-binding (CREB) protein is a cellular transcription factor that mediates responses to different physiological and pathological signals. Using a model of human neuronal cells we demonstrate herein, that CREB is phosphorylated after oxidative stress induced by hydrogen peroxide. This phosphorylation is largely independent of PKA and of the canonical phosphoacceptor site at ser-133, and is accompanied by an upregulation of CREB expression at both mRNA and protein levels. In accordance with previous data, we show that CREB upregulation promotes cell survival and that its silencing results in an increment of apoptosis after oxidative stress. Interestingly, we also found that CREB promotes DNA repair after treatment with hydrogen peroxide. Using a cDNA microarray we found that CREB is responsible for the regulation of many genes involved in DNA repair and cell survival after oxidative injury. In summary, the neuroprotective effect mediated by CREB appears to follow three essential steps following oxidative injury. First, the upregulation of CREB expression that allows sufficient level of activated and phosphorylated protein is the primordial event that promotes the induction of genes of the DNA Damage Response. Then and when the DNA repair is effective, CREB induces detoxification and survival genes. This kinetics seems to be important to completely resolve oxidative-induced neuronal damages.

Linking CREB function with altered metabolism in murine fibroblast-based model cell lines

“…By upregulation of the AKT pathway the phosphorylation of CREB at Ser 133 was increased. Similar results were reported in a PKA-independent pathway by Pregni and co-authors [ 53 ] in neuronal cells, while treatment of melanoma cells with H 2 O 2 increased CREB expression by the cAMP/PKA pathway [ 54 ]. Furthermore, H 2 O 2 could stimulate phosphorylation of CREB by AKT thereby promoting mitochondrial respiration and biosynthesis [ 55 ], while the expression levels of esterase D (formyl glutathione hydrolase), an enzyme important for formaldehyde detoxification and upregulated by K-Ras mutations in murine fibroblasts [ 56 ], were not altered under these conditions.…”

Promoter activity of earthworm metallothionein in mouse embryonic fibroblasts

“…We suggest that MRE2 is the most important MRE in response to Cd in the earthworm. The cAMP response element-binding (CREB) protein is one of the transcription factors that are activated upon various types of stress in control of gene expression [42,49]. A previous finding that the CRE binding site might be responsible for the activation of MT gene activation in earthworms [32,40] was tested herein using a CHIP assay.…”

Effect of willed movement training on neurorehabilitation after focal cerebral ischemia and on the neural plasticity-associated signaling pathway

“…In addition, resveratrol-mediated neuroprotection in a chronic cerebral hypoperfusion rat model has been suggested to act via CREB activation that restores functional and structural synaptic plasticity (11). The neuroprotection of CREB activation may also be associated with the effect on DNA repair and anti-oxidation (12). It is known that reactive oxygen species resulting from cerebral ischemia and reperfusion lead to significant neuronal damage (12).…”

“…The neuroprotection of CREB activation may also be associated with the effect on DNA repair and anti-oxidation (12). It is known that reactive oxygen species resulting from cerebral ischemia and reperfusion lead to significant neuronal damage (12).…”