Mutant Mice Phosphatase (SHP)-1-Deficient ''Motheaten'' Apoptosis in Src Homology Protein Tyrosine -Irradiation-Induced g Resistance to ) Gene Is Associated with Hcph Phosphatase ( Mutation of the Hematopoietic Cell

To determine the role of Src homology protein tyrosine phosphatase (SHP-1) in the ionizing radiation-induced stress response, we analyzed the apoptotic response and cell cycle function in irradiated spleen cells of motheaten ( me / me ) mice. The defect in me/me mice has been attributed to mutations of the Hcph gene, which encodes SHP-1. Homozygotes develop severe systemic autoimmune and inflammatory disease, whereas heterozygotes live longer and develop hematopoietic and lymphoid malignance. Spleen cells from C57BL/6 (B6)- me / me and B6- 1 / 1 controls were analyzed after g -irradiation from a 137 Cs source. B6- me / me cells were significantly more resistant than B6- 1 / 1 cells to g -irradiation-induced apoptosis exhibiting a higher LD 50 . The defective apoptosis response of the B6- me / me cells was exhibited by T and B cells and macrophages. Of the Bcl-2 family members analyzed, a significant difference was observed in the transcription of Bax mRNA, which was up-regulated early after irradiation in B6- 1 / 1 cells, but not B6- me / me cells. Analysis of 3,3 * -dihexyloxacarbocyanine iodide revealed resistance to the g -irradiation-induced mitochondrial transmembrane permeability transition in the B6- me / me cells. The blocking of the cell cycle in the G 0 /G 1 phase characteristic of the irradiated B6- 1 / 1 cells was not observed in the B6- me / me cells. There was decreased phosphorylation of p38 mitogen-activated protein kinase and increased phosphorylation of p53 from spleen cell lysates of irradiated B6- me/me mice compared with wild-type mice. These data suggest that SHP-1 plays an important role in regulation of apoptosis and cell cycle arrest after a g -irradiation-induced stress response. The Journal of Immunology, 2001, 166: 772–780.

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