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J. Biol. Chem., Vol. 280, Issue 22, 21078-21090, June 3, 2005

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Two Discrete Promoters Regulate the Alternatively Spliced Human Interferon Regulatory Factor-5 Isoforms

MULTIPLE ISOFORMS WITH DISTINCT CELL TYPE-SPECIFIC EXPRESSION, LOCALIZATION, REGULATION, AND FUNCTION^*

Margo E. Mancl, Guodong Hu, Niquiche Sangster-Guity, Stacey L. Olshalsky¶, Katherine Hoops, Patricia Fitzgerald-Bocarsly¶, Paula M. Pitha, Karen Pinder, and Betsy J. Barnes||

From the Division of Viral Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, ^¶University of Medicine and Dentistry of New Jersey, New Jersey Medical School, and the Graduate School of Biomedical Sciences, Newark, New Jersey 07103

Interferon regulatory factor-5 (IRF-5) is a mediator of virus-induced immune activation and type I interferon (IFN) gene regulation. In human primary plasmacytoid dendritic cells (PDC), IRF-5 is transcribed into four distinct alternatively spliced isoforms (V1, V2, V3, and V4), whereas in human primary peripheral blood mononuclear cells two additional new isoforms (V5 and V6) were identified. The IRF-5 V1, V2, and V3 transcripts have different noncoding first exons and distinct insertion/deletion patterns in exon 6. Here we showed that V1 and V3 have distinct transcription start sites and are regulated by two discrete promoters. The V1 promoter (P-V1) is constitutively active, contains an IRF-E consensusbinding site, and is further stimulated in virus-infected cells by IRF family members. In contrast, endogenous V3 transcripts were up-regulated by type I IFNs, and the V3 promoter (P-V3) contains an IFN-stimulated responsive element-binding site that confers responsiveness to IFN through binding of the ISGF3 complex. In addition to V5 and V6, we have identified three more alternatively spliced IRF-5 isoforms (V7, V8, and V9); V5 and V6 were expressed in peripheral blood mononuclear cells from healthy donors and in immortalized B and T cell malignancies, whereas expression of V7, V8, and V9 transcripts were detected only in human cancers. The results of this study demonstrated the existence of multiple IRF-5 spliced isoforms with distinct cell type-specific expression, cellular localization, differential regulation, and dissimilar functions in virus-mediated type I IFN gene induction.

Received for publication, January 18, 2005 , and in revised form, March 18, 2005.

^* This work was supported by the American Cancer Society Grant IRG-58-005-41, a FAMRI Young Clinical Scientist award, NCI SPORE Lymphoma P50CA96888 Project Award (to B. J. B.), and National Institutes of Health Grants R01 AI19737-21 (to P. M. P.) and R01 AI26806 (to P. F.-B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^|| To whom correspondence and reprint requests should be addressed: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, 1650 Orleans St., Baltimore, MD 21231. Tel.: 443-287-2758; Fax: 410-955-0840; E-mail: barnebe{at}jhmi.edu.

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