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Forkhead Box Protein P3 (FOXP3) Represses ATF3 Transcriptional Activity.

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.

SUBMITTER: Wang CM

PROVIDER: S-EPMC8583784 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Assessment of the Relationship between Ulcerative Colitis and Forkhead Box P3 Polymorphisms.

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| S-EPMC8975443 | biostudies-literature

Forkhead Box P3 Methylation and Expression in Men with Obstructive Sleep Apnea.

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| S-EPMC7139835 | biostudies-literature

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| S-EPMC7576988 | biostudies-literature

Genetic association study of intron variants in the forkhead box protein P3 gene in Chinese patients diagnosed with cervical cancer.

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| S-EPMC9077298 | biostudies-literature

Forkhead box protein A2 (FOXA2) protein stability and activity are regulated by sumoylation.

Project description:The forkhead box protein A2 (FOXA2) is an important regulator of glucose and lipid metabolism and organismal energy balance. Little is known about how FOXA2 protein expression and activity are regulated by post-translational modifications. We have identified that FOXA2 is post-translationally modified by covalent attachment of a small ubiquitin related modifier-1 (SUMO-1) and mapped the sumoylation site to the amino acid lysine 6 (K6). Preventing sumoylation by mutating the SUMO acceptor K6 to arginine resulted in downregulation of FOXA2 protein but not RNA expression in INS-1E insulinoma cells. K6R mutation also downregulated FOXA2 protein levels in HepG2 hepatocellular carcinoma cells, HCT116 colon cancer cells and LNCaP and DU145 prostate cancer cells. Further, interfering with FOXA2 sumoylation through siRNA mediated knockdown of UBC9, an essential SUMO E2 conjugase, resulted in downregulation of FOXA2 protein levels. Stability of sumoylation deficient FOXA2K6R mutant protein was restored when SUMO-1 was fused in-frame. FOXA2 sumoylation and FOXA2 protein levels were increased by PIAS1 SUMO ligase but not a SUMO ligase activity deficient PIAS1 mutant. Although expressed at lower levels, sumoylation deficient FOXA2K6R mutant protein was detectable in the nucleus indicating that FOXA2 nuclear localization is independent of sumoylation. Sumoylation increased the transcriptional activity of FOXA2 on Pdx-1 area I enhancer. Together, our results show that sumoylation regulates FOXA2 protein expression and activity.

| S-EPMC3485284 | biostudies-literature

Forkhead Box F1 (FOXF1) represses fibroblast functions relevant to fibrogenesis

Project description:Aberrant expression of master phenotype regulators by lung fibroblasts may play a central role in idiopathic pulmonary fibrosis (IPF). Interrogating IPF fibroblast transcriptome datasets, we identified Forkhead Box F1 (FOXF1), a DNA-binding protein required for lung development, as a candidate actor in IPF. Thus, we determined FOXF1 expression levels in fibroblasts cultured from normal or IPF lungs in vitro, and explored FOXF1 functions in these cells using transient and stable loss-of-function and gain-of-function models. FOXF1 mRNA and protein were expressed at higher levels in IPF compared with controls. In normal lung fibroblasts, FOXF1 repressed key fibroblast functions such as proliferation, survival, and expression of collagen-1 (COL1) and actin related protein 2/3 complex, subunit 2 (ARPC2). ARPC2 knockdown mimicked FOXF1 overexpression with regard to proliferation and COL1 expression. FOXF1 expression was induced by the antifibrotic mediator prostaglandin E2 (PGE2). Ex vivo, FOXF1 knockdown conferred CCL-210 lung fibroblasts the ability to implant and survive in uninjured mouse lungs. In IPF lung fibroblasts, FOXF1 regulated COL1 but not ARPC2 expression. In conclusion, FOXF1 functions and regulation were consistent with an antifibrotic role in lung fibroblasts. Higher FOXF1 levels in IPF fibroblasts may thus participate in a compensatory response to fibrogenesis. Lung fibroblasts derived from 4 different IPF patients (P313, P355, P375 and P426) were transiently transfected with pcfoxf1 or control pcDNA3.1-constructs. Total RNAs were extracted 24 h after transfection and hybridized on microarrays. One color experiment with 2 experimental conditions: pcfoxf1 and pcDNA3.1

2014-10-01 | E-GEOD-52612 | biostudies-arrayexpress

Forkhead Box F1 (FOXF1) represses fibroblast functions relevant to fibrogenesis

2014-10-01 | GSE52612 | GEO

Forkhead box P3 regulates ARHGAP15 expression and affects migration of glioma cells through the Rac1 signaling pathway.

