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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Update of human and mouse forkhead box (<italic>FOX</italic>) gene families</title><author><name sortKey="Jackson, Brian C" sort="Jackson, Brian C" uniqKey="Jackson B" first="Brian C" last="Jackson">Brian C. Jackson</name><affiliation><nlm:aff id="I1">Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO 80045, USA</nlm:aff></affiliation></author><author><name sortKey="Carpenter, Christopher" sort="Carpenter, Christopher" uniqKey="Carpenter C" first="Christopher" last="Carpenter">Christopher Carpenter</name><affiliation><nlm:aff id="I1">Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO 80045, USA</nlm:aff></affiliation></author><author><name sortKey="Nebert, Daniel W" sort="Nebert, Daniel W" uniqKey="Nebert D" first="Daniel W" last="Nebert">Daniel W. Nebert</name><affiliation><nlm:aff id="I2">Department of Environmental Health and Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA</nlm:aff></affiliation></author><author><name sortKey="Vasiliou, Vasilis" sort="Vasiliou, Vasilis" uniqKey="Vasiliou V" first="Vasilis" last="Vasiliou">Vasilis Vasiliou</name><affiliation><nlm:aff id="I1">Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO 80045, USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20650821</idno><idno type="pmc">3500164</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3500164</idno><idno type="RBID">PMC:3500164</idno><idno type="doi">10.1186/1479-7364-4-5-345</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">002A99</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002A99</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Update of human and mouse forkhead box (<italic>FOX</italic>) gene families</title><author><name sortKey="Jackson, Brian C" sort="Jackson, Brian C" uniqKey="Jackson B" first="Brian C" last="Jackson">Brian C. Jackson</name><affiliation><nlm:aff id="I1">Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO 80045, USA</nlm:aff></affiliation></author><author><name sortKey="Carpenter, Christopher" sort="Carpenter, Christopher" uniqKey="Carpenter C" first="Christopher" last="Carpenter">Christopher Carpenter</name><affiliation><nlm:aff id="I1">Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO 80045, USA</nlm:aff></affiliation></author><author><name sortKey="Nebert, Daniel W" sort="Nebert, Daniel W" uniqKey="Nebert D" first="Daniel W" last="Nebert">Daniel W. Nebert</name><affiliation><nlm:aff id="I2">Department of Environmental Health and Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA</nlm:aff></affiliation></author><author><name sortKey="Vasiliou, Vasilis" sort="Vasiliou, Vasilis" uniqKey="Vasiliou V" first="Vasilis" last="Vasiliou">Vasilis Vasiliou</name><affiliation><nlm:aff id="I1">Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO 80045, USA</nlm:aff></affiliation></author></analytic><series><title level="j">Human Genomics</title><idno type="ISSN">1473-9542</idno><idno type="eISSN">1479-7364</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The forkhead box (FOX) proteins are transcription factors that play complex and important roles in processes from development and organogenesis to regulation of metabolism and the immune system. There are 50 <italic>FOX </italic>genes in the human genome and 44 in the mouse, divided into 19 subfamilies. All human <italic>FOX </italic>genes have close mouse orthologues, with one exception: the mouse has a single <italic>Foxd4</italic>, whereas the human gene has undergone a recent duplication to a total of seven (<italic>FOXD4 </italic>and <italic>FOXD4L1 </italic>→ <italic>FOXD4L6</italic>). Evolutionarily ancient family members can be found as far back as the fungi and metazoans. The DNA-binding domain, the forkhead domain, is an example of the winged-helix domain, and is very well conserved across the FOX family and across species, with a few notable exceptions in which divergence has created new functionality. Mutations in <italic>FOX </italic>genes have been implicated in at least four familial human diseases, and differential expression may play a role in a number of other pathologies -- ranging from metabolic disorders to autoimmunity. Furthermore, <italic>FOX </italic>genes are differentially expressed in a large number of cancers; their role can be either as an oncogene or tumour suppressor, depending on the family member and cell type. Although some drugs that target <italic>FOX </italic>gene expression or activity, notably proteasome inhibitors, appear to work well, much more basic research is needed to unlock the complex interplay of upstream and downstream interactions with FOX family transcription factors.