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

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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.

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Abbreviations

H2O2 :

Hydrogen peroxide

DDR:

DNA damage response

Aβ:

Amyloid beta peptide

CREB:

cAMP response element binding

ROS:

Reactive oxygen species

BER:

Base excision repair

CNS:

Central nervous system

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Acknowledgements

This research was supported by grants from the University of Buenos Aires (UBA 2011–2013; UBA 2011-2014), the National Council of Scientific and Technical Research (CONICET, Argentina), and the National Agency for Scientific and Technologic Promotion (ANPCYT) (PICT 2012–2014; PICT 2010–2013).

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    1. 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

      Nicolás Pregi, Laura María Belluscio, Bruno Gabriel Berardino, Daniela Susana Castillo & Eduardo Tomás Cánepa

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    1. Nicolás Pregi
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    2. Laura María Belluscio
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    Correspondence to Nicolás Pregi.

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    Nicolás Pregi and Laura María Belluscio have contributed equally to this work.

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    Pregi, N., Belluscio, L.M., Berardino, B.G. et al. Oxidative stress-induced CREB upregulation promotes DNA damage repair prior to neuronal cell death protection. Mol Cell Biochem 425, 9–24 (2017). https://doi.org/10.1007/s11010-016-2858-z

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