Amino acid residues required for physical and cooperative transcriptional interaction of STAT3 and AP-1 proteins c-jun and c-fos
Amino acid residues required for physical and cooperative transcriptional interaction of STAT3 and AP-1 proteins c-jun and c-fos
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DOI：
10.1128/mcb.00613-07
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发表时间：
2007-09-01
影响因子：
5.3
通讯作者：
Darnell, James E., Jr.
中科院分区：
文献类型：
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作者：
Ginsberg, Michael;Czeko, Elmar;Darnell, James E., Jr.
STAT3和c-Jun在转染报告基因构建过程中协同驱动转录已经得到证实，这两种蛋白都存在于染色体位点上的一些白细胞介素-6 （IL-6）依赖STAT3的启动子上。我们报道，c-Jun或c-Fos的小干扰RNA敲低会减少IL-6对一些但不是全部stat3依赖性mrna的诱导。已知STAT3中负责STAT3结构域与c-Jun相互作用的特定接触位点。在这里，我们发现c-Jun的B-zip结构域与STAT3相互作用，并且c-Jun突变R261A或R261D在DNA结合结构域附近而不是在DNA结合结构域内阻断了体外STAT3-c-Jun相互作用，并在转染实验中减少了转录的共刺激。观察到酪氨酸磷酸化的STAT3与野生型和R261A突变体c-Jun的DNA协同结合。即使是本身不结合DNA的c-Jun突变体R261D，在STAT3存在下也能弱结合DNA。我们得出结论，STAT3和c-Jun结合到染色体DNA元件时存在功能性相互作用，并且对于驱动至少一些STAT3靶基因的转录是必要的。识别这些必需的相互作用蛋白界面应该是一种刺激，可以寻找最终抑制STAT3活性的化合物，这些化合物在依赖于持续活性STAT3的肿瘤中。
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.