Forkhead box L2: Difference between revisions

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{{Infobox_gene}}
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'''Forkhead box protein L2''' is a [[protein]] that in humans is encoded by the ''FOXL2'' [[gene]].<ref name="pmid1941972">{{cite journal | vauthors = de Die-Smulders CE, Engelen JJ, Donk JM, Fryns JP | title = Further evidence for the location of the BPES gene at 3q2 | journal = Journal of Medical Genetics | volume = 28 | issue = 10 | pages = 725 | date = October 1991 | pmid = 1941972 | pmc = 1017067 | doi = 10.1136/jmg.28.10.725 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: FOXL2 forkhead box L2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=668 }}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
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== Function ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = Forkhead box L2
| HGNCid = 1092
| Symbol = FOXL2
| AltSymbols =; BPES; BPES1; PFRK; PINTO; POF3
| OMIM = 605597
| ECnumber = 
| Homologene = 74992
| MGIid = 1349428
| GeneAtlas_image1 = PBB_GE_FOXL2_220102_at_tn.png
| Function = {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0043028 |text = caspase regulator activity}} {{GNF_GO|id=GO:0043565 |text = sequence-specific DNA binding}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}}
| Process = {{GNF_GO|id=GO:0001541 |text = ovarian follicle development}} {{GNF_GO|id=GO:0002074 |text = extraocular skeletal muscle development}} {{GNF_GO|id=GO:0006309 |text = DNA fragmentation during apoptosis}} {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0019101 |text = female somatic sex determination}} {{GNF_GO|id=GO:0030154 |text = cell differentiation}} {{GNF_GO|id=GO:0042703 |text = menstruation}} {{GNF_GO|id=GO:0043065 |text = positive regulation of apoptosis}} {{GNF_GO|id=GO:0043280 |text = positive regulation of caspase activity}} {{GNF_GO|id=GO:0045944 |text = positive regulation of transcription from RNA polymerase II promoter}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 668
    | Hs_Ensembl = ENSG00000183770
    | Hs_RefseqProtein = XP_001131060
    | Hs_RefseqmRNA = XM_001131060
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 3
    | Hs_GenLoc_start = 140147124
    | Hs_GenLoc_end = 140148254
    | Hs_Uniprot = P58012
    | Mm_EntrezGene = 26927
    | Mm_Ensembl = ENSMUSG00000050397
    | Mm_RefseqmRNA = XM_976602
    | Mm_RefseqProtein = XP_981696
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 9
    | Mm_GenLoc_start = 98765013
    | Mm_GenLoc_end = 98766140
    | Mm_Uniprot = Q2TVT7
  }}
}}
'''Forkhead box L2''', also known as '''FOXL2''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: FOXL2 forkhead box L2| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=668| accessdate = }}</ref>


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FOXL2 is a [[FOX proteins|forkhead]] [[transcription factor]]. The protein contains a fork-head [[DNA-binding domain]] and plays a role in ovarian development and function.<ref name="entrez"/>  FoxL2 is a marker for ovarian differentiation, and is required for granulosa cell differentiation. In addition, the foxl2 protein will prevent the formation of testes by suppressing expression of SOX9.<ref>{{cite journal | vauthors = Yang YJ, Wang Y, Li Z, Zhou L, Gui JF | title = Sequential, Divergent, and Cooperative Requirements of Foxl2a and Foxl2b in Ovary Development and Maintenance of Zebrafish | journal = Genetics | volume = 205 | issue = 4 | pages = 1551–1572 | date = April 2017 | pmid = 28193729 | pmc = 5378113 | doi = 10.1534/genetics.116.199133 }}</ref>
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==See also==
In postnatal ovaries FOXL2 regulates granulosa cell differentiation and also supports the growth of the pre-ovulatory follicles during adult life.<ref name="Leung 51–54">{{cite journal | vauthors = Leung DT, Fuller PJ, Chu S | title = Impact of FOXL2 mutations on signaling in ovarian granulosa cell tumors | journal = The International Journal of Biochemistry & Cell Biology | volume = 72 | pages = 51–4 | date = March 2016 | pmid = 26791928 | doi = 10.1016/j.biocel.2016.01.003 }}</ref>
 
