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Volume 271, Number 24, Issue of June 14, 1996 pp. 14020-14027
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Cooperation between Core Binding Factor and Adjacent Promoter Elements Contributes to the Tissue-specific Expression of Interleukin-3

(Received for publication, August 10, 1995, and in revised form, December 20, 1995)

From the Divisions of Pediatric Hematology and Oncology, Dana Farber Cancer Institute and Children's Hospital and the Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115

Tissue-specific expression of interleukin-3 (IL-3) is mediated via cis-acting elements located within 315 base pairs of the transcription start. This is achieved in part through the positive activities of the AP-1 and Elf-1 sites in the IL-3 promoter. The contribution to T cell-specific expression by other promoter sites was assessed in a transient expression assay with IL-3 promoter constructs linked to a luciferase gene, focusing initially on the core binding factor (CBF) site, which is footprinted in vivo upon T cell activation. Activity of the CBF site is shown to be critically dependent on the adjacent activator site Act-1. Together the Act-1 and CBF sites form a functional unit (AC unit) with dual activity. The AC unit is demonstrated to enhance basal activity of promoters both in fibroblasts and T cells. This activity is further inducible in activated T cells, but not in fibroblasts. In addition to the already identified NIP repressor site, evidence is presented for a second repressor region that restricts promoter activity in fibroblasts. Finally, a novel positive regulatory element has been mapped in the IL-3 promoter between nucleotide 180 and 210 that leads to increased expression in T cells. Together these results demonstrate that T cell expression of IL-3 is not specified by the activity of a single tissue-specific element, but instead involves multiple interacting elements that provide both specific positive regulation in T cells and specific negative regulation in fibroblasts.

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