Project description:Forkhead box P3 (FOXP3) plays a crucial role in the development and function of regulatory T cells and was recently identified as a tumor suppressor in different cancer types. Forkhead box P3 is expressed in normal brain tissues, but is strongly downregulated or absent in glioblastomas. In order to understand the FOXP3 adjustment mechanisms in glioma cells, we performed a DNA microarray in U87 cells overexpressing FOXP3 and validated the differences using quantitative real-time PCR, Western blot analysis, and immunohistochemistry in vitro and in vivo. We found that FOXP3 can regulate the expression of ARHGAP15. Expression of FOXP3 was also correlated with ARHGAP15 in glioma samples. Overexpression of FOXP3 inhibited glioma cell migration through ARHGAP15 upregulation and Rac1 inactivation. Silencing of FOXP3 promoted migration through ARHGAP15 downregulation and Rac1 activation. ARHGAP15, a GTPase-activating protein for Rac1, inhibits small GTPase signaling in a dual negative manner. We found that there is a correlation between expression of ARHGAP15 and glioma level. The small GTPase Rac1 plays an important role in cell migration. In addition, we found that FOXP3 regulates expression of epithelial-mesenchymal transition markers E-cadherin and N-cadherin, which is important given that epithelial-mesenchymal transition is critically involved in tumor spreading and dissemination. Thus, FOXP3 or ARHGAP15 may serve as a new molecular target for antimetastatic therapies in treating glioma.

| S-EPMC5276829 | biostudies-literature

The Prognostic Value of Forkhead Box P3 Expression in Operable Breast Cancer: A Large-Scale Meta-Analysis.

Project description:BackgroundRecent studies have shown that the forkhead box P3 (FOXP3) protein has a prognostic role in breast cancer. However, these results are controversial. Therefore, the aim of this meta-analysis was to clarify the prognostic role of FOXP3 expression in operable breast cancer cases.MethodsEligible studies describing the use of FOXP3 as a prognostic factor for operable breast cancer cases were identified. Clinicopathological features, disease-free survival (DFS), and overall survival (OS) data were collected from these studies and were analyzed using Stata software.ResultsA total of 16 articles containing data from 13,217 breast cancer patients met the inclusion criteria established for this study. The subsequent meta-analysis that was performed showed that high levels of FOXP3 are not significantly associated with DFS and OS with significant heterogeneity. An additional subgroup analysis demonstrated that intratumoral FOXP3+ regulatory T cells (Tregs) were positively correlated with adverse clinicopathological parameters, yet they did not show an association with DFS or OS. For tumor cells, the pooled results revealed that FOXP3 is significantly associated with DFS (HR: 2.55, 95% CI: 1.23-5.30) but is not associated with clinicopathological parameters or OS. We also observed a significant correlation between FOXP3 expression and survival in the estrogen receptor-positive (ER)+ subgroup (HR: 1.83, 95% CI: 1.36-2.47 for DFS, HR: 1.87, 95% CI 1.28-2.73 for OS), in the Asian region (HR: 1.98, 95% CI: 1.56-2.50 for DFS, HR: 1.93, 95% CI: 1.12-3.35 for OS) and using the median as the FOXP3-positive cut-off value (HR: 1.94, 95% CI: 1.57-2.39 for DFS, HR: 2.06; 95% CI: 1.36-3.11 for OS).ConclusionThis meta-analysis indicates that a prognostic role for FOXP3 expression in operable breast cancer cases depends on the FOXP3-positive region, ER status, geographic region and the FOXP3-positive cut-off value.

| S-EPMC4549287 | biostudies-literature

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