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Gene Review

FOXA2  -  forkhead box A2

Homo sapiens

Synonyms: Forkhead box protein A2, HNF-3-beta, HNF-3B, HNF3B, Hepatocyte nuclear factor 3-beta, ...
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Disease relevance of FOXA2


High impact information on FOXA2


Chemical compound and disease context of FOXA2


Biological context of FOXA2


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


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


  1. Tissue-specific deletion of Foxa2 in pancreatic beta cells results in hyperinsulinemic hypoglycemia. Sund, N.J., Vatamaniuk, M.Z., Casey, M., Ang, S.L., Magnuson, M.A., Stoffers, D.A., Matschinsky, F.M., Kaestner, K.H. Genes Dev. (2001) [Pubmed]
  2. Foxa2 regulates alveolarization and goblet cell hyperplasia. Wan, H., Kaestner, K.H., Ang, S.L., Ikegami, M., Finkelman, F.D., Stahlman, M.T., Fulkerson, P.C., Rothenberg, M.E., Whitsett, J.A. Development (2004) [Pubmed]
  3. A transcriptional profiling study of CCAAT/enhancer binding protein targets identifies hepatocyte nuclear factor 3 beta as a novel tumor suppressor in lung cancer. Halmos, B., Bassères, D.S., Monti, S., D'Aló, F., Dayaram, T., Ferenczi, K., Wouters, B.J., Huettner, C.S., Golub, T.R., Tenen, D.G. Cancer Res. (2004) [Pubmed]
  4. Identification of missense mutations in the hepatocyte nuclear factor-3beta gene in Japanese subjects with late-onset Type II diabetes mellitus. Zhu, Q., Yamagata, K., Yu, L., Tomura, H., Yamada, S., Yang, Q., Yoshiuchi, I., Sumi, S., Miyagawa, J., Takeda, J., Hanafusa, T., Matsuzawa, Y. Diabetologia (2000) [Pubmed]
  5. Expression and role of Foxa proteins in prostate cancer. Mirosevich, J., Gao, N., Gupta, A., Shappell, S.B., Jove, R., Matusik, R.J. Prostate (2006) [Pubmed]
  6. Wnt and TGF-beta signaling are required for the induction of an in vitro model of primitive streak formation using embryonic stem cells. Gadue, P., Huber, T.L., Paddison, P.J., Keller, G.M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  7. Insulin regulates the activity of forkhead transcription factor Hnf-3beta/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic localization. Wolfrum, C., Besser, D., Luca, E., Stoffel, M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  8. Hepatocyte nuclear factor 3 beta contains two transcriptional activation domains, one of which is novel and conserved with the Drosophila fork head protein. Pani, L., Overdier, D.G., Porcella, A., Qian, X., Lai, E., Costa, R.H. Mol. Cell. Biol. (1992) [Pubmed]
  9. Human bone marrow mesenchymal stem cells can express insulin and key transcription factors of the endocrine pancreas developmental pathway upon genetic and/or microenvironmental manipulation in vitro. Moriscot, C., de Fraipont, F., Richard, M.J., Marchand, M., Savatier, P., Bosco, D., Favrot, M., Benhamou, P.Y. Stem Cells (2005) [Pubmed]
  10. The human organic anion transporting polypeptide 8 (SLCO1B3) gene is transcriptionally repressed by hepatocyte nuclear factor 3beta in hepatocellular carcinoma. Vavricka, S.R., Jung, D., Fried, M., Grützner, U., Meier, P.J., Kullak-Ublick, G.A. J. Hepatol. (2004) [Pubmed]
  11. 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. Ben-Shushan, E., Marshak, S., Shoshkes, M., Cerasi, E., Melloul, D. J. Biol. Chem. (2001) [Pubmed]
