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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Apoptosis / genetics
-
Apoptosis / immunology
-
Apoptosis / radiation effects*
-
Cell Cycle / genetics
-
Cell Cycle / immunology
-
Cell Cycle / radiation effects
-
Cell Death / immunology
-
Cell Death / radiation effects
-
Cell Line
-
Gamma Rays*
-
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*
-
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
-
Spleen / cytology
-
Spleen / immunology
-
Spleen / radiation effects
-
Tumor Suppressor Protein p53 / metabolism
-
Tumor Suppressor Protein p53 / radiation effects
-
bcl-2-Associated X Protein
-
p38 Mitogen-Activated Protein Kinases
-
src Homology Domains / genetics*
-
src Homology Domains / immunology*
-
src Homology Domains / radiation effects
Substances
-
Bax protein, mouse
-
Intracellular Signaling Peptides and Proteins
-
Proto-Oncogene Proteins
-
Proto-Oncogene Proteins c-bcl-2
-
RNA, Messenger
-
Tumor Suppressor Protein p53
-
bcl-2-Associated X Protein
-
Mitogen-Activated Protein Kinases
-
p38 Mitogen-Activated Protein Kinases
-
Protein Tyrosine Phosphatase, Non-Receptor Type 11
-
Protein Tyrosine Phosphatase, Non-Receptor Type 6
-
Protein Tyrosine Phosphatases
-
Ptpn11 protein, mouse
-
Ptpn6 protein, mouse
-
SH2 Domain-Containing Protein Tyrosine Phosphatases