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J. Biol. Chem., Vol. 280, Issue 15, 14989-14996, April 15, 2005

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The Transcriptional Co-activator Protein p100 Recruits Histone Acetyltransferase Activity to STAT6 and Mediates Interaction between the CREB-binding Protein and STAT6^*

Tuuli Välineva, Jie Yang¶, Riitta Palovuori, and Olli Silvennoinen||**

From the Institute of Medical Technology, University of Tampere, FIN-33014 Tampere, Finland, the ^||Department of Clinical Microbiology, Tampere University Hospital, FIN-33521 Tampere, Finland, and the ^¶Department of Immunology, Tianjin Medical University, Tianjin 300070, Peoples Republic of China

STAT6 is a critical regulator of transcription for interleukin-4 (IL-4)-induced genes. Activation of gene expression involves recruitment of coactivator proteins that function as bridging factors connecting sequence-specific transcription factors to the basal transcription machinery, and as chromatin-modifying enzymes. Coactivator proteins CBP/p300 have been implicated in regulation of transcription in all STATs. CBP is also required for STAT6-mediated gene activation, but the underlying molecular mechanisms are still elusive. In this study we investigated the mechanisms by which STAT6 recruits CBP and chromatin-modifying activities to the promoter. Our results indicate that while STAT1-interacted directly with CBP, the interaction between STAT6 and CBP was found to be mediated through p100 protein, a coactivator protein that has previously been shown to stimulate the transcription of IL-4-induced genes. The staphylococcal nuclease-like (SN)-domains of p100 directly interacted with amino acids 1099–1758 of CBP, while p100 did not associate with SRC-1, another coactivator of STAT6. p100 was found to recruit histone acetyltransferase (HAT) activity to STAT6 in vivo. Chromatin immunoprecipitation studies demonstrated that p100 increases the STAT6-p100-CBP ternary complex formation in the human Ig promoter. p100 also increased the amount of acetylated histone H4 at the Ig promoter, and siRNAs directed against p100 effectively inhibited Ig reporter gene expression. Our results suggest that p100 has an important role in the assembly of STAT6 transcriptosome, and that p100 stimulates IL-4-dependent transcription by mediating interaction between STAT6 and CBP and recruiting chromatin modifying activities to STAT6-responsive promoters.

Received for publication, September 13, 2004 , and in revised form, February 3, 2005.

^* This work was supported by the Medical Research Council of Academy of Finland, Medical Research Fund of Tampere University Hospital, the Finnish Foundation for Cancer Research, the Sigrid Juselius Foundation, the National Natural Science Foundation of China No. 30300070, and the Tuberculosis Foundation of Tampere. 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.

Both authors contributed equally to this work.

^** To whom correspondence should be addressed: Institute of Medical Technology, University of Tampere, Biokatu 8, FIN-33014 Tampere, Finland. Tel.: 358-3-215-7845; Fax: 358-3-215-7332; E-mail: olli.silvennoinen{at}uta.fi.

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