  12. Identification of 20 genes aberrantly methylated in human breast cancers. Miyamoto, K., Fukutomi, T., Akashi-Tanaka, S., Hasegawa, T., Asahara, T., Sugimura, T., Ushijima, T. Int. J. Cancer (2005) [Pubmed]
  13. Differential expression of chitinases identify subsets of murine airway epithelial cells in allergic inflammation. Homer, R.J., Zhu, Z., Cohn, L., Lee, C.G., White, W.I., Chen, S., Elias, J.A. Am. J. Physiol. Lung Cell Mol. Physiol. (2006) [Pubmed]
  14. Exendin-4 differentiation of a human pancreatic duct cell line into endocrine cells: involvement of PDX-1 and HNF3beta transcription factors. Zhou, J., Pineyro, M.A., Wang, X., Doyle, M.E., Egan, J.M. J. Cell. Physiol. (2002) [Pubmed]
  15. Endoderm and pancreatic islet lineage differentiation from human embryonic stem cells. Xu, X., Kahan, B., Forgianni, A., Jing, P., Jacobson, L., Browning, V., Treff, N., Odorico, J. Cloning Stem Cells (2006) [Pubmed]
  16. Roles of organizer factors and BMP antagonism in mammalian forebrain establishment. Yang, Y.P., Klingensmith, J. Dev. Biol. (2006) [Pubmed]
  17. The Foxa family of transcription factors in development and metabolism. Friedman, J.R., Kaestner, K.H. Cell. Mol. Life Sci. (2006) [Pubmed]
  18. Foxa2 (HNF3beta ) controls multiple genes implicated in metabolism-secretion coupling of glucose-induced insulin release. Wang, H., Gauthier, B.R., Hagenfeldt-Johansson, K.A., Iezzi, M., Wollheim, C.B. J. Biol. Chem. (2002) [Pubmed]
  19. Melatonin stimulates glucose transport via insulin receptor substrate-1/phosphatidylinositol 3-kinase pathway in C2C12 murine skeletal muscle cells. Ha, E., Yim, S.V., Chung, J.H., Yoon, K.S., Kang, I., Cho, Y.H., Baik, H.H. J. Pineal Res. (2006) [Pubmed]
  20. The chum salmon IGF-II gene promoter is activated by hepatocyte nuclear factor 3beta. Palamarchuk, A.Y., Kavsan, V.M., Sussenbach, J.S., Holthuizen, P.E. FEBS Lett. (1999) [Pubmed]
  21. Beta-cell transcription factors and diabetes: no evidence for diabetes-associated mutations in the hepatocyte nuclear factor-3beta gene (HNF3B) in Japanese patients with maturity-onset diabetes of the young. Hinokio, Y., Horikawa, Y., Furuta, H., Cox, N.J., Iwasaki, N., Honda, M., Ogata, M., Iwamoto, Y., Bell, G.I. Diabetes (2000) [Pubmed]
  22. Effects of nitrofen and vitamins A, C and E on maturation of cultured human H441 pneumocytes. Gonzalez-Reyes, S., Martinez, L., Martinez-Calonge, W., Fernandez-Dumont, V., Tovar, J.A. Biol. Neonate (2006) [Pubmed]
  23. Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease. Zheng, W., Rosenstiel, P., Huse, K., Sina, C., Valentonyte, R., Mah, N., Zeitlmann, L., Grosse, J., Ruf, N., Nürnberg, P., Costello, C.M., Onnie, C., Mathew, C., Platzer, M., Schreiber, S., Hampe, J. Genes Immun. (2006) [Pubmed]
  24. Islet Neogenesis Associated Protein (INGAP) modulates gene expression in cultured neonatal rat islets. Barbosa, H., Bordin, S., Stoppiglia, L., Silva, K., Borelli, M., Del Zotto, H., Gagliardino, J., Boschero, A. Regul. Pept. (2006) [Pubmed]
  25. Identification of transcriptional targets during pancreatic growth after partial pancreatectomy and exendin-4 treatment. De León, D.D., Farzad, C., Crutchlow, M.F., Brestelli, J., Tobias, J., Kaestner, K.H., Stoffers, D.A. Physiol. Genomics (2006) [Pubmed]
  26. Does chasing selected 'Fox' to the nucleus prevent diabetes? Wang, H., Wollheim, C.B. Trends in molecular medicine. (2005) [Pubmed]
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