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The STAT3 DNA-Binding Domain Mediates Interaction with NF-B p65 and Inducible Nitric Oxide Synthase Transrepression in Mesangial Cells

Departments of Internal Medicine and of Integrative Biology and Pharmacology, The University of Texas Medical School at Houston, and The Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Sciences Center at Houston, Houston, Texas

Correspondence to Dr. Bruce C. Kone, The University of Texas Medical School at Houston, 6431 Fannin, MSB 4.148, Houston, TX 77030. Phone: 713-500-6873; Fax: 713-500-6882; E-mail: Bruce.C.Kone{at}uth.tmc.edu

ABSTRACT. Signal transducer and activator of transcription 3 (STAT3) and nuclear factor B (NF-B) are important transcription factors involved in glomerulonephritis and other inflammatory processes, including transcription of the inducible nitric oxide synthase (iNOS) gene. The ability of STAT3 to interact physically with NF-B p65 in glomerular mesangial cells and thereby to inhibit NF-B–mediated transactivation of the iNOS gene was demonstrated previously. STAT3 is a modular protein with several structurally and functionally defined domains. For defining STAT3 domains that interact with NF-B p65, ³⁵S-labeled proteins that corresponded to each STAT3 domain were synthesized, and their ability to bind specifically a GST-NF-B p65 fusion protein in GST pulldown assays was tested. The coiled-coil and DNA-binding domains were specifically retained by GST-NF-B p65, whereas the N-terminal, linker domain, Src homology 2 domain, and transcriptional activation domain failed to interact with NF-B p65. Deletion of the region L³⁵⁸ through I³⁶⁹ of the STAT3 DNA-binding domain greatly reduced binding to GST-NF-B p65. Alanine substitution mutations at four highly conserved residues—L³⁵⁸, N³⁵⁹, K³⁶³, and V³⁶⁶—in this region greatly abrogated the ability of STAT3 to bind NF-B p65. Moreover, in contrast to the transrepression afforded by wild-type STAT3, a STAT3 construct harboring these mutations, failed to suppress endogenous NO production and to transrepress iNOS promoter-reporter and B element-reporter constructs in IL-–stimulated mesangial cells. These data reveal a novel role for the DNA-binding domain in the physical and functional coupling of STAT3 to NF-B p65 that is important for regulating the transcriptional activity of iNOS and likely other NF-B p65 responsive genes that are important for mesangial cell responses.

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