Abstract
Inosine-5'-monophosphate dehydrogenase (IMPDH) activity and mRNA levels are induced up to 15-fold upon mitogenic or antigenic stimulation of human peripheral blood T lymphocytes. This increase in IMPDH activity is required for cellular proliferation and has been associated with malignant transformation. We have cloned the human IMPDH type II gene and show that it contains 14 exons and is approximately 5.8 kilobases in length. Exons vary in size from 49 to 207 base pairs and introns from 73 to 1065 base pairs. The transcription start site was mapped to a position 50 nucleotides upstream of the translation initiation site. The 5'-flanking region consisting of 463 base pairs upstream of the translation initiation site confers induced transcription and differential regulation upon a chloramphenicol acetyltransferase reporter gene when transfected into Jurkat T cells and human peripheral blood T lymphocytes, respectively. DNase I footprinting analysis using Jurkat T cell nuclear extract identified four protected regions in the promoter which coincide with consensus transcription factor binding sites for the nuclear factors AP2, ATF, CREB, Egr-1, Nm23, and Sp1. These findings suggest that several of these nuclear factors may play a critical role in the regulation of IMPDH type II gene expression during T lymphocyte activation.
Highlights
From the Departments of tpharmacology and §Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599
The 5' -flanking region consisting of 463 base pairs upstream of the translation initiation site confers induced transcription and differential regulation upon a chloramphenicol acetyltransferase reporter gene when transfected into Jurkat T cells and human peripheral blood T lymphocytes, respectively
These findings suggest that several of these nuclear factors may play a critical role in the regulation of Inosine-5'-monophosphate dehydrogenase (IMPDH) type II gene expression during T lymphocyte activation
Summary
Vol 270, No 12, Issue of March 24, pp. 6808--B814, 1995 Printed in U.S.A. Characterization of the Human Inosine-5'-monophosphate Dehydrogenase Type II Gene*. Inosine-5'-monophosphate dehydrogenase (IMPDH) activity and mRNA levels are induced up to IS-fold upon mitogenic or antigenic stimulation of human peripheral blood T lymphocytes. This increase in IMPDH activity is required for cellular proliferation and has been associated with malignant transformation. This association has led to the search for and development of several inhibitors with demonstrated antineoplastic and immunosuppressive potential [10, 11] Such inhibitors of IMPDH activity have been demonstrated to inhibit cell proliferation and induce cellular differentiation as a consequence of the reduction of guanine nucleotide levels [12,13,14,15,16].
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