Transactivation of the interleukin-1alpha promoter by human T-cell leukemia virus type I and type II Tax proteins.
Human T-cell leukemia virus type I (HTLV-I)-infected T-cell lines constitutively produce high levels of interleukin-1alpha (IL-1alpha). To analyze the mechanisms that lead to the expression of IL-1alpha in HTLV-I-infected cell lines, we studied regulatory regions of the human IL-1alpha promoter involved in activation of the IL-1alpha gene. IL-1alpha promoter constructs drive transcription of the chloramphenicol acetyltransferase (CAT) reporter gene in HTLV-I-positive MT-2 cells, which constitutively produce IL-1alpha. In a cotransfection assay, the Tax protein of both HTLV-I and HTLV-II specifically activated transcription from the IL-1alpha promoter in an uninfected Jurkat cell line. A mutant Tax protein deficient in transactivation of genes by the nuclear factor (NF)-kappaB pathway was unable to induce transcriptional activity of IL-1alpha promoter-CAT constructs, but was rescued by exogenous provision of p65/p50 NF-kappaB. We found that two IL-1alpha kappaB-like sites (positions -1,065 to -1,056 and +646 to +655) specifically formed a complex with NF-kappaB-containing nuclear extract from MT-2 cells and that NF-kappaB bound with higher affinity to the 3' NF-kappaB binding site than to the 5' NF-kappaB site. Moreover, deletion of either 5' or 3' NF-kappaB sites reduced IL-1alpha promoter activity in MT-2 cells and transactivation of the IL-1alpha promoter by exogenous NF-kappaB and Tax in Jurkat cells. These data suggest a general role for Tax induction of IL-1alpha gene transcription by the NF-kappaB pathway. Expression of IL-1alpha by HTLV-I productively infected cells may be important in the hypercalcemia, osteolytic bone lesions, neutrophilia, elevation of C-reactive protein, and fever frequently seen in patients with HTLV-I-induced adult T-cell leukemia/lymphoma.
Mori
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Department of Medicine, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles CA, 90048, USA.
Prager
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D000328:Adult; D001483:Base Sequence; D001862:Bone Resorption / Q000209:etiology; D005334:Fever / Q000209:etiology; D015973:Gene Expression Regulation, Leukemic; D015967:Gene Expression Regulation, Viral; D016356:Gene Products, tax / Q000502:physiology*; D017930:Genes, Reporter; D016355:Genes, pX; D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D015367:Human T-lymphotropic virus 2 / Q000235:genetics*; D006801:Humans; D006934:Hypercalcemia / Q000209:etiology; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D013601:T-Lymphocytes / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D016356:Gene Products, tax; D007375:Interleukin-1; D016328:NF-kappa B; D009363:Neoplasm Proteins