== Regulation ==
 
FOXL2 has several post-translational modifications that modulate its stability, subcellular localization and pro-apoptotic activity.<ref name="pmid22022399">{{cite journal | vauthors = Georges A, Benayoun BA, Marongiu M, Dipietromaria A, L'Hôte D, Todeschini AL, Auer J, Crisponi L, Veitia RA | title = SUMOylation of the Forkhead transcription factor FOXL2 promotes its stabilization/activation through transient recruitment to PML bodies | journal = PLOS ONE | volume = 6 | issue = 10 | pages = e25463 | date = Oct 2011 | pmid = 22022399 | doi = 10.1371/journal.pone | pmc=3192040}}</ref>
By a yeast-two-hybrid screening, 10 novel protein partners of FOXL2 are discovered. The interactions were confirmed by co-immunoprecipitation experiments between FOXL2 and CXXC4 (IDAX), CXXC5 (RINF/WID), CREM, GMEB1 (P96PIF), NR2C1 (TR2), SP100, RPLP1, BAF (BANF1), XRCC6 (KU70) and SIRT1.<ref name="pmid22544055">{{cite journal | vauthors = L'Hôte D, Georges A, Todeschini AL, Kim JH, Benayoun BA, Bae J, Veitia RA | title = Discovery of novel protein partners of the transcription factor FOXL2 provides insights into its physiopathological roles | journal = Human Molecular Genetics | volume = 21 | issue = 14 | pages = 3264–74 | date = July 2012 | pmid = 22544055 | doi = 10.1093/hmg/dds170 }}</ref>
 
== Clinical significance ==
 
===Sex determination===
This protein is involved in sex determination. Female missing the ''FOXL2'' gene appear male. ''FOXL2'' knockout in mature mouse ovaries cause them to develop into [[testes]], however [[oocytes]] are still formed.<ref name="pmid20005806">{{cite journal | vauthors = Uhlenhaut NH, Jakob S, Anlag K, Eisenberger T, Sekido R, Kress J, Treier AC, Klugmann C, Klasen C, Holter NI, Riethmacher D, Schütz G, Cooney AJ, Lovell-Badge R, Treier M | title = Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation | journal = Cell | volume = 139 | issue = 6 | pages = 1130–42 | date = December 2009 | pmid = 20005806 | doi = 10.1016/j.cell.2009.11.021 | laysummary = http://www.nature.com/news/2009/091210/full/news.2009.1135.html | laysource = Nature News }}</ref>
 
===Blepharophimosis-ptosis-epicanthus inversus syndrome===
Mutations in this gene are a cause of [[blepharophimosis|blepharophimosis syndrome]] and/or [[premature ovarian failure]] 3.<ref name="entrez" />
Predicting the occurrence of POF based on the nature of the missense mutations in FOXL2 was a medical challenge. However, a correlation between the transcriptional activity of FOXL2 variants and the type of BPES has been founded.<ref name="pmid19515849">{{cite journal | vauthors = Dipietromaria A, Benayoun BA, Todeschini AL, Rivals I, Bazin C, Veitia RA | title = Towards a functional classification of pathogenic FOXL2 mutations using transactivation reporter systems | journal = Human Molecular Genetics | volume = 18 | issue = 17 | pages = 3324–33 | date = September 2009 | pmid = 19515849 | doi = 10.1093/hmg/ddp273 }}</ref>
Moreover by studying the effects of natural and artificial mutations in the forkhead domain of FOXL2, a clear correlation between the orientation of amino-acid side chains in the DNA-binding domain and transcriptional activity is founded, providing the first (in silico) predictive tool of the effects of FOXL2 missense mutations.<ref name="pmid21632871">{{cite journal | vauthors = Todeschini AL, Dipietromaria A, L'hôte D, Boucham FZ, Georges AB, Pandaranayaka PJ, Krishnaswamy S, Rivals I, Bazin C, Veitia RA | title = Mutational probing of the forkhead domain of the transcription factor FOXL2 provides insights into the pathogenicity of naturally occurring mutations | journal = Human Molecular Genetics | volume = 20 | issue = 17 | pages = 3376–85 | date = September 2011 | pmid = 21632871 | doi = 10.1093/hmg/ddr244 }}</ref>
 
===Adult Granulosa Cell Tumors AGCT===
A missense mutation in the FOXL2 gene C134W is found in adult granulosa cell tumors, but not in other ovarian cancers nor in juvenile granulosa cell tumors.<ref name="Leung 51–54"/>
 
===Endometriosis===
In addition to ovarian expression of FOXL2, there has been recent studies to suggest that overexpression of FOXL2 has been implicated in endometriosis in addition to activin A.<ref>{{cite journal | vauthors = Governini L, Carrarelli P, Rocha AL, Leo VD, Luddi A, Arcuri F, Piomboni P, Chapron C, Bilezikjian LM, Petraglia F | title = FOXL2 in human endometrium: hyperexpressed in endometriosis | language = en | journal = Reproductive Sciences | volume = 21 | issue = 10 | pages = 1249–55 | date = October 2014 | pmid = 24520083 | doi = 10.1177/1933719