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Molecular and Cellular Biology, February 2005, p. 1113-1123, Vol. 25, No. 3
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.3.1113-1123.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Negative Regulation of NF-{kappa}B Signaling by PIAS1{dagger}

Bin Liu,1 Randy Yang,2 Kelly A. Wong,3,4,5 Crescent Getman,1 Natalie Stein,1 Michael A. Teitell,6 Genhong Cheng,3,7 Hong Wu,3,4,5 and Ke Shuai1,2,3*

Division of Hematology-Oncology, Department of Medicine,1 Department of Biological Chemistry,2 Molecular Biology Institute,3 Department of Molecular and Medical Pharmacology,4 Department of Pathology and Pediatrics,6 Department of Microbiology, Immunology, and Molecular Genetics,7 Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, California5

Received 17 September 2004/ Returned for modification 18 October 2004/ Accepted 10 November 2004

The NF-{kappa}B family of transcription factors is activated by a wide variety of signals to regulate a spectrum of cellular processes. The proper regulation of NF-{kappa}B activity is critical, since abnormal NF-{kappa}B signaling is associated with a number of human illnesses, such as chronic inflammatory diseases and cancer. We report here that PIAS1 (protein inhibitor of activated STAT1) is an important negative regulator of NF-{kappa}B. Upon cytokine stimulation, the p65 subunit of NF-{kappa}B translocates into the nucleus, where it interacts with PIAS1. The binding of PIAS1 to p65 inhibits cytokine-induced NF-{kappa}B-dependent gene activation. PIAS1 blocks the DNA binding activity of p65 both in vitro and in vivo. Consistently, chromatin immunoprecipitation assays indicate that the binding of p65 to the promoters of NF-{kappa}B-regulated genes is significantly enhanced in Pias1–/– cells. Microarray analysis indicates that the removal of PIAS1 results in an increased expression of a subset of NF-{kappa}B-mediated genes in response to tumor necrosis factor alpha and lipopolysaccharide. Consistently, Pias1 null mice showed elevated proinflammatory cytokines. Our results identify PIAS1 as a novel negative regulator of NF-{kappa}B.

* Corresponding author. Mailing address: Division of Hematology-Oncology, 11-934 Factor Bldg., 10833 Le Conte Ave., Los Angeles, CA 90095-1678. Phone: (310) 206-9168. Fax: (310) 825-2493. E-mail: kshuai{at}mednet.ucla.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, February 2005, p. 1113-1123, Vol. 25, No. 3
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.3.1113-1123.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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