Title

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.

Document Type

Article

Publication Date

2001

Keywords

Cell-Cycle, Cell-Death, Cell-Line, Gamma-Rays, Hybridomas, Immunity-Natural, Intracellular-Membranes, Membrane-Potentials, Mice, Mice-Inbred-C57BL, Mice-Mutant-Strains, Mitochondria, Mitogen-Activated-Protein-Kinases, Mutation, Permeability, Phosphorylation, Protein-p53, Proto-Oncogene-Proteins, Proto-Oncogene-Proteins-c-bcl-2, RNA-Messenger, Spleen, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S, src-Homology-Domains

JAX Source

J Immunol 2001 Jan; 166(2):772-80.

Grant

NO1, RO1, RO1-AI-42900/AI/NIAID

Abstract

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.