Mutation of the hematopoietic cell phosphatase (Hcph) gene is associated with resistance to gamma-irradiation-induced apoptosis in Src homology protein tyrosine phosphatase (SHP)-1-deficient "motheaten" mutant mice

To determine the role of Src homology protein tyrosine phosphatase (SHP-1) in the ionizing radiation-induced stress response, we analyzed the apoptoti c 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 aut oimmune and inflammatory disease, whereas heterozygotes live longer and dev elop hematopoietic and lymphoid malignance. Spleen cells from C57BL/6 (B6)- me/me and B6-+/+ controls were analyzed after gamma -irradiation from a Cs- 137 source, B6-me/me cells were significantly more resistant than B6-+/+ ce lls to gamma -irradiation-induced apoptosis exhibiting a higher LD50. The d efective 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-regu lated early after irradiation in B6-+/+ cells, but not B6-me/me cells. Anal ysis of 3,3'-dihexyloxacarbocyanine iodide revealed resistance to the gamma -irradiation-induced mitochondrial transmembrane permeability transition i n the B6-me/me cells. The blocking of the cell cycle in the cdc, phase char acteristic of the irradiated B6-+/+ 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 ir radiated B6-me/me mice compared with wild-type mice. These data suggest tha t SHP-1 plays an important role in regulation of apoptosis and cell cycle a rrest after a gamma -irradiation-induced stress response.