Wip1 Phosphatase-Deficient Mice Exhibit Defective T Cell Maturation Due To Sustained p53 Activation

Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
The Journal of Immunology (Impact Factor: 4.92). 05/2006; 176(8):4818-25. DOI: 10.4049/jimmunol.176.8.4818
Source: PubMed


The PP2C phosphatase Wip1 dephosphorylates p38 and blocks UV-induced p53 activation in cultured human cells. Although the level of TCR-induced p38 MAPK activity is initially comparable between Wip1-/- and wild-type thymocytes, phosphatase-deficient cells failed to down-regulate p38 MAPK activity after 6 h. Analysis of young Wip1-deficient mice showed that they had fewer splenic T cells. Their thymi were smaller, contained significantly fewer cells, and failed to undergo age-dependent involution compared with wild-type animals. Analysis of thymocyte subset numbers by flow cytometry suggested that cell numbers starting at the double-negative (DN)4 stage are significantly reduced in Wip1-deficient mice, and p53 activity is elevated in cell-sorted DN4 and double-positive subpopulations. Although apoptosis and proliferation was normal in Wip1-/- DN4 cells, they appeared to be in cell cycle arrest. In contrast, a significantly higher percentage of apoptotic cells were found in the double-positive population, and down-regulation of thymocyte p38 MAPK activation by anti-CD3 was delayed. To examine the role of p38 MAPK in early thymic subpopulations, fetal thymic organ cultures cultured in the presence/absence of a p38 MAPK inhibitor did not correct the thymic phenotype. In contrast, the abnormal thymic phenotype of Wip1-deficient mice was reversed in the absence of p53. These data suggest that Wip1 down-regulates p53 activation in the thymus and is required for normal alphabeta T cell development.

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Available from: Marco L Schito, Aug 28, 2014
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    • "Mice were treated with two injections daily for 2 days by the i.p. injection of 25 μg of I45CII anti-CD3ε mAb (BD PharMingen), which can induce thymocyte apoptosis (Freywald et al., 2006; Lamhamedi-Cherradi et al., 2003) or stimulate thymocyte maturation (Boursalian et al., 2004; Porcellini et al., 1999; Schito et al., 2006). Forty-eight hours after the first injection, mice were sacrificed (3–4 mice per group); the thymocytes and splenocytes were prepared and analyzed by flow cytometry. "
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