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Weigel, D" uniqKey="Weigel D">D Weigel</name></author><author><name sortKey="Jurgens, G" uniqKey="Jurgens G">G Jurgens</name></author><author><name sortKey="Kuttner, F" uniqKey="Kuttner F">F Kuttner</name></author><author><name sortKey="Seifert, E" uniqKey="Seifert E">E Seifert</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lai, E" uniqKey="Lai E">E Lai</name></author><author><name sortKey="Prezioso, Vr" uniqKey="Prezioso V">VR Prezioso</name></author><author><name sortKey="Smith, E" uniqKey="Smith E">E Smith</name></author><author><name sortKey="Litvin, O" uniqKey="Litvin 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Wan</name></author><author><name sortKey="Birnbaum, Mj" uniqKey="Birnbaum M">MJ Birnbaum</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Salih, Da" uniqKey="Salih D">DA Salih</name></author><author><name sortKey="Brunet, A" uniqKey="Brunet A">A Brunet</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gross, Dn" uniqKey="Gross D">DN Gross</name></author><author><name sortKey="Van Den Heuvel, Ap" uniqKey="Van Den Heuvel A">AP van den Heuvel</name></author><author><name sortKey="Birnbaum, Mj" uniqKey="Birnbaum M">MJ Birnbaum</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nakae, J" uniqKey="Nakae J">J Nakae</name></author><author><name sortKey="Kitamura, T" uniqKey="Kitamura T">T Kitamura</name></author><author><name sortKey="Kitamura, Y" uniqKey="Kitamura Y">Y Kitamura</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Calnan, Dr" uniqKey="Calnan 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Hum Genomics</journal-id><journal-id journal-id-type="iso-abbrev">Hum. Genomics</journal-id><journal-title-group><journal-title>Human Genomics</journal-title></journal-title-group><issn pub-type="ppub">1473-9542</issn><issn pub-type="epub">1479-7364</issn><publisher><publisher-name>BioMed Central</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">20650821</article-id><article-id pub-id-type="pmc">3500164</article-id><article-id pub-id-type="publisher-id">1479-7364-4-5-345</article-id><article-id pub-id-type="doi">10.1186/1479-7364-4-5-345</article-id><article-categories><subj-group subj-group-type="heading"><subject>Genome Update</subject></subj-group></article-categories><title-group><article-title>Update of human and mouse forkhead box (<italic>FOX</italic>) gene families</article-title></title-group><contrib-group><contrib contrib-type="author" id="A1"><name><surname>Jackson</surname><given-names>Brian C</given-names></name><xref ref-type="aff" rid="I1">1</xref></contrib><contrib contrib-type="author" id="A2"><name><surname>Carpenter</surname><given-names>Christopher</given-names></name><xref ref-type="aff" rid="I1">1</xref></contrib><contrib contrib-type="author" corresp="yes" id="A3"><name><surname>Nebert</surname><given-names>Daniel W</given-names></name><xref ref-type="aff" rid="I2">2</xref><email>dan.nebert@uc.edu</email></contrib><contrib contrib-type="author" corresp="yes" id="A4"><name><surname>Vasiliou</surname><given-names>Vasilis</given-names></name><xref ref-type="aff" rid="I1">1</xref><email>vasilis.vasiliou@ucdenver.edu</email></contrib></contrib-group><aff id="I1"><label>1</label>Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO 80045, USA</aff><aff id="I2"><label>2</label>Department of Environmental Health and Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA</aff><pub-date pub-type="collection"><year>2010</year></pub-date><pub-date