MCB Accepts, published online ahead of print on 16 July 2007

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Mol. Cell. Biol. doi:10.1128/MCB.00613-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Amino acid residues required for physical and cooperative transcriptional interaction of STAT3 and AP-1 proteins (cJun, cFos)

Michael Ginsberg, Elmar Czeko, Patrick Müller, Zhiyong Ren, Xiaomin Chen, and James E. Darnell Jr.^*

Laboratory of Molecular Cell Biology, The Rockefeller University, New York, NY 10021-6399; Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; Ph.D. Program in Structural Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, TX 77030

^* To whom correspondence should be addressed. Email: darnell{at}rockefeller.edu.

Cooperation between STAT3 and cJun in driving transcription during transfection of reporter constructs is well established and both proteins are present on some IL-6 (STAT3) dependent promoters on chromosomal loci. We report that siRNA knockdown of cJun or cFos diminishes IL-6 induction of some but not all STAT3 dependent mRNAs. Specific contact sites in STAT3 responsible for interaction of a domain of STAT3 with cJun were known. Here we show the B-zip domain of cJun interacts with STAT3 and that cJun mutations R261A or R261D near but not in the DNA binding domain block in vitro STAT3-cJun interaction and decreases co-stimulation of transcription in transfection assays. Cooperative binding to DNA was observed of tyrosine phosphorylated STAT3 and both wild-type and the R261A mutant of cJun. Even a cJun mutant R261D that on its own did not bind DNA bound DNA weakly in the presence of STAT3. We conclude that a functional interaction exists between STAT3 and cJun while bound to chromosomal DNA elements that is necessary for driving transcription on at least some STAT3 target genes. Identifying such required interactive protein interfaces should be a stimulus to search for compounds that could ultimately inhibit the activity of STAT3 in tumors dependent on persistently active STAT3.

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