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J. Biol. Chem., Vol. 279, Issue 12, 11553-11561, March 19, 2004

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A Mutant Stat5b with Weaker DNA Binding Affinity Defines a Key Defective Pathway in Nonobese Diabetic Mice^*

Abdoreza Davoodi-Semiromi¶, Malini Laloraya¶||**, G. Pradeep Kumar||**, Sharad Purohit||, Rajesh Kumar Jha**, and Jin-Xiong She||

From the Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida 32610, ^||Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta, Georgia 30912, and ^**School of Life Sciences, Devi Ahilya University, Vigyan Bhawan, Khandwa Road, Indore (MP) 452001, India

A number of cytokines that finely regulate immune response have been implicated in the pathogenesis or protection of type 1 diabetes and other autoimmune diseases. It is, therefore, of pivotal importance to examine a family of proteins that serve as signal transducers and activators of transcription (STATs), which regulate the transcription of a variety of cytokines. We report here a defective gene (Stat5b) located on chromosome 11 within a previously mapped T1D susceptibility interval (Idd4) in the nonobese diabetic (NOD) mice. Our sequencing analysis revealed a unique mutation C1462A that results in a leucine to methionine (L327M) in Stat5b of NOD mice. Leu³²⁷, the first residue in the DNA binding domain of STAT proteins, is conserved in all identified mammalian STAT proteins. Homology modeling predicted that the mutant Stat5b has a weaker DNA binding, which was confirmed by DNA-protein binding assays. The inapt transcriptional regulation ability of the mutated Stat5b is proved by decreased levels of RNA of Stat5b-regulated genes (IL-2R and Pim1). Consequently, IL-2R and Pim1 proteins were shown by Western blotting to have lower levels in NOD compared with normal B6 mice. These proteins have been implicated in immune regulation, apoptosis, activation-induced cell death, and control of autoimmunity. Therefore, the Stat5b pathway is a key molecular defect in NOD mice.

Received for publication, November 5, 2003 , and in revised form, December 22, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AYO4O231 (Stat5b of NOD) and AYO429O6 (Stat5b of B6).

^* This work was supported in part by National Institutes of Health Grant POI AI-42288 (to J.-X. S.). 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.

Supported by postdoctoral fellowships from the Juvenile Diabetes Research Foundation (JDF3-1999-671 and JDFl0-200l-589).

^¶ These authors contributed equally to this work.

To whom correspondence should be addressed: Center for Biotech nology and Genomic Medicine, Medical College of Georgia, 1120 15th St., PV6B108, Augusta, GA 30912. Tel.: 706-823-3973; Fax: 706-823-2269; E-mail: jshe{at}mail.mcg.edu.

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