pub-type="epub"><day>1</day><month>6</month><year>2010</year></pub-date><volume>4</volume><issue>5</issue><fpage>345</fpage><lpage>352</lpage><history><date date-type="received"><day>29</day><month>4</month><year>2010</year></date><date date-type="accepted"><day>29</day><month>4</month><year>2010</year></date></history><permissions><copyright-statement>Copyright ©2010 Henry Stewart Publications</copyright-statement><copyright-year>2010</copyright-year><copyright-holder>Henry Stewart Publications</copyright-holder></permissions><self-uri xlink:href="http://www.humgenomics.com/content/4/5/345"></self-uri><abstract><p>The forkhead box (FOX) proteins are transcription factors that play complex and important roles in processes from development and organogenesis to regulation of metabolism and the immune system. There are 50 <italic>FOX </italic>genes in the human genome and 44 in the mouse, divided into 19 subfamilies. All human <italic>FOX </italic>genes have close mouse orthologues, with one exception: the mouse has a single <italic>Foxd4</italic>, whereas the human gene has undergone a recent duplication to a total of seven (<italic>FOXD4 </italic>and <italic>FOXD4L1 </italic>→ <italic>FOXD4L6</italic>). Evolutionarily ancient family members can be found as far back as the fungi and metazoans. The DNA-binding domain, the forkhead domain, is an example of the winged-helix domain, and is very well conserved across the FOX family and across species, with a few notable exceptions in which divergence has created new functionality. Mutations in <italic>FOX </italic>genes have been implicated in at least four familial human diseases, and differential expression may play a role in a number of other pathologies -- ranging from metabolic disorders to autoimmunity. Furthermore, <italic>FOX </italic>genes are differentially expressed in a large number of cancers; their role can be either as an oncogene or tumour suppressor, depending on the family member and cell type. Although some drugs that target <italic>FOX </italic>gene expression or activity, notably proteasome inhibitors, appear to work well, much more basic research is needed to unlock the complex interplay of upstream and downstream interactions with FOX family transcription factors.</p></abstract><kwd-group><kwd>FOX</kwd><kwd>forkhead domain</kwd><kwd>winged-helix domain</kwd><kwd>transcription factors</kwd><kwd>gene family</kwd><kwd>evolution</kwd><kwd>cancer</kwd><kwd>metabolism</kwd><kwd>immunity</kwd></kwd-group></article-meta></front><body><sec><title>Introduction</title><p>Gene expression is controlled at multiple levels, including modulation of transcriptional activity, mRNA processing, and post-translational modification of proteins. The forkhead box (<italic>FOX</italic>) gene family encodes proteins that regulate the transcription of genes participating in a number of functions -- including development of various organs, regulation of senescence or proliferation, and metabolic homeostasis. The first <italic>FOX </italic>gene to be discovered was <italic>forkhead </italic>(<italic>fkh</italic>) in <italic>Drosophila</italic>, which, when mutated, gives the insect a fork-headed appearance [<xref ref-type="bibr" rid="B1">1</xref>]. Independently, another group characterised <italic>FOXA1 </italic>in the rat [<xref ref-type="bibr" rid="B2">2</xref>]. In 1990, Weigel <italic>et al</italic>. discovered that these two proteins shared a similar DNA-binding domain, and named this domain the forkhead domain (also referred to as the winged-helix domain); this domain is well conserved among all FOX family members [<xref ref-type="bibr" rid="B3">3</xref>]. At about 100 amino acids in length, the prototypical forkhead domain is monomeric and consists of three alpha-helices, three beta-sheets and two large loops ('wing' regions) that flank the third beta-sheet [<xref ref-type="bibr" rid="B4">4</xref>]. In 1993, the crystal structure of the forkhead domain bound to DNA was solved for FOXA1 [<xref ref-type="bibr" rid="B5">5</xref>]. Since then, several other structures have been solved, including the DNA-binding domains of FOXK1, FOXK2, FOXM1, FOXO1, FOXO3, FOXO4, FOXP1 and FOXP2 (Protein Data Bank search[<xref ref-type="bibr" rid="B6">6</xref>]).