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-Irradiation-Induced Apoptosis in Src Homology Protein Tyrosine Phosphatase (SHP)-1-Deficient "Motheaten" Mutant Mice1
*
Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham and
Birmingham Veterans Administration Medical Center, Birmingham, AL 35294;
The Jackson Laboratory, Bar Harbor, ME 04609; and
Alexion Pharmaceuticals, New Haven, CT 06511
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 
-irradiation from a 137Cs source.
B6-me/me cells were significantly more
resistant than B6-+/+ cells to -irradiation-induced apoptosis
exhibiting a higher LD50. 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
-irradiation-induced mitochondrial transmembrane permeability
transition in the B6-me/me cells. The
blocking of the cell cycle in the G0/G1 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 -irradiation-induced stress
response.
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