Expression of a Pim-1 transgene accelerates lymphoproliferation and inhibits apoptosis in lpr/lpr mice.
Transgenic mice expressing the Pim-1 kinase are predisposed to develop T-cell lymphomas with a long latency period of about 7-9 months. However, the exact functional basis of the oncogenic activity of Pim-1 remains obscure. C57BL/6 mice homozygous for the lpr mutation develop a well-described lymphoproliferative syndrome at about 26-30 weeks of age. This syndrome is characterized mainly by the accumulation of abnormal T cells in lymph nodes because of the lack of Fas receptor-induced apoptosis. We find that backcross of E mu-Pim-1 transgenics (mice with a transgene that carries the mouse Pim-1 gene under the transcriptional control of the immunoglobulin heavy chain gene enhancer E mu) into lpr/lpr mice results in strong acceleration of lymphoproliferation and dramatic enlargement of lymph nodes. In addition, we show here that cultured lymph node cells from E mu-Pim-1 lpr/lpr mice are rescued from rapid apoptosis that normally occurs in nontransgenic lpr cells in vitro. We also present evidence that CD4+/CD8+ double-positive thymocytes from lpr/lpr mice are sensitive to dexamethasone-induced apoptosis, although lpr/lpr mice lack the Fas receptor. In contrast, E mu-Pim-1 lpr/lpr animals show considerable protection from dexamethasone-induced apoptosis. These results show that Pim-1 can strongly accelerate lymphoproliferation through inhibition of apoptosis and thereby provide first insight into the functional basis for the oncogenic activity of Pim-1.
Möröy
T
T
Institut für Molekularbiologie und Tumorforschung, Philipps Universität Marburg, Germany.
Grzeschiczek
A
A
Petzold
S
S
Hartmann
K U
KU
D000818:Animals; D000954:Antigens, Surface / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects; D001327:Autoimmune Diseases / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D016827:CD8 Antigens / Q000032:analysis; D003907:Dexamethasone / Q000494:pharmacology; D006410:Hematopoiesis; D008198:Lymph Nodes / Q000166:cytology; D008232:Lymphoproliferative Disorders / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains / Q000502:physiology*; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051573:Proto-Oncogene Proteins c-pim-1; D016176:T-Lymphocyte Subsets / Q000166:cytology; D019014:fas Receptor
D000954:Antigens, Surface; D016827:CD8 Antigens; D011518:Proto-Oncogene Proteins; D019014:fas Receptor; D003907:Dexamethasone; D011505:Protein-Tyrosine Kinases; C496636:Pim1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1