Oxidative stress-induced CREB upregulation promotes DNA damage repair prior to neuronal cell death protection.
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.
Laboratorio de Neuroepigenética, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQuiBiCEN-CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Universitaria Pabellón II Piso 4, C1428EHA, Buenos Aires, Argentina. npregi@qb.fcen.uba.ar.
Nicolás
http://orcid.org/0000-0002-5367-360X
N
Pregi
Laboratorio de Neuroepigenética, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQuiBiCEN-CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Universitaria Pabellón II Piso 4, C1428EHA, Buenos Aires, Argentina.
Laura María
LM
Belluscio
Laboratorio de Neuroepigenética, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQuiBiCEN-CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Universitaria Pabellón II Piso 4, C1428EHA, Buenos Aires, Argentina.
Bruno Gabriel
BG
Berardino
Laboratorio de Neuroepigenética, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQuiBiCEN-CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Universitaria Pabellón II Piso 4, C1428EHA, Buenos Aires, Argentina.
Daniela Susana
DS
Castillo
Laboratorio de Neuroepigenética, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQuiBiCEN-CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Universitaria Pabellón II Piso 4, C1428EHA, Buenos Aires, Argentina.
Eduardo Tomás
ET
Cánepa
D016923:Cell Death; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation / Q000235:genetics; D015854:Up-Regulation
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases
Apoptosis; CREB transcription factor; DNA damage response; Genotoxic stress; Neuronal cells; Phosphorylation