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J. Biol. Chem., Vol. 280, Issue 14, 13648-13657, April 8, 2005

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Granulin and Granulin Repeats Interact with the Tat·P-TEFb Complex and Inhibit Tat Transactivation^*

Mainul Hoque, Bin Tian, Michael B. Mathews, and Tsafi Pe'ery¶

From the Departments of Biochemistry and Molecular Biology and Medicine, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103-2714

The cellular positive transcription elongation factor b (P-TEFb), containing cyclin T1 and cyclin-dependent kinase 9 (CDK9), interacts with the human immunodeficiency virus, type 1 (HIV-1) regulatory protein Tat to enable viral transcription and replication. Cyclin T1 is an unusually long cyclin and is engaged by cellular regulatory proteins. Previous studies showed that the granulin/epithelin precursor (GEP) binds the histidine-rich region of cyclin T1 and inhibits P-TEFb function. GEP is composed of repeats that vary in sequence and properties. GEP also binds directly to Tat. Here we show that GEP and some of its constituent granulin repeats can inhibit HIV-1 transcription via Tat without directly binding to cyclin T1. The interactions of granulins with Tat and cyclin T1 differ with respect to their binding sites and divalent cation requirements, and we identified granulin repeats that bind differentially to Tat and cyclin T1. Granulins DE and E bind Tat but do not interact directly with cyclin T1. These granulins are present in complexes with Tat and P-TEFb in which Tat forms a bridge between the cellular proteins. Granulins DE and E repress transcription from the HIV-1 LTR and gene expression from the viral genome, raising the possibility of developing granulin-based inhibitors of viral infection.

Received for publication, August 20, 2004 , and in revised form, January 3, 2005.

^* This work was supported by Grant 02-1134-CCR-SO from the New Jersey Commission on Cancer Research, a grant from Wendy Will Case Cancer Fund, and Grants AI31802 and AI055331 from the National Institutes of Health. 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.

^¶ To whom correspondence should be addressed: Dept. of Biochemistry, NJMS-University of Medicine and Dentistry of New Jersey, 185 South Orange Ave., MSB E615b, Newark, NJ 07013-2714. Tel.: 973-972-8763; Fax: 973-972-5594; E-mail: peeryts{at}umdnj.edu.

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