</p><p>Before 2000, <italic>FOX </italic>genes lacked a unified naming convention and were assigned a confusing array of names by the researchers who discovered them. The winged helix/forkhead nomenclature committee defined the FOX family as all genes/proteins having sequence homology to the canonical winged helix/forkhead DNA-binding domain; subclasses FOXA to FOXO were defined based on a phylogenetic analysis of the forkhead domain (other domains were highly divergent, and alignment was unclear between subclasses) [<xref ref-type="bibr" rid="B7">7</xref>]. Since then, the family has been expanded to include subclasses FOXP to FOXS.</p></sec><sec><title>The <italic>FOX </italic>gene family</title><p>The <italic>FOX </italic>family consists of 50 members in the human genome (plus two known pseudogenes, <italic>FOXO1B </italic>and <italic>FOXO3B</italic>) and 44 members in the mouse genome (Table <xref ref-type="table" rid="T1">1</xref>). Ancient and diverse, the FOX family plays a role in a wide array of developmental, general and tissue-specific functions, and thousands of papers and hundreds of reviews have been published on the topic (PubMed search, April 2010). In 2007, Tuteja and Kaestner published a snapshot of human <italic>FOX </italic>genes, including a table of potential regulatory partners, cellular and developmental roles, known mouse mutant phenotypes and roles in human disease [<xref ref-type="bibr" rid="B8">8</xref>,<xref ref-type="bibr" rid="B9">9</xref>].</p><table-wrap id="T1" position="float"><label>Table 1</label><caption><p>List of the <italic>FOX </italic>genes in humans and mice, chromosomal locations and percentage sequence similarity between the human and mouse orthologous proteins.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left">Human</th><th></th><th align="center" colspan="2">Mouse</th><th></th></tr><tr><th colspan="4"><hr></hr></th><th></th></tr><tr><th align="left">Protein</th><th align="left">Chromosome</th><th align="left">Orthologue</th><th align="center">Chromosome</th><th align="center">%<break></break>Similarity</th></tr></thead><tbody><tr><td align="left">FOXA1</td><td align="left">14q12-q13</td><td align="left">FOXA1A</td><td align="center">12</td><td align="center">96.2</td></tr><tr><td align="left">FOXA2</td><td align="left">20p11</td><td align="left">FOXA2</td><td align="center">2</td><td align="center">97.4</td></tr><tr><td align="left">FOXA3</td><td align="left">19q13.2-q13.4</td><td align="left">FOXA3</td><td align="center">7</td><td align="center">90.4</td></tr><tr><td align="left">FOXB1</td><td align="left">15q22</td><td align="left">FOXB1</td><td align="center">9</td><td align="center">99.7</td></tr><tr><td align="left">FOXB2</td><td align="left">9q21.2</td><td align="left">FOXB2</td><td align="center">19</td><td align="center">92.6</td></tr><tr><td align="left">FOXC1</td><td align="left">6p25</td><td align="left">FOXC1</td><td align="center">13</td><td align="center">95.1</td></tr><tr><td align="left">FOXC2</td><td align="left">16q24.1</td><td align="left">FOXC2</td><td align="center">8</td><td align="center">92.6</td></tr><tr><td align="left">FOXD1</td><td align="left">5q12-q13</td><td align="left">FOXD1</td><td align="center">13</td><td align="center">85.8</td></tr><tr><td align="left">FOXD2</td><td align="left">1p34-p32</td><td align="left">FOXD2</td><td align="center">4</td><td align="center">94.3</td></tr><tr><td align="left">FOXD3</td><td align="left">1p31.3</td><td align="left">FOXD3</td><td align="center">4</td><td align="center">90.8</td></tr><tr><td align="left">FOXD4</td><td align="left">9p24.3</td><td></td><td></td><td></td></tr><tr><td align="left">FOXD4L1</td><td align="left">2q14.1</td><td align="left">FOXD4</td><td align="center">19</td><td align="center">63.7</td></tr><tr><td align="left">FOXD4L2</td><td align="left">9p12</td><td></td><td></td><td></td></tr><tr><td align="left">FOXD4L3</td><td align="left">9q13</td><td></td><td></td><td></td></tr><tr><td align="left">FOXD4L4</td><td