An Immunological Renal Disease in Transgenic Mice That Overexpress Fli-1, a Member of the ets Family of Transcription Factor Genes

Abstract

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 genes 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-2K k -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

Ets factors and a newly identified polymorphism regulate Fli1 promoter activity in lymphocytes

“…Over-expression of Fli1 in otherwise healthy mice results in an abnormal expansion of autoreactive lymphocytes, production of autoantibodies and the development of an autoimmune kidney disease similar to that observed in murine models of lupus (Zhang et al, 1995). Subsequently, it was observed that Fli1 is over-expressed in the lymphocytes of lupus prone mouse models MRL/lpr and NZB/NZW f1 (Georgiou, 1996;Zhang et al, 2004) and in PBMCs from human lupus patients (Georgiou, 1996).…”

“…However, the induction of lupus by increasing Fli1 levels in non-autoimmune prone mice (Zhang et al, 1995) and reduction of disease by reducing Fli1 levels in lupus prone mice (Zhang et al, 2004) indicate strongly that the immune system and lupus disease progression are sensitive to the levels of Fli1. Gaining a better understanding of how Fli1 gene expression is controlled normally will be critical for determining how it becomes dysregulated in lupus.…”

“…These results suggest that Fli1 may autoregulate its expression in lymphocytes. Indeed, Fli1 has been shown to bind and stimulate its own promoter in other cell lines (Lelievre et al, 2002;Starck et al, 1999) and to up-regulate endogenous Fli1 expression in Fli1 transgenic mice (Zhang et al, 1995).…”

“…Additionally, we identified a GA n microsatellite in the Fli1 promoter that is polymorphic in lupus prone mice and its length is inversely proportional to promoter activity in a T cell line. Because the immune system and lupus disease expression are sensitive to the levels of Fli1 (Georgiou, 1996;Zhang et al, 1995;Zhang et al, 2004), further studies to decipher the precise control of Fli1 gene expression in lymphocytes will be important for understanding the pathogenesis of lupus and also may provide insight into the role of Fli1 in hematopoietic malignancies. 5' deletion analysis of Fli1 promoter activity in B and T cells.…”

Overexpression of Frat1 in transgenic mice leads to glomerulosclerosis and nephrotic syndrome, and provides direct evidence for the involvement of Frat1 in lymphoma progression

“…We have tested extensively the possibility that the nephrotic syndrome in Em-pp-Frat1 transgenic mice is caused by a systemic autoimmune disease, but we have thus far obtained no evidence for this notion. Em-pp-Frat1 animals do not display the accumulation of immune deposits in the kidney, nor do they show the hypergammaglobinemia, splenomegaly, and selfreactive T and B cell populations as observed in lupus nephritis or Fli1-induced renal disease (Zhang et al, 1995;Kotzin, 1996). Moreover, the responses of Empp-Frat1 thymocytes to various apoptotic stimuli (including a-Fas), and the apoptotic response of activated peripheral T cells to IL-2 withdrawal were found to be normal.…”