1. FoxP3 Acts as a Cotranscription Factor with STAT3 in Tumor-Induced Regulatory T Cells.
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Hossain, Dewan?Md?Sakib, Panda, Abir?K., Manna, Argha, Mohanty, Suchismita, Bhattacharjee, Pushpak, Bhattacharyya, Sankar, Saha, Taniya, Chakraborty, Sreeparna, Kar, Rajiv?K., Das, Tanya, Chatterjee, Subhrangsu, and Sa, Gaurisankar
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FORKHEAD transcription factors , *TRANSCRIPTION factors , *STAT proteins , *T cells , *ANTINEOPLASTIC agents , *INTERLEUKIN-10 , *GENE targeting - Abstract
Summary: FoxP3, a lineage-specification factor, executes its multiple activities mostly through transcriptional regulation of target genes. We identified an interleukin-10 (IL-10)-producing FoxP3+ T regulatory cell population that contributes to IL-10-dependent type 2 cytokine bias in breast-cancer patients. Although genetic ablation of FOXP3 inhibited IL10 transcription, genome-wide analysis ruled out its role as a transcription factor for IL10. In-depth analysis revealed that histone acetyl transterase-1, in association with FoxP3, modified the IL10 promoter epigenetically, making a space for docking STAT3-FoxP3 complexes. A predictive docking module with target-receptor specificity, along with exon-deletion and site-directed mutagenesis studies, showed that STAT3 binds through its N-terminal floppy domain to the exon 2 β sheet region of FoxP3 to form STAT3-FoxP3 complexes. Such cotranscriptional activity of FoxP3 extended to other STAT3-target genes that lack FoxP3-binding sites. These results suggest a function of FoxP3, where, failing to achieve direct promoter occupancy, FoxP3 promotes transcription in association with the locus-specific transcription factor STAT3. [Copyright &y& Elsevier]
- Published
- 2013
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