align="left">9q13</td><td></td><td></td><td></td></tr><tr><td align="left">FOXD4L5</td><td align="left">9q13</td><td></td><td></td><td></td></tr><tr><td align="left">FOXD4L6</td><td align="left">9q12</td><td></td><td></td><td></td></tr><tr><td align="left">FOXE1</td><td align="left">9q22</td><td align="left">FOXE1</td><td align="center">4</td><td align="center">91.2</td></tr><tr><td align="left">FOXE3</td><td align="left">1p32</td><td align="left">FOXE3</td><td align="center">4</td><td align="center">79.3</td></tr><tr><td align="left">FOXF1</td><td align="left">16q24</td><td align="left">FOXF1</td><td align="center">8</td><td align="center">97.4</td></tr><tr><td align="left">FOXF2</td><td align="left">6p25.3</td><td align="left">FOXF2</td><td align="center">13</td><td align="center">94.6</td></tr><tr><td align="left">FOXG1</td><td align="left">14q11-q13</td><td align="left">FOXG1</td><td align="center">12</td><td align="center">96.3</td></tr><tr><td align="left">FOXH1</td><td align="left">8q24</td><td align="left">FOXH1</td><td align="center">15</td><td align="center">76.3</td></tr><tr><td align="left">FOXI1</td><td align="left">5q34</td><td align="left">FOXI1</td><td align="center">11</td><td align="center">89.9</td></tr><tr><td align="left">FOXI2</td><td align="left">10q26.2</td><td align="left">FOXI2</td><td align="center">7</td><td align="center">78.6</td></tr><tr><td align="left">FOXI3</td><td align="left">2p11.2</td><td align="left">FOXI3</td><td align="center">6</td><td align="center">84.5</td></tr><tr><td align="left">FOXJ1</td><td align="left">17q25.1</td><td align="left">FOXJ1</td><td align="center">11</td><td align="center">94.5</td></tr><tr><td align="left">FOXJ2</td><td align="left">12p13.31</td><td align="left">FOXJ2</td><td align="center">6</td><td align="center">93.2</td></tr><tr><td align="left">FOXJ3</td><td align="left">1p34.2</td><td align="left">FOXJ3</td><td align="center">4</td><td align="center">96.5</td></tr><tr><td align="left">FOXK1</td><td align="left">7p22</td><td align="left">FOXK1</td><td align="center">5</td><td align="center">92</td></tr><tr><td align="left">FOXK2</td><td align="left">17q25</td><td align="left">FOXK2</td><td align="center">11</td><td align="center">95</td></tr><tr><td align="left">FOXL1</td><td align="left">16q24</td><td align="left">FOXL1</td><td align="center">8</td><td align="center">73</td></tr><tr><td align="left">FOXL2</td><td align="left">3q23</td><td align="left">FOXL2</td><td align="center">9</td><td align="center">96.8</td></tr><tr><td align="left">FOXM1</td><td align="left">12p13</td><td align="left">FOXM1</td><td align="center">6</td><td align="center">88.6</td></tr><tr><td align="left">FOXN1</td><td align="left">17q11-q12</td><td align="left">FOXN1</td><td align="center">11</td><td align="center">90.9</td></tr><tr><td align="left">FOXN2</td><td align="left">2p22-p16</td><td align="left">FOXN2</td><td align="center">17</td><td align="center">48</td></tr><tr><td align="left">FOXN3</td><td align="left">14q24.3-q31</td><td align="left">FOXN3</td><td align="center">12</td><td align="center">90</td></tr><tr><td align="left">FOXN4</td><td align="left">12q24.12</td><td align="left">FOXN4</td><td align="center">5</td><td align="center">86.2</td></tr><tr><td align="left">FOXO1</td><td align="left">13q14.1</td><td align="left">FOXO1</td><td align="center">3</td><td align="center">95.4</td></tr><tr><td align="left">FOXO3</td><td align="left">6q21</td><td align="left">FOXO3</td><td align="center">10</td><td align="center">96.1</td></tr><tr><td align="left">FOXO4</td><td align="left">Xq13.1</td><td align="left">FOXO4</td><td align="center">X</td><td align="center">93.3</td></tr><tr><td align="left">FOXO6</td><td align="left">1p34.2</td><td align="left">FOXO6</td><td align="center">4</td><td align="center">86</td></tr><tr><td align="left">FOXP1</td><td align="left">3p14.1</td><td align="left">FOXP1</td><td align="center">6</td><td align="center">94.6</td></tr><tr><td align="left">FOXP2</td><td align="left">7q31</td><td align="left">FOXP2</td><td align="center">6</td><td align="center">99.7</td></tr><tr><td align="left">FOXP3</td><td align="left">Xp11.23</td><td align="left">FOXP3</td><td align="center">X</td><td align="center">91.4</td></tr><tr><td align="left">FOXP4</td><td align="left">6p21.1</td><td align="left">FOXP4</td><td align="center">17</td><td align="center">80.5</td></tr><tr><td align="left">FOXQ1</td><td align="left">6p25</td><td align="left">FOXQ1</td><td align="center">13</td><td align="center">93.6</td></tr><tr><td align="left">FOXR1</td><td align="left">11q23.3</td><td align="left">FOXR1</td><td align="center">9</td><td align="center">77.7</td></tr><tr><td align="left">FOXR2</td><td align="left">Xp11</td><td align="left">FOXR2</td><td align="center">X</td><td align="center">73</td></tr><tr><td align="left">FOXS1</td><td align="left">20q11.1-q11.2</td><td align="left">FOXS1</td><td align="center">2</td><td align="center">83.3</td></tr></tbody></table></table-wrap><sec><title>FOXO subfamily</title><p>A great deal of attention has been given to the FOXO subfamily, which plays a role in the regulation of metabolism, oxidative stress resistance and cell-cycle arrest. Under fasting conditions, FOXO transcriptionally activates insulin-responsive genes, which include genes encoding enzymes responsible for gluconeogenesis (including glucose-6-phosphatase and phosphoenolpyruvate carboxykinase) in the liver. If nutrients are plentiful, however, insulin activates the phosphatidylinositol 3-kinase (PI3K) pathway, which causes AKT/protein kinase B to phosphorylate FOXO, excluding it from the nucleus and turning off insulin-responsive genes [<xref ref-type="bibr" rid="B10">10</xref>]. FOXO1 appears to be the primary protein in this pathway, but there is overlap in many FOXO functions. In pancreatic beta cells, FOXO1 has been shown to protect against glucotoxic and lipotoxic oxidative stress by upregulating manganese superoxide dismutase and catalase [<xref ref-type="bibr" rid="B11">11</xref>]. FOXO1 has also been shown to be a cell-cycle inhibitor in beta cells[<xref ref-type="bibr" rid="B12">12</xref>] and in lipocytes with a correlated increased expression of p2 [<xref ref-type="bibr" rid="B13">13</xref>]. The post-transcriptional regulation of the FOXO family allows for complex and sensitive actions from each family member. The variety of possible phosphorylation, acetylation, methylation and <italic>O</italic>-linked glycosylation has been dubbed the FOXO code [<xref ref-type="bibr" rid="B14">14</xref>].</p></sec><sec><title>FOXA subfamily</title><p>FOXA proteins have been shown to act as 'pioneer' factors -- proteins that can open tightly compacted chromatin without the involvement of the switching-sucrose non-fermenting (SWI-SNF) chromatin remodelling complex [<xref ref-type="bibr" rid="B15">15</xref>]. This is accomplished by interaction of the C-terminal domain of FOXA proteins with histones H3 and H4. This helps FOXA factors to regulate the development of multiple organ systems -- including liver, pancreas, lung, prostate and kidney [<xref ref-type="bibr" rid="B16">16</xref>]. The 'pioneer' function of FOXA has also been shown to facilitate the binding of nuclear hormone receptors, including the glucocorticoid receptor and oestrogen receptor (ER). In the adult, FOXA proteins have been shown to play a role in metabolism -- for example, in the expression of gluconeogenic enzymes in the liver in response to fasting, and energy utilisation by adipose tissue in response to excess caloric intake.</p></sec><sec><title>FOXP subfamily</title><p>The FOXP subfamily plays a role in immune response; specifically, constitutively expressed FOXP3 is considered a critical biomarker for thymus-derived natural T<sub>reg </sub>cells. FOXP3 expression is required for self-tolerance and immune homeostasis [<xref ref-type="bibr" rid="B17">17</xref>]. The forkhead domain of FOXP members is different from that in other FOX family members: wing 1 is truncated and wing 2 forms a helix rather than a loop; in addition, the forkhead domain is located near the C-terminus, rather than the N-terminus, as in most subclasses. FOXP members are also unusual in that they can form dimers by domain swapping (two monomers interact by exchanging helix H3 and strands S2 and S3) [<xref ref-type="bibr" rid="B18">18</xref>]. The orientation of the dimers requires the protein to bind opposing (non-adjacent) DNA sites; the result is that FOXP proteins may participate in the regulation of higher-order protein-DNA complexes. FOXP2 is involved in the development of speech, and a mutation in this gene has been linked to speech and language disorders [<xref ref-type="bibr" rid="B19">19</xref>].</p></sec></sec><sec><title>Evolution of the <italic>FOX </italic>genes</title><p>As mentioned previously, the 100-amino acid forkhead-binding domain is well conserved across species and families. This domain is often exclusively used for phylogenetic analysis. Figure <xref ref-type="fig" rid="F1">1</xref> shows a neighbour-joining dendrogram of human and mouse forkhead domains. Nineteen subfamilies, denoted by different letters (A, B, C, etc.) can be distinguished based on evolutionary divergence. Note that FOXN proteins are split into two distinct subgroups, at the top and bottom of the dendrogram, and that the FOXL proteins are also split into different branches. Figure <xref ref-type="fig" rid="F2">2</xref> shows the same alignment using the full FOX protein sequence. Due to high divergence on either side of the forkhead domains, the full sequence is difficult to align between subfamilies, but has been helpful in defining each subfamily [<xref ref-type="bibr" rid="B7">7</xref>]. In Figure <xref ref-type="fig" rid="F2">2</xref>, however, one again can see the splitting of the FOXN proteins and the FOXL proteins into distinctly separate branches. This global alignment also divides the FOXJ members into far different branches. One can conclude that alignment of the forkhead domain only provides a better assessment of evolutionary divergence.</p><fig id="F1" position="float"><label>Figure 1</label><caption><p><bold>Neighbour-joining dendrogram of the forkhead domains of all human and mouse FOX proteins</bold>. Protein sequences were aligned using ClustalW. Labels at branches indicate subclasses. Sequence information was downloaded from UniProt[<xref ref-type="bibr" rid="B20">20</xref>] through the Hugo Gene Nomenclature Committee (HGNC) website at <ext-link ext-link-type="uri" xlink:href="http://www.genenames.org">http://www.genenames.org</ext-link>[<xref ref-type="bibr" rid="B21">21</xref>] for human, and Mouse Genome Informatics (MGI) at <ext-link ext-link-type="uri" xlink:href="http://www.informatics.jax.org">http://www.informatics.jax.org</ext-link>[<xref ref-type="bibr" rid="B22">22</xref>] for mouse. Alignment and trees were created using CLUSTALW[<xref ref-type="bibr" rid="B23">23</xref>] through the GenomeNet server at <ext-link ext-link-type="uri" xlink:href="http://align.genome.jp">http://align.genome.jp</ext-link>.</p></caption><graphic xlink:href="1479-7364-4-5-345-1"></graphic></fig><fig id="F2" position="float"><label>Figure 2</label><caption><p><bold>Neighbour-joining dendrogram of the full sequences of all human and mouse FOX proteins</bold>. Sequences were aligned using ClustalW. Labels at branches indicate subfamilies.</p></caption><graphic xlink:href="1479-7364-4-5-345-2"></graphic></fig><p>Where possible, the nomenclature committee gave the same name to orthologues across species. Based on analysis of full sequences, mice have orthologues of all human <italic>FOX </italic>genes with high sequence similarity, with one exception. The murine FOXD4 protein clusters together with seven human proteins -- FOXD4, and the FOXD4-like FOXD4L1 to FOXD4L6, and shares the most identity with FOXD4L1. The duplications that gave rise to the FOXD4 group appear to be relatively recent -- that is, during hominid evolution. Very little information is available about these proteins, but researchers have shown that at least two <italic>FOXD4L </italic>genes are transcriptionally active; furthermore, evidence of purifying selection in the forkhead domain of these proteins suggests that they may play a physiological role [<xref ref-type="bibr" rid="B24">24</xref>].