Involvement of NF-AT in type I human T-cell leukemia virus Tax-mediated Fas ligand promoter transactivation.
Human T-cell leukemia virus type I (HTLV-I)-infected T-cells constitutively express surface Fas ligand (FasL), which may serve as a mechanism of viral pathogenesis. HTLV-I induces transcription of FasL gene through the viral transactivator Tax, although the underlying molecular mechanism remains unclear. In the present study, we have analyzed both the cis-activating element and transactivating factors involved in Tax activation of the FasL promoter. We show that the 486-base pair upstream region of the human FasL gene is sufficient for Tax-mediated transactivation in Jurkat T-cells. Interestingly, a palindromic DNA sequence (GGAAACTTCC) covering the consensus NF-ATp binding site (GGAAA), is required for Tax activation of FasL promoter. The involvement of NF-AT in this transactivation event is suggested by the finding that Tax fails to activate the FasL promoter in a Jurkat T-cell line defective in capacitative calcium entry, a signaling mechanism involved in NF-AT activation. Furthermore, activation of FasL promoter by Tax is largely attenuated in the nonlymphoid F9 embryonal and COS kidney cells deficient in NF-ATp expression. DNA-protein interaction assays reveal that the NF-AT-like motif in the FasL promoter is bound by both NF-ATp and NF-AT4 in Jurkat T-cells expressing Tax. The binding of NF-ATp, although not NF-AT4, to this enhancer also occurs along with HTLV-I-mediated infection of human peripheral blood T-cells. Furthermore, exogenously transfected NF-ATp binds to the NF-AT-like enhancer and participates in Tax-mediated FasL promoter transactivation. These results suggest an important role for proteins of the NF-AT family in HTLV-I Tax-mediated FasL gene transactivation.
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
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D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D004247:DNA; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D053222:Fas Ligand Protein; D016356:Gene Products, tax / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000235:genetics*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D016356:Gene Products, tax; D008562:Membrane Glycoproteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D004247:DNA; D002118:Calcium