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
First Page
772
Last Page
780
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.
Recommended Citation
Hsu HC,
Shultz LD,
Su X,
Shi J,
Yang PA,
Relyea MJ,
Zhang HG,
Mountz JD.
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. J Immunol 2001 Jan; 166(2):772-80.