p38 MAP kinase in early thymocyte development

University Of Vermont & St Agric College, Burlington VT

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Abstract

DESCRIPTION (provided by applicant): The p38 MAP kinase (MAPK) pathway is activated in response to stress stimuli (e.g. ionizing irradiation) that induce DNA double stranded breaks (DSBs) and plays a role in the induction of cell cycle checkpoints (primarily G2/M) to facilitate DNA repair. DSBs are also generated during the development of T cells while undergoing V(D)J recombination in the thymus. V(D)J-mediated DSBs (coding and signal ends) trigger a DNA damage response and DNA repair similar to those induced by DSBs generated by ionizing irradiation. Although joining of coding ends is critical for the formation of functional TCR, repairing of signal ends flanking the excised DNA fragment is also important to prevent integration of the DNA fragments randomly in the genome and genomic instability. We have previously shown that p38 MAPK is activated in double negative (DN)3 thymocytes undergoing V(D)J recombination of the TCR2 and contributes to the induction of a G2/M cell cycle checkpoint. In addition, p38 MAPK also provides survival to DN3 thymocytes. Our recent studies show that p38 MAPK phosphorylates GSK32 at a non-previously characterized residue (Ser389) and this phosphorylation inactivates GSK32. Inactivation of GSK32 is associated with increased survival. We propose that p38 MAPK is activated in DN3 thymocytes by the DNA damage response (Atm activation) triggered by V(D)J-mediated DSBs and contributes to repairing of signal ends and prevention of signal end integration not only by inducing a cell cycle checkpoint, but also by promoting survival through inactivation of GSK32. We will investigate whether: 1) activation of p38 MAPK in DN3 thymocytes is mediated by ATM as a result of the DNA damage response triggered by V(D)J-mediated DSBs (Aim 1); 2) p38 MAPK provides survival signals to DN3 thymocytes by phosphorylating and inactivating GSK32 (Aim 2); 3) activation of p38 MAPK promotes the repair of signal ends and diminishes integration of signal end fragments in the genome (Aim 3).