An immunological renal disease in transgenic mice that overexpress Fli-1, a member of the ets family of transcription factor genes.
The proto-oncogene Fli-1 is a member of the ets family of transcription factor genes. Its high expression in the thymus and spleen and the presence of DNA binding sites for Fli-1 in a number of lymphoid cell-specific gene suggest that Fli-1 is involved in the regulation of lymphopoiesis. Activation of the Fli-1 gene by either chromosomal translocation or viral insertion leads to Ewing's sarcoma in humans and erythroleukemia in mice, respectively. Thus, Fli-1 is normally involved in pathways involved in the regulation of cell growth and differentiation. We have generated H-2Kk-Fli-1 transgenic mice that overexpress Fli-1 in various mouse tissues, with the highest levels of Fli-1 protein in the thymus and spleen. These Fli-1 transgenic mice developed a high incidence of a progressive immunological renal disease and ultimately died of renal failure caused by tubulointerstitial nephritis and immune-complex glomerulonephritis. The incidences of renal disease correlated with the levels of Fli-1 protein in lymphoid tissues of transgenic lines. The hypergammaglobulinemia, splenomegaly, B-cell hyperplasia, accumulation of abnormal CD3+ B220+ T lymphoid cells and CD5+ B220+ B cells in peripheral lymphoid tissues, and detection of various autoantibodies in the sera of diseased Fli-1 transgenic mice suggested the involvement of an immune dysfunction in the pathogenesis of the renal disease. In addition, splenic B cells from transgenic mice exhibited increased proliferation and prolonged survival in vitro in response to mitogens. Taken together, these data suggest that overexpression or ectopic expression of Fli-1 perturbs normal lymphoid cell function and programmed cell death. Thus, H-2Kk-Fli-1 transgenic mice may serve as a murine model for autoimmune disease in humans, such as systemic lupus erythematosus.
Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
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L
Zhang
A
A
Eddy
Y T
YT
Teng
M
M
Fritzler
M
M
Kluppel
F
F
Melet
A
A
Bernstein
D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007136:Immunoglobulins / Q000032:analysis; D007668:Kidney / Q000276:immunology / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D000090063:Proto-Oncogene Mas; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D011519:Proto-Oncogenes; D013154:Spleen / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis*
D004268:DNA-Binding Proteins; C497426:Fli1 protein, mouse; D007136:Immunoglobulins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors