Forkhead box protein A2

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Foxa2
Properties of human protein
Mass / length primary structure 463 and 457 amino acids, respectively
Identifier
Gene name FOXA2
External IDs
Occurrence
Parent taxon Chordates

The forkhead box protein A2 (Foxa2) (also: hepatocyte nuclear factor 3-beta , HNF3b ) is a transcription factor in chordates . The transcription factor Foxa2 binds to DNA as a monomer . Foxa2 plays a role in gastrulation , fetal development of the gastrointestinal tract , pancreas development and the regulation of insulin release . Foxa2 regulates the gene expression of many enzymes in the liver . Foxa2 expression has also been reported in the thyroid and prostate . Foxa2 defects are probably lethal even in utero : the OMIM database does not contain any monogenic disease due to a congenital Foxa2 defect.

Foxa2 is one of the forkhead box proteins . The expression of Foxa2 in the embryo is regulated by TEAD proteins , as was shown in zebrafish . In the adult organism, insulin inhibits the Foxa2 function through direct phosphorylation . On the other hand, the phosphorylation of Foxa2 on the amino acid serine-283 by the protein kinase DNA-PK is essential for its function. Foxa2 also interacts directly with the androgen receptor .

Structure and genetics

The human FOXA2 gene is located on chromosome 20 , gene locus p11. There are two types of transcription. The longer variant (var 2) contains an untranslated exon 1 and the translated exons 2 and 3, while the shorter variant (var 1) results from two exons, both of which are partially translated.

A protein with a length of 463 amino acids is translated from var 1 RNA, the protein from var 2 has 457 amino acids.

Foxa2 and alternative splicing

Calcitonin (Calc) and calcitonin-gene-related peptides (CGRP) are alternative splice products of the same gene and are considered examples of alternative splicing. The gene has six exons. In neurons, the CGRP mRNA is generated from exons 1, 2, 3, 5 and 6. In thyroid C cells, on the other hand, the Calc mRNA is generated from exons 1, 2, 3 and 4. Zhou and Baranika have recently demonstrated that by binding to a piece of UGCAUG RNA near the 3 'splicing site, Foxa2 (and Fox-1) shift processing towards CGRP.

Ancestral history of Foxa2 and other forkhead box proteins

Phylogenetic tree with the probable origins of some forkhead box proteins. FOXA2 are marked in green

The closest protein related to Foxa2 is vertebrate Foxa1. The time of gene duplication occurs before or when the vertebrates emerge . More precise statements are also dependent on the functional description of the proteins in phylogenetically older living beings. In any case, there does not seem to be a directly orthologous gene from FOXA2 in the model chorus data Branchiostoma and Ciona . The proteins described as Foxa2 in the worm Hydroides elegans and in the lancetfish ( Branchiostoma floridae ) are more extensive relatives than Foxa4 (see figure).

Function of the transcription factor Foxa2

Gastrulation

Mangold and Spemann described the Spemann organizer for amphibians as early as 1924 . This structure, which is indispensable for the formation of patterns in the fetal development of chordates , is shaped by the Foxa2 protein. The expression of Foxa2 in the organizer depends on FoxH1 / Smad. There is a mutual dependency between Foxa2 and Brachyury / T expression. Other transcription factors depend on Foxa2, such as Noto, Shh, Foxa1, Foxd4, MLF1, Pim1, Smoc1, as Templin and colleagues published in 2008.

Development of dopaminergic neurons

The loss of dopaminergic neurons in the midbrain is believed to be the cause of Parkinson's disease. Foxa2 is both involved in the development of these neurons and likely in their early degeneration. Starting from the organizer, the first attachment of the central nervous system, the neural tube , is created through control of Foxa2 . Foxa2 expression determines the so-called floor plate of the neural tube. From here, Foxa2-positive cells develop dopaminergic neurons.

Loss of both Foxa2 alleles leads to lethality in utero . Mice that carry only one Foxa2 allele develop musculoskeletal deficits as adults. In animals showing these deficits, a loss of dopaminergic neurons in the substantia nigra was found ; this picture corresponds to Parkinson's disease in humans.

Development of the liver

The development of the liver within the fetal development takes place in two stages: First, cells within the foregut endothelium are enabled to react to organ-specific signals, then liver-specific genes are expressed. In the first step, both Foxa1 and Foxa2 are involved together. Without the expression of both genes, no liver can develop, since obviously no reaction to other necessary stimulators such as e. B. fibroblast growth factor can occur. Mouse fetuses that have defective Foxa1 and Foxa2 genes develop in the same way as control fetuses up to day 8.5. After that, development lags and the fetuses die before birth.

The most important change compared to normal animals concerns the absence of the liver primordia, the absence of hepatoblasts. In contrast, animals in which either the Foxa1 gene or the Foxa2 gene were defective were able to develop the liver primordia. Other genes, in which defects also disrupt liver development, only work after the liver is created: Hex, HNF4alpha, HNF1beta or HNF6.

The later development of the bile ducts also depends on the joint expression of Foxa1 and Foxa2: If both genes are switched off after the development of the liver anlage, an enlarged bile duct structure develops in the fetal liver: Because of Foxa1 / a2 suppression, interleukin-6 is increased (IL-6), which promotes the growth of cholangiocytes. In the absence of Foxa1 / a2, the glucocorticoid receptor (a nuclear receptor and transcription factor) cannot bind to the IL-6 gene promoter and suppress IL-6 expression.

Development of the pancreas and regulation of insulin release

The pancreas developed starting from fetal endoderm under the control of P ankreatischen and d uodenalem Homeobo x protein Pdx1. The Pdx1 protein, in turn, is under the joint control of the Foxa1 and Foxa2 proteins. With the help of genetically modified mice, in which Foxa1 and Foxa2 formation was only suppressed in pancreatic cells, it was shown that pancreas formation could be almost completely suppressed in affected animals. The newborns died within two days of birth.

The later development of insulin-producing islet cells also depends on the expression of MafA - transcription factor from. This in turn is activated by Foxa2, Nkx2.2 and Pdx1.

In mature pancreatic - islet cells both express glucagon -forming alpha cells, the insulin -forming beta cells and somatostatin -forming delta cells Foxa2. Targeted inactivation of Foxa2 exclusively in beta cells reduced the formation of numerous proteins, including ATP-dependent potassium channels , HADHSC, dopa decarboxylase and others; Pdx1 expression remains Foxa2-dependent. Above all, increased insulin secretion can be measured, which is based on an incorrectly increased rate of basal fusion of secretory insulin-containing granules with the plasma membrane and thus the release of insulin.

Foxa2, in turn, can be inhibited in the liver by insulin. Two independent mechanisms are effective: On the one hand, Foxa2 is released from the cell nucleus under the influence of insulin and can therefore no longer act as a transcription factor. On the other hand, the Foxa2 activity is inhibited by phosphorylation on threonine-156.

Regulation of food intake

Orexin and melanin-concentrating hormone (MCH) are two neuropeptides found in food . The nuclei of the nerve cells that form orexin or MCH are found in the lateral hypothalamus and in the zone incerta. The formation of the RNA for both hormones is activated by Foxa2. Under the influence of insulin , Foxa2 is exported from the nucleus in these nerve cells, as in liver cells, so that the orexin and MCH formation is suppressed. The Foxa2 expression is retained, only the presence of Foxa2 in the cell nucleus is prevented.

Regulation of liver enzyme expression in adults

The concerted action between Foxa2 and the transcription coactivator PGC-1β is responsible for ramping up the beta-oxidation of fatty acids and the triglyceride-associated secretion of VLDL from the liver.

The expression of the organo-anion transporter LST-2 in hepatocytes is regulated by Foxa2, among others.

The balanced synthesis and transport of bile acids from the liver depends on Foxa2. If the protein in the liver of mice was missing, the serum levels of the bile acids increased - a mild cholestasis developed, which increased with the intake of choline . Kidneys of people who suffered from PSC or biliary atresia , examined for their Foxa2 content , showed corresponding deficiencies. The cause was an insufficient expression of the bile salt membrane transporter Mpr2 / 3/4, which is apparently regulated by Foxa2. The lack of regulation of other genes in the bile acid metabolism is a factor in what is known as ER stress , a symptom of cholestasis.

Regulation of aquaporin-3 expression

The production of aquaporin -3, a glycerin - transport protein in the intestine and the kidney , is activated inter alia by Foxa2 and consequently suppressed insulin secretion. In connection with the beta-oxidation activated by Foxa2 and the permeability for glycerine, it can be concluded that aquaporin-3 is involved in sugar and lipid metabolism.

FOXA2 and human diseases

Metabolism types and diabetes 2

In an Indian study with 1,656 participants, associations between FoxA2 polymorphisms and several properties such as fasting blood sugar level , C-peptide and type II diabetes risk were found: Carriers of the (TCC) n -A5 polymorphism had an increased risk of diabetes, increased fasting sugar, as well decreased insulin and C-peptide levels during fasting. Carriers of GG at the rs1055080 gene locus, on the other hand, had a reduced risk of diabetes with normal weight.

In diabetic rats, an increased release of Foxa2 due to the administration of insulin is associated with an increase in GLUT-2 expression.

Overexpression in cancer and metastases

The enzymes regulated by Foxa2 may be responsible for the progression of prostate cancer to the stage of androgen independence. Metastases of colorectal carcinomas in the liver overexpress Foxa2, which is associated with overexpression of HNF6. In contrast, the production of Foxa2 in thyroid cancer cells was suppressed compared to the normal state.

Suspected role in sepsis

In 2006, Berg and colleagues used animal models to show that the serine protease protein C content is an early prognostic parameter that can be used to predict the outcome of a septic event: the lower the protein C content, the more likely a fatal outcome. In the same publication, the authors state that reduced Foxa2 expression can be regarded as the trigger for protein C reduction. The down-regulation of Foxa2 in the course of an infection, which can turn into sepsis with fatal consequences, thus plays an important role.

Mucus secretion in asthma

In mice with respiratory tract - allergies suffered, the expression of Foxa2 was associated with the production of mucus. An increase in FoxA2 expression in transgenic mice led to a decrease in the secretion of mucus . In a study of ten people, five of whom suffered from asthma , a reduction in FoxA2 expression was found in all asthma sufferers.

Individual evidence

  1. ↑ Orthologist at eggNOG
  2. ^ Forkhead box protein A2.  In: Online Mendelian Inheritance in Man . (English)
  3. ^ Besnard V, Wert SE, Hull WM, Whitsett JA: Immunohistochemical localization of Foxa1 and Foxa2 in mouse embryos and adult tissues . In: Gene Expr. Patterns . 5, No. 2, December 2004, pp. 193-208. doi : 10.1016 / j.modgep.2004.08.006 . PMID 15567715 .
  4. ↑ Sawada A, Nishizaki Y, Sato H, et al. : Tead proteins activate the Foxa2 enhancer in the node in cooperation with a second factor . In: Development . 132, No. 21, November 2005, pp. 4719-29. doi : 10.1242 / dev.02059 . PMID 16207754 .
  5. ^ Howell JJ, Stoffel M: Nuclear export-independent inhibition of Foxa2 by insulin . In: J. Biol. Chem. . 284, No. 37, September 2009, pp. 24816-24. doi : 10.1074 / jbc.M109.042135 . PMID 19589781 .
  6. ↑ Nock A, Ascano JM, Jones T, et al. : Identification of DNA-dependent protein kinase as a cofactor for the forkhead transcription factor FoxA2 . In: J. Biol. Chem. . 284, No. 30, July 2009, pp. 19915-26. doi : 10.1074 / jbc.M109.016295 . PMID 19478084 .
  7. ↑ Yu X, Gupta A, Wang Y, et al. : Foxa1 and Foxa2 interact with the androgen receptor to regulate prostate and epididymal genes differentially . In: Ann. NY Acad. Sci. . 1061, December 2005, pp. 77-93. doi : 10.1196 / annals.1336.009 . PMID 16467259 .
  8. ↑ 'FOXA2' transcription variants
  9. ↑ Zhou HL, Baraniak AP, Lou H: Role for Fox-1 / Fox-2 in mediating the neuronal pathway of calcitonin / calcitonin gene-related peptide alternative RNA processing . In: Mol. Cell. Biol . 27, No. 3, February 2007, pp. 830-41. doi : 10.1128 / MCB.01015-06 . PMID 17101796 . PMC 1800674 (free full text).
  10. ↑ Tamplin OJ, Kinzel D, Cox BJ, Bell CE, Rossant J , Lickert H: Microarray analysis of Foxa2 mutant mouse embryos reveals novel gene expression and inductive roles for the gastrula organizer and its derivatives . In: BMC Genomics . 9, 2008, p. 511. doi : 10.1186 / 1471-2164-9-511 . PMID 18973680 . PMC 2605479 (free full text).
  11. ↑ Kimura-Yoshida C, Tian E, Nakano H, et al. : Crucial roles of Foxa2 in mouse anterior-posterior axis polarization via regulation of anterior visceral endoderm-specific genes . In: Proc. Natl. Acad. Sci. USA . 104, No. 14, April 2007, pp. 5919-24. doi : 10.1073 / pnas.0607779104 . PMID 17389379 . PMC 1851592 (free full text).
  12. ↑ Burtscher I, Lickert H: Foxa2 Regulates polarity and epithelialization in the endoderm germ layer of the mouse embryo . In: Development . 136, No. 6, March 2009, pp. 1029-38. doi : 10.1242 / dev.028415 . PMID 19234065 .
  13. ↑ a b Kittappa R, Chang WW, Awatramani RB, McKay RD: The foxa2 gene controls the birth and spontaneous degeneration of dopamine neurons in old age . In: PLoS Biol . . 5, No. 12, December 2007, p. E325. doi : 10.1371 / journal.pbio.0050325 . PMID 18076286 . PMC 2121110 (free full text).
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  15. ↑ Lin W, Metzakopian E, Mavromatakis YE, et al. : Foxa1 and Foxa2 function both upstream of and cooperatively with Lmx1a and Lmx1b in a feedforward loop promoting mesodiencephalic dopaminergic neuron development . In: Dev. Biol. . 333, No. 2, September 2009, pp. 386-96. doi : 10.1016 / j.ydbio.2009.07.006 . PMID 19607821 .
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  17. ↑ Li Z, White P, Tuteja G, Rubins N, Sackett S, Kaestner KH: Foxa1 and Foxa2 regulate bile duct development in mice . In: J. Clin. Invest. . 119, No. 6, June 2009, pp. 1537-45. doi : 10.1172 / JCI38201 . PMID 19436110 . PMC 2689124 (free full text).
  18. Jump up ↑ Levon N, Yanuka O, Benvenisty N: The effect of overexpression of PDX1 and FOXA2 on the differentiation of human embryonic stem cells into pancreatic cells . In: Stem Cells . August 24, pp. 1923-1930. doi : 10.1634 / stemcells.2005-0397 .
  19. ↑ Gao N, LeLay J, Vatamaniuk MZ, et al. : Dynamic regulation of Pdx1 enhancers by Foxa1 and foxa2 is essential for pancreas development . (PDF) In: Genes Developm. . 22, No. 24, 2008, pp. 3435-3448. doi : 10.1101 / gad.1752608 . PMID 19141476 .
  20. ^ Room JC, Gerrish K, Artner I, et al. : FoxA2, ​​Nkx2.2, and PDX-1 regulate islet beta-cell-specific mafA expression through conserved sequences located between base pairs -8118 and -7750 upstream from the transcription start site . In: Mol. Cell. Biol . 26, No. 15, August 2006, pp. 5735-43. doi : 10.1128 / MCB.00249-06 . PMID 16847327 . PMC 1592775 (free full text).
  21. ↑ Gao N, White P, Doliba N, Golson ML, Matschinsky FM, Kaestner KH: Foxa2 controls vesicle docking and insulin secretion in mature beta cells . In: Cell Metab. . 6, No. 4, October 2007, pp. 267-79. doi : 10.1016 / j.cmet.2007.08.015 . PMID 17908556 .
  22. ^ Howell JJ, Stoffel M: Nuclear export-independent inhibition of Foxa2 by insulin . In: J. Biol. Chem. . 284, No. 37, September 2009, pp. 24816-24. doi : 10.1074 / jbc.M109.042135 . PMID 19589781 .
  23. ↑ Silva JP, von Meyenn F, Howell J, Thorens B, Wolfrum C, Stoffel M: Regulation of adaptive behavior during fasting by hypothalamic Foxa2 . In: Nature . 462, No. 7273, December 2009, pp. 646-50. doi : 10.1038 / nature08589 . PMID 19956259 .
  24. ↑ Wolfrum C, Stoffel M: Coactivation of Foxa2 through Pgc-1beta promotes liver fatty acid oxidation and triglyceride / VLDL secretion . In: Cell Metab. . 3, No. 2, February 2006, pp. 99-110. doi : 10.1016 / j.cmet.2006.01.001 . PMID 16459311 .
  25. ↑ Ohtsuka H, ​​Abe T, Onogawa T, et al. : Farnesoid X receptor, hepatocyte nuclear factors 1alpha and 3beta are essential for transcriptional activation of the liver-specific organic anion transporter-2 gene . In: J. Gastroenterol. . 41, No. 4, April 2006, pp. 369-77. doi : 10.1007 / s00535-006-1784-3 . PMID 16741617 .
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  27. ↑ Bochkis IM, Schug J, Rubin NE, AR Chopra, O'Malley BW, Kaestner KH: Foxa2-dependent hepatic gene regulatory networks depend on physiological state . In: Physiol. Genomics . 38, No. 2, July 2009, pp. 186-95. doi : 10.1152 / physiolgenomics.90376.2008 . PMID 19417011 .
  28. ↑ Higuchi S, Kubota M, Iguchi K, Usui S, Kiho T, Hirano K: Transcriptional regulation of aquaporin 3 by insulin . In: J. Cell. Biochem. . 102, No. 4, November 2007, pp. 1051-8. doi : 10.1002 / jcb.21350 . PMID 17471492 .
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  30. ↑ Freitas HS, Schaan BD, David-Silva A, et al. : SLC2A2 gene expression in kidney of diabetic rats is regulated by HNF-1alpha and HNF-3beta . In: Mol. Cell. Endocrinol. . 305, No. 1-2, June 2009, pp. 63-70. doi : 10.1016 / j.mce.2009.02.014 . PMID 19433262 .
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  32. ↑ Lehner F, Kulik U, Klempnauer J, Borlak J: The hepatocyte nuclear factor 6 (HNF6) and FOXA2 are key regulators in colorectal liver metastases . In: FASEB J . . 21, No. 7, May 2007, pp. 1445-62. doi : 10.1096 / fj.06-6575com . PMID 17283222 .
  33. ↑ Akagi T, Luong QT, Gui D, et al. : Induction of sodium iodide symporter gene and molecular characterization of HNF3 beta / FoxA2, ​​TTF-1 and C / EBP beta in thyroid carcinoma cells . In: Br. J. Cancer . 99, No. 5, September 2008, pp. 781-8. doi : 10.1038 / sj.bjc.6604544 . PMID 18682709 . PMC 2528161 (free full text).
  34. ^ Berg DT, Gerlitz. B. Sharma GR, et al. : FoxA2 involvement in suppression of protein C, an outcome predictor in experimental sepsis . In: Clin. Vaccine Immunol. . 13, No. 3, March 2006, pp. 426-32. doi : 10.1128 / CVI.13.3.426-432.2006 . PMID 16522789 . PMC 1391958 (free full text).
  35. ^ Park SW, Verhaeghe C, Nguyenvu LT, et al. : Distinct roles of FOXA2 and FOXA3 in allergic airway disease and asthma . In: Am. J. Respir. Crit. Care Med . 180, No. 7, October 2009, pp. 603-10. doi : 10.1164 / rccm.200811-1768OC . PMID 19628779 .