</p><p>Many authors have performed detailed phylogenetic analyses, but the first analysis and naming scheme has been generally upheld,[<xref ref-type="bibr" rid="B4">4</xref>] with a few criticisms illustrated in Figures <xref ref-type="fig" rid="F1">1</xref> and <xref ref-type="fig" rid="F2">2</xref>. In analysis of the forkhead domain, FOXR falls within the FOXN subclass and some authors have proposed combining these two groups. In analysis of the full sequence, however, FOXR1 and FOXR2 are associated more closely with FOXN1 and FOXN4, but not with FOXN2 and FOXN3. Thus, some researchers have proposed splitting these into three subclasses. Finally, in many analyses, FOXL1 and FOXL2 do not cluster together.</p><p>In an analysis of the origin and expansion of early transcription factors, it was found that FOXJ1 was probably the oldest family member, present in the opisthokont last common ancestor of the fungi and metazoans [<xref ref-type="bibr" rid="B25">25</xref>]. Expansion occurred early, with bilaterians having 19 <italic>FOX </italic>genes and most mammals more than 40.</p></sec><sec><title>FOXs in disease</title><p>Immune dysregulation/polyendocrinopathy/enteropathy/X-linked syndrome (IPEX) is a human disease caused by a mutation in <italic>FOXP3</italic>. The disorder is characterised by a wide range of auto-immune symptoms, including type 1 diabetes, eczema, food allergy, thyroid disorders and inflammatory bowel disease [<xref ref-type="bibr" rid="B26">26</xref>]. The link between FOXP3 and autoimmune disease has been ascribed to the function of T<sub>reg </sub>cells; replacement or stimulation of these cells has been suggested as an aetiology for a number of autoimmune disorders [<xref ref-type="bibr" rid="B17">17</xref>].</p><p>Given their key role in the expression of many genes that affect cell proliferation and survival, FOX family members have been suggested as possible cancer therapeutic targets. FOX family members have been shown to be up- or downregulated in many cancers. FOXP1 has been suggested as a tumour promoter and an oncogene, depending on the cell type, although these observations are primarily based on correlations between mRNA levels and clinical outcomes [<xref ref-type="bibr" rid="B27">27</xref>]. FOXA1 is a pioneer factor, which is required for the expression of many oestrogen-responsive genes. Nakshatri and Badve[<xref ref-type="bibr" rid="B28">28</xref>] suggest that maintenance of FOXA1 expression may force ER-alpha-positive breast cancers to remain oestrogen dependent, increasing their responsiveness to anti-oestrogens. There is a correlation between retinoic acid (a FOXA1 inducer) and growth inhibition in cells, and insulin (which inhibits FOXA1) and anti-oestrogen resistance [<xref ref-type="bibr" rid="B14">14</xref>]. FOXM1 is an oncogene that is highly expressed in most carcinomas, but expressed in low amounts in normal cells, and has been recently identified as a key target of both well known and new classes of proteasome inhibitors [<xref ref-type="bibr" rid="B29">29</xref>].</p><p>The Online Mendelian Inheritance in Man (OMIM) database lists four known <italic>FOX </italic>genes that cause human diseases: <italic>FOXC1 </italic>mutations elicit dominantly inherited glaucoma phenotypes, <italic>FOXC2 </italic>mutations lead to lymphoedema-distichiasis syndrome, <italic>FOXP2 </italic>loss of function leads to language acquisition defects and <italic>FOXP3 </italic>mutations are associated with severe autoimmune disorders such as IPEX [<xref ref-type="bibr" rid="B4">4</xref>].</p></sec><sec sec-type="conclusions"><title>Conclusions</title><p>It is clear that the FOX family is an important and complex family of proteins that is a tantalising therapeutic target in many disease states -- especially given their role in the regulation of metabolism (metabolic syndromes), the immune system (auto-immunity) and proliferation (cancer). The family includes 50 genes in human and 44 in mouse. Each of these targets requires a protein- and tissue-specific approach. 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