1. Forkhead Box Protein P3 (FOXP3) Represses ATF3 Transcriptional Activity
- Author
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Leticia Cardoso, Richard Henry Yang, Chiung-Min Wang, Wei-Hsiung Yang, Ninoska M. Gutierrez, and William H. Yang
- Subjects
Transcriptional Activation ,QH301-705.5 ,FOXP3 ,Activating transcription factor ,Gene Expression ,chemical and pharmacologic phenomena ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,Article ,Catalysis ,Inorganic Chemistry ,Cell Line, Tumor ,medicine ,Humans ,ATF3 ,Physical and Theoretical Chemistry ,Biology (General) ,Phosphorylation ,Promoter Regions, Genetic ,Molecular Biology ,Transcription factor ,QD1-999 ,Spectroscopy ,transcriptional activity ,Gene knockdown ,Mutation ,Activating Transcription Factor 3 ,Binding Sites ,Chemistry ,Organic Chemistry ,Promoter ,hemic and immune systems ,Acetylation ,Forkhead Transcription Factors ,General Medicine ,Computer Science Applications ,Cell biology ,post-translational modification ,Protein Processing, Post-Translational - Abstract
Activating transcription factor 3 (ATF3), a transcription factor and acute stress sensor, is rapidly induced by a variety of pathophysiological signals and is essential in the complex processes in cellular stress response. FOXP3, a well-known breast and prostate tumor suppressor from the X chromosome, is a novel transcriptional repressor for several oncogenes. However, it remains unknown whether ATF3 is the target protein of FOXP3. Herein, we demonstrate that ATF3 expression is regulated by FOXP3. Firstly, we observed that overexpression of FOXP3 reduced ATF3 protein level. Moreover, knockdown FOXP3 by siRNA increased ATF3 expression. Secondly, FOXP3 dose-dependently reduced ATF3 promoter activity in the luciferase reporter assay. Since FOXP3 is regulated by post-translational modifications (PTMs), we next investigated whether PTMs affect FOXP3-mediated ATF3 expression. Interestingly, we observed that phosphorylation mutation on FOXP3 (Y342F) significantly abolished FOXP3-mediated ATF3 expression. However, other PTM mutations on FOXP3, including S418 phosphorylation, K263 acetylation and ubiquitination, and K268 acetylation and ubiquitination, did not alter FOXP3-mediated ATF3 expression. Finally, the FOXP3 binding site was found on ATF3 promoter region by deletion and mutagenesis analysis. Taken together, our results suggest that FOXP3 functions as a novel regulator of ATF3 and that this novel event may be involved in tumor development and progression. more...
- Published
- 2021