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

• Published in: The Journal of immunology (1950) 2001-01, Vol.166 (2), p.772-780
• Main Authors: Hsu, H C, Shultz, L D, Su, X, Shi, J, Yang, P A, Relyea, M J, Zhang, H G, Mountz, J D
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - genetics; Apoptosis - immunology; Apoptosis - radiation effects; bcl-2-Associated X Protein; Cell Cycle - genetics; Cell Cycle - immunology; Cell Cycle - radiation effects; Cell Death - immunology; Cell Death - radiation effects; Cell Line; Gamma Rays; Hcph gene; Hybridomas; Immunity, Innate - radiation effects; Intracellular Membranes - radiation effects; Intracellular Signaling Peptides and Proteins; Membrane Potentials - radiation effects; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mitochondria - radiation effects; Mitogen-Activated Protein Kinases - metabolism; Mitogen-Activated Protein Kinases - radiation effects; Mutation; p38 Mitogen-Activated Protein Kinases; Permeability - radiation effects; Phosphorylation - radiation effects; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein Tyrosine Phosphatases - deficiency; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - metabolism; Protein Tyrosine Phosphatases - radiation effects; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - radiation effects; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - radiation effects; RNA, Messenger - biosynthesis; RNA, Messenger - radiation effects; SH2 Domain-Containing Protein Tyrosine Phosphatases; SHP-1 protein; Spleen - cytology; Spleen - immunology; Spleen - radiation effects; src Homology Domains - genetics; src Homology Domains - immunology; src Homology Domains - radiation effects; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Protein p53 - radiation effects
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.2.772

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-+/+ controls were analyzed after gamma-irradiation from a (137)Cs source. B6-me/me cells were significantly more resistant than B6-+/+ cells to gamma-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-+/+ cells, but not B6-me/me cells. Analysis of 3,3'-dihexyloxacarbocyanine iodide revealed resistance to the gamma-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-+/+ 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 gamma-irradiation-induced stress response.