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- W4313350025 startingPage "111.47" @default.
- W4313350025 abstract "Abstract In addition to environmentally induced DNA double strand breaks (DSBs), developmentally programmed DSBs are also generated in T and B cells during V(D)J recombination. We have shown that in response to DSBs, p38 MAPK is activated and translocated to the nucleus. Although typically associated with cell death, we found that p38 MAPK promoted survival of cells following DNA damage by phosphorylating GSK3β at a novel residue (S389). GSK3β is a constitutively active kinase that can promote death by phosphorylating and targeting survival factors for destruction. GSK3β has been shown to be inhibited by the phosphorylation of S9 by Akt. Our biochemical analysis showed that phosphorylation of GSK3β at S389 resulted in inhibition of GSK3β similar to the S9 phosphorylation of GSK3β. Here we show that in response to DSBs in the development of T and B cells, activation of p38 MAPK leads to S389 phosphorylation and inactivation of GSK3β. We also show that unlike S9 phosphorylation that occurs in the cytosol, S389 phosphorylation occurs within the nucleus. To investigate the role of this pathway in vivo, we generated knockin mice (KI) where the S389 has been mutated to alanine. Lymphocytes for our KI mice appear to be more sensitive to death in response to DSBs. Our data indicate that GSK3β inactivation by p38 MAPK is selectively induced by DSBs as a mechanism to inhibit GSK3β activity within the nucleus allowing for the accumulation of survival factors." @default.
- W4313350025 created "2023-01-06" @default.
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- W4313350025 date "2012-05-01" @default.
- W4313350025 modified "2023-10-02" @default.
- W4313350025 title "The role of p38 MAPK/GSK3β signaling in T and B lymphocytes undergoing programmed DNA recombination (111.47)" @default.
- W4313350025 doi "https://doi.org/10.4049/jimmunol.188.supp.111.47" @default.
- W4313350025 hasPublicationYear "2012" @default.
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