Modulation by Post-Translational Modifications of Kinases implied in genotoxic stress

Abstract

Endocannabinoids are released in response to pathogenic insults and may play an important role in neuroprotection. In this study we have found a number of NADA targets responsible in biological processes of great significance. On the one hand, we demonstrate that NADA induces p38 MAPK phosphorylation which triggers the accumulation of COX-2 protein, which mediates inflammation, immunomodulation, blood flow, apoptosis and fever. On the other hand, we show that NADA down-regulates SIAH2, a key ubiquitin ligase in hypoxia and tumorogenesis, leading to an increase of HIF-1¿ protein. This confirms previous data that verify the role of NADA and HIF-1¿ as neuroprotective markers. With the aim of getting to know how SIAH2 activity is regulated at a post-translational level a kinase screening was performed. We found, among other kinases, that DYRK2 (crucial in the p53 apoptotic response) directly phosphorylates SIAH2 at fives residues: S16, T26, S28, S68 and T119. Such phosphorylation meant a change in activity of SIAH2, enhancing its ability to degrade its well known substrate PHD3. Likewise, SIAH2 degraded DYRK2 very efficiently by means of ubiquitination via proteasome. Such degradation reduced p53 Ser 46 phosphorylation, which could explain how cells can escape chemotherapeutic drug treatment.