Disease relevance of FOXA2

• The Foxa2(loxP/loxP); Ins.Cre mice will serve as a unique model to investigate the regulation of insulin secretion by the beta cell and suggest the human FOXA2 as a candidate gene for familial hyperinsulinism [1].
• Analysis of lung tissue from patients with a variety of pulmonary diseases revealed a strong inverse correlation between FOXA2 and goblet cell hyperplasia [2].
• A transcriptional profiling study of CCAAT/enhancer binding protein targets identifies hepatocyte nuclear factor 3 beta as a novel tumor suppressor in lung cancer [3].
• Identification of missense mutations in the hepatocyte nuclear factor-3beta gene in Japanese subjects with late-onset Type II diabetes mellitus [4].
• Foxa1 protein expression was always observed in human prostate carcinomas, regardless of Gleason grade score, while Foxa2 was only detected in neuroendocrine small cell carcinomas and in some high Gleason score adenocarcinomas [5].

High impact information on FOXA2

• A GFP-Bry(+) population expressing variable levels of CD4-Foxa2 developed upon differentiation of this ES cell line [6].
• To model these developmental stages in vitro, an ES cell line was established that expresses CD4 from the foxa2 locus in addition to GFP from the brachyury locus [6].
• Mutant Foxa-2T156A is resistant to Akt-mediated phosphorylation, nuclear exclusion, and transcriptional inactivation of Foxa-2-regulated gene expression [7].
• This Akt phosphorylation site in Foxa-2 is highly conserved from mammals to insects [7].
• Hepatocyte nuclear factor 3 beta contains two transcriptional activation domains, one of which is novel and conserved with the Drosophila fork head protein [8].

Chemical compound and disease context of FOXA2

• In particular, Foxa2 may be involved in progression of prostate cancer to androgen independence [5].

Biological context of FOXA2

• Ectopic expression of IPF1, HLXB9, and FOXA2 with or without islet coculture or islet-conditioned medium results in insulin gene expression [9].
• An HNF3beta binding site was located at nt -39/-23 by EMSA [10].
• A pancreatic beta -cell-specific enhancer in the human PDX-1 gene is regulated by hepatocyte nuclear factor 3beta (HNF-3beta ), HNF-1alpha, and SPs transcription factors [11].
• Among the 13 genes whose CGI were completely methylated in one or more cell lines, FOXA2 and XT3 were expressed in normal human mammary epithelial cells (HMEC) and were not expressed in cancer cell lines with complete methylation [12].
• These AMCase-expressing cells retain expression of FOXA2, a transcription factor whose downregulation in association with IL-13 signaling has previously been associated with production of mucus in proximal airway epithelial cells [13].

Anatomical context of FOXA2

• Exendin-4 differentiation of a human pancreatic duct cell line into endocrine cells: involvement of PDX-1 and HNF3beta transcription factors [14].
• HESCs are capable of spontaneous differentiation to cells expressing the definitive endoderm and pancreatic progenitor markers Foxa2, Sox17, and Pdx1, and ultimately, some cells express islet endocrine hormones [15].
• FOXA2 is required for alveolarization and regulates airway epithelial cell differentiation in the postnatal lung [2].
• Foxa2(-/-) embryos lack both the organizer and its BMP antagonists, yet about 25% show weak forebrain gene expression [16].
• Foxa1 and Foxa2 cooperate to establish competence in foregut endoderm and are required for normal development of endoderm-derived organs such as the liver, pancreas, lungs, and prostate [17].

Associations of FOXA2 with chemical compounds

• Overexpression of Foxa2 results in blunted glucose-stimulated insulin secretion, whereas induction of DN-Foxa2 causes a left shift of glucose-induced insulin release [18].
• Importantly, in vitro functional assays demonstrated that Foxa2 could activate androgen-dependent prostate-specific genes in an androgen receptor and ligand-independent manner [5].
• In addition, melatonin increased the expression level of forkhead box A2, which was recently discovered to regulate fatty acid oxidation and to be inhibited by insulin [19].

Physical interactions of FOXA2

• EMSA results indicated that EX-4 caused a 12-fold increase in HNF3beta binding to PDX-1 promoter area II [14].

Regulatory relationships of FOXA2

• In transfected Huh7 cells, OATP8 promoter activity was inhibited by 70% when HNF3beta was cotransfected [10].
• The chum salmon IGF-II gene promoter is activated by hepatocyte nuclear factor 3beta [20].

Other interactions of FOXA2

• Expression of the liver-enriched transcription factor hepatocyte nuclear factor 3beta (HNF3beta) was increased in 70% of HCC and correlated inversely with OATP8 mRNA (r=-0.75, P<0.05) and protein [10].
• The OATP-C promoter was not inhibited by HNF3beta [10].
• We have tested this hypothesis by screening a panel of 57 unrelated Japanese subjects with a clinical diagnosis of MODY for mutations in HNF3B [21].
• CONCLUSIONS: The changes induced by nitrofen in cultured H441 human pneumocytes are reverted in part by anti-oxidant vitamins by upregulating TTF-1, HNF-3beta and SP-B and stimulating proliferation and maturity in nitrofen-treated cells [22].
• Luciferase assays of the AGR2 promoter showed regulation by the goblet cell-specific transcription factors FOXA1 and FOXA2 [23].

Analytical, diagnostic and therapeutic context of FOXA2

• The expression of three transcripts (HNF3beta, SUR1, and SNAP-25) was confirmed by Western blotting for the corresponding proteins [24].
• Prominent Foxa1 and Foxa2 expression was observed in 12T-10 invasive undifferentiated neuroendocrine carcinomas, in the hormone independent and metastasizing 12T-10 derived, NE-10 allograft tumors, and in all metastatic lesions isolated from 12T-10 mice [5].
• Multiple binding sites for HNF-3beta were identified within the 5'-UTR using electrophoretic mobility shift assays and mutation of these sites prevents binding of HNF-3beta [20].
• Chromatin immunoprecipitation analyses confirmed Reg3gamma as a novel transcriptional target of Foxa2 (HNF3beta) [25].
• Hyperinsulinemia-mediated inactivation of Foxa2 by nuclear exclusion has recently been implicated in the development of liver steatosis and insulin resistance in three animal models of diabetes [26].

References