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Molecular and Cellular Biology, September 2007, p. 6300-6308, Vol. 27, No. 18
0270-7306/07/$08.00+0     doi:10.1128/MCB.00613-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Amino Acid Residues Required for Physical and Cooperative Transcriptional Interaction of STAT3 and AP-1 Proteins c-Jun and c-Fos

Michael Ginsberg,¹ Elmar Czeko,^1, Patrick Müller,^1, Zhiyong Ren,² Xiaomin Chen,^2,3 and James E. Darnell Jr.^1*

Laboratory of Molecular Cell Biology, The Rockefeller University, New York, New York 10021-6399,¹ Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030,² Ph.D. Program in Structural Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas 77030³

Received 9 April 2007/ Returned for modification 7 May 2007/ Accepted 5 July 2007

Cooperation between STAT3 and c-Jun in driving transcription during transfection of reporter constructs is well established, and both proteins are present on some interleukin-6 (IL-6) STAT3-dependent promoters on chromosomal loci. We report that small interfering RNA knockdown of c-Jun or c-Fos 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 c-Jun were known. Here we show that the B-zip domain of c-Jun interacts with STAT3 and that c-Jun mutation R261A or R261D near but not in the DNA binding domain blocks in vitro STAT3-c-Jun interaction and decreases costimulation of transcription in transfection assays. Cooperative binding to DNA of tyrosine-phosphorylated STAT3 and both wild-type and R261A mutant c-Jun was observed. Even c-Jun mutant R261D, which on its own did not bind DNA, bound DNA weakly in the presence of STAT3. We conclude that a functional interaction between STAT3 and c-Jun while bound to chromosomal DNA elements exists and 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.

Published ahead of print on 16 July 2007.

Present address: Ludwig-Maximillian-Universität, Munich, Germany.

Present address: Georg-August-Universität, Göttingen, Germany.