Fox transcription factors: from development to disease

Golson, Maria L.; Kaestner, Klaus H.

doi:10.1242/dev.112672

Cited by 329 publications

(289 citation statements)

References 174 publications

(189 reference statements)

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“…In accordance with its inhibitory function, FOXA1 was down‐regulated in NEC tissues and in mimic miR‐431‐overexpressing Caco‐2 cells. FOXA1, a winged‐helix transcription factor of the 44‐member FOX family, is known to play critical roles in the development and homeostasis of multiple tissues and facilitating the binding of many other transcription factors to their targets (27). A brief summary of the functions of FOXA1 is presented in Supplemental Table S5.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of miR‐431 and target gene FOXA1 in intestinal tissues of infants with necrotizing enterocolitis

Chan

Leung

et al. 2019

FASEB j.

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The level of microRNA (miR)‐431 was found to be markedly up‐regulated in intestinal tissue of necrotizing enterocolitis (NEC). The objective of this study was to identify the target gene of miR‐431 and to investigate the role of the miR‐431‐FOXA1 axis in the pathophysiology of NEC. The target gene of miR‐431 was identified by in silico target prediction bioinformatics, luciferase assay, and Western blotting. Effects of miR‐431 on downstream expression signals, cell proliferation, and apoptosis were investigated by overexpression in Caco‐2 cells upon stimulation by LPS or lipoteichoic acid (LTA). FOXA1 was identified as the target gene of miR‐431. Overexpression of miR‐431 in Caco‐2 cells significantly inhibited FOXA1, ESRRG, and HNF4A and activated IL‐6, LGR5, NFKB2, PLA2G2A, PRKCZ, and TNF. IL‐8 and ‐10 were enhanced when costimulated with LPS or LTA. These potential downstream genes were also significantly dysregulated in primary NEC tissues compared with surgical‐control tissues. Overexpression of miR‐431 significantly decreased proliferation and increased apoptosis of Caco‐2 cells. A proposed network of miR‐431‐FOXA1 interaction with LPS and LTA receptors demonstrates dysregulation of transcription factors, inflammatory mediators, epithelium tight junction regulators, and cell proliferation and apoptosis signals. The miR‐431‐FOXA1 axis could in part be responsible for the intensification of the inflammatory response in NEC tissues and contribute to the proinflammatory pathophysiology.—Wu, Y. Z., Chan, K. Y. Y., Leung, K. T., Lam, H. S., Tam, Y. H., Lee, K. H., Li, K., Ng, P. C. Dysregulation of miR‐431 and target gene FOXA1 in intestinal tissues of infants with necrotizing enterocolitis. FASEB J. 33, 5143–5152 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Dysregulation of miR‐431 and target gene FOXA1 in intestinal tissues of infants with necrotizing enterocolitis

Chan

Leung

et al. 2019

FASEB j.

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“…Activation of β‐catenin signalling can further exert different biological effects by inducing the transcription of corresponding target genes. β‐catenin binds to T cell factor (TCF) to promote transdifferentiation and fibrosis and connects to foxhead frame transcription factor (Foxo) to promote anti‐inflammatory and wound repair response . Joo et al confirmed that sitagliptin can restore Foxo3a activity and reduce renal structural and functional impairment by reducing the ratio of P‐Foxo3a/total Foxo3a in 5/6 nephrectomy rats.…”

Section: Discussionmentioning

confidence: 99%

Effect of sitagliptin on tubulointerstitial Wnt/β‐catenin signalling in diabetic nephropathy

et al. 2019

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Aim To investigate the effect of sitagliptin on Wnt/β‐catenin signalling in the tubulointerstitium of diabetic nephropathy. Methods Forty male Wistar rats were divided into normal control (NC), diabetic model (DM), low and high‐dose sitagliptin intervention groups (ST1 and ST2, respectively). Changes in the biochemical parameters and tubulointerstitial fibrosis index were observed. The levels of protein and gene expression of different indicators were detected via immunohistochemistry and real‐time polymerase chain reaction. NRK‐52E cells were divided into the normal control group, mannitol control group, high glucose group (HG), high glucose plus sitagliptin intervention group (HG + ST) and high glucose plus Wnt/β‐catenin inhibitor group (HG + XAV939). The relevant indicators were examined by Western blot or enzyme‐linked immunosorbent assay. Results Compared with the NC group, the blood glucose, glycosylated haemoglobin, 24 h urinary albumin, creatinine clearance and tubulointerstitial fibrosis index were significantly increased in the DM group. These parameters were decreased in the ST1 and ST2 groups compared to the DM group. Compared with the NC group, the levels of Wnt4, β‐catenin, dipeptidyl peptidase‐4 and α‐smooth muscle actin were higher and E‐cadherin was lower in the DM group. Sitagliptin treatment reversed these changes. In the high glucose‐stimulated NRK‐52E cells, sitagliptin and XAV939 inhibited the elevated expression of Wnt4, β‐catenin, dipeptidyl peptidase‐4, α‐smooth muscle actin, transforming growth factor‐β and fibronectin and restored E‐cadherin activity. Conclusion Sitagliptin may inhibit the tubulointerstitial Wnt/β‐catenin signalling pathway in diabetic nephropathy and provide renal protection by alleviatinge renal tubulointerstitial transdifferentiation and fibrosis.

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“…Sequence analysis of EWS‐FLI1‐binding peaks suggested possible cooperative binding with FOX family transcription factors. There are 44 members of the FOX family genes in human and mouse . Gene expression and functional analysis identified FOXQ1 as the FOX protein responsible for serving as a co‐binding partner of EWS‐FLI1.…”

Section: Discussionmentioning

confidence: 99%

EWS‐FLI1 regulates a transcriptional program in cooperation with Foxq1 in mouse Ewing sarcoma

et al. 2018

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EWS‐FLI1 constitutes an oncogenic transcription factor that plays key roles in Ewing sarcoma development and maintenance. We have recently succeeded in generating an ex vivo mouse model for Ewing sarcoma by introducing EWS‐FLI1 into embryonic osteochondrogenic progenitors. The model well recapitulates the biological characteristics, small round cell morphology, and gene expression profiles of human Ewing sarcoma. Here, we clarified the global DNA binding properties of EWS‐FLI1 in mouse Ewing sarcoma. GGAA microsatellites were found to serve as binding sites of EWS‐FLI1 albeit with less frequency than that in human Ewing sarcoma; moreover, genomic distribution was not conserved between human and mouse. Nevertheless, EWS‐FLI1 binding sites within GGAA microsatellites were frequently associated with the histone H3K27Ac enhancer mark, suggesting that EWS‐FLI1 could affect global gene expression by binding its target sites. In particular, the Fox transcription factor binding motif was frequently observed within EWS‐FLI1 peaks and Foxq1 was identified as the cooperative partner that interacts with the EWS portion of EWS‐FLI1. Trib1 and Nrg1 were demonstrated as target genes that are co‐regulated by EWS‐FLI1 and Foxq1, and are important for cell proliferation and survival of Ewing sarcoma. Collectively, our findings present novel aspects of EWS‐FLI1 function as well as the importance of GGAA microsatellites.

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Fox transcription factors: from development to disease

Cited by 329 publications

References 174 publications

Dysregulation of miR‐431 and target gene FOXA1 in intestinal tissues of infants with necrotizing enterocolitis

Dysregulation of miR‐431 and target gene FOXA1 in intestinal tissues of infants with necrotizing enterocolitis

Effect of sitagliptin on tubulointerstitial Wnt/β‐catenin signalling in diabetic nephropathy

EWS‐FLI1 regulates a transcriptional program in cooperation with Foxq1 in mouse Ewing sarcoma

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