Abstract
FLI-1 is a transcriptional regulator of the ETS family of proteins. Insertional activation at the FLI-1 locus is an early event in F-murine leukemia virus-induced erythroleukemia. Consistent with its essential role in erythroid transformation, enforced expression of FLI-1 in primary erythroblasts strongly impairs the response of these cells to erythropoietin (Epo), a cytokine essential to erythropoiesis. We show here that point mutations in the ETS domain that abolished FLI-1 binding to specific DNA elements (ETS-binding sites) suppressed the ability of FLI-1 to transform erythroblasts. The exchange of the entire ETS domain (DNA binding domain) of FLI-1 for that of PU.1 changed the DNA binding specificity of FLI-1 for that of PU.1 and impaired FLI-1 transforming properties. In contrast, ETS domain swapping mutants that maintained the DNA binding specificity of FLI-1 did not affect the ability of FLI-1 to transform erythroblasts. Deletion and swapping mutants that failed to inhibit the DNA binding activity of FLI-1 but impaired its transcriptional activation properties were also transformation-defective. Taken together, these results show that both the ability of FLI-1 to inhibit Epo-induced differentiation of erythroblasts and to confer enhanced cell survival in the absence of Epo critically depend upon FLI-1 ETS-binding site-dependent transcriptional activation properties.
Highlights
FLI-1 is a member of the ETS family of transcriptional regulators, which plays an essential role in development and oncogenesis
NMR studies have shown that the DNA binding domain (ETS domain) of FLI-1 is composed of three ␣-helices (␣1–␣3) and a four-stranded -sheet [36]; see Fig. 1)
The early and recurrent activation of FLI-1 by retroviral insertional mutagenesis in F-murine leukemia virus-induced erythroleukemia suggests that up-regulation of FLI-1 expression is the initiating event in this multistep leukemia model
Summary
FLI-1 is a member of the ETS family of transcriptional regulators, which plays an essential role in development and oncogenesis (for review see Ref. 1). ETS domain swapping mutants that maintained the DNA binding specificity of FLI-1 did not affect the ability of FLI-1 to transform erythroblasts.
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