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.
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.
Hsu
H C
HC
Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham and Birmingham Veterans Administration Medical Center, Birmingham, AL 35294, USA.
Shultz
L D
LD
Su
X
X
Shi
J
J
Yang
P A
PA
Relyea
M J
MJ
Zhang
H G
HG
Mountz
J D
JD
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology / Q000528:radiation effects*; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology / Q000528:radiation effects; D016923:Cell Death / Q000276:immunology / Q000528:radiation effects; D002460:Cell Line; D005720:Gamma Rays; D006825:Hybridomas; D007113:Immunity, Innate / Q000528:radiation effects; D007425:Intracellular Membranes / Q000528:radiation effects; D047908:Intracellular Signaling Peptides and Proteins; D008564:Membrane Potentials / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000528:radiation effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000528:radiation effects; D009154:Mutation; D010539:Permeability / Q000528:radiation effects; D010766:Phosphorylation / Q000528:radiation effects; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism / Q000528:radiation effects; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000528:radiation effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000528:radiation effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000528:radiation effects; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000528:radiation effects; D051028:bcl-2-Associated X Protein; D048051:p38 Mitogen-Activated Protein Kinases; D018909:src Homology Domains / Q000235:genetics* / Q000276:immunology* / Q000528:radiation effects
C494827:Bax protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases