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Blood, 15 July 2006, Vol. 108, No. 2, pp. 566-574. Prepublished online as a Blood First Edition Paper on March 28, 2006; DOI 10.1182/blood-2005-12-4777. This Article Full Text (PDF) All Versions of this Article: 2005-12-4777v1 108/2/566    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chen, Y. Articles by Wang, D. Search for Related Content PubMed PubMed Citation Articles by Chen, Y. Articles by Wang, D. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 2, 2005 Accepted March 6, 2006 Proteasome-dependent down-regulation of activated Stat5A in the nucleus Yuhong Chen, Xuezhi Dai, Arthur L Haas, Renren Wen, and Demin Wang* Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, China; Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA Department of Biochemistry and Molecular Biology, LSUHSC School of Medicine, New Orleans, LA, USA State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, China; Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI, USA; Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA * Corresponding author; email: demin.wang{at}bcw.edu. A broad spectrum of cytokines can activate the signal transducer and activator of transcription 5 (Stat5) by inducing a single tyrosine phosphorylation of the molecule. Although the process of Stat5 activation has been well studied, the mechanism by which it is inactivated is not fully understood. We demonstrate that the proteasome inhibitor MG132, but not the nuclear export inhibitor LMB, stabilizes active nuclear Stat5A whereas MG132 only partially stabilizes active cytoplasmic Stat5A. Importantly, ubiquitinated Stat5A is detected in the nucleus and the poly-ubiquitination of active Stat5A is K48-linked, a linkage type targeting proteins for degradation. Ubiquitination of Stat5A is recapitulated in a cell-free system and Ubc5 is identified as the E2 conjugating enzyme for Stat5A ubiquitination. Interestingly, phosphorylation of Stat5A per se is not required for ubiquitination. Finally, C-terminal deletion analysis of Stat5A localizes the amphipathic region of amino acids 751-762 as a ubiquitination signal, possibly representing an E3 recognition motif. Taken together, these results demonstrate that the down-regulation of nuclear and cytoplasmic active Stat5A is differentially regulated. In the nucleus, ubiquitin/proteasome-mediated protein degradation is the dominant mechanism for the down-regulation of active Stat5A; whereas in the cytoplasm, protein tyrosine phasphatase is a major player in the down-regulation of active Stat5A. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Bai, J. Zha, H. Zhao, F. P. Ross, and S. L. Teitelbaum Tumor Necrosis Factor Receptor-associated Factor 6 Is an Intranuclear Transcriptional Coactivator in Osteoclasts J. Biol. Chem., November 7, 2008; 283(45): 30861 - 30867. [Abstract] [Full Text] [PDF] B. L. Conway-Campbell, M. A. McKenna, C. C. Wiles, H. C. Atkinson, E. R. de Kloet, and S. L. Lightman Proteasome-Dependent Down-Regulation of Activated Nuclear Hippocampal Glucocorticoid Receptors Determines Dynamic Responses to Corticosterone Endocrinology, November 1, 2007; 148(11): 5470 - 5477. [Abstract] [Full Text] [PDF] G. Cassese, E. Parretta, L. Pisapia, A. Santoni, J. Guardiola, and F. Di Rosa Bone marrow CD8 cells down-modulate membrane IL-7R{alpha} expression and exhibit increased STAT-5 and p38 MAPK phosphorylation in the organ environment. Blood, September 15, 2007; 110(6): 1960 - 1969. [Abstract] [Full Text] [PDF] H. Zeng, L. Di, G. Fu, Y. Chen, X. Gao, L. Xu, X. Lin, and R. Wen Phosphorylation of Bcl10 Negatively Regulates T-Cell Receptor-Mediated NF-{kappa}B Activation Mol. Cell. Biol., July 15, 2007; 27(14): 5235 - 5245. [Abstract] [Full Text] [PDF] A. M. Weaver and C. M. Silva Modulation of Signal Transducer and Activator of Transcription 5b Activity in Breast Cancer Cells by Mutation of Tyrosines within the Transactivation Domain Mol. Endocrinol., October 1, 2006; 20(10): 2392 - 2405. [Abstract] [Full Text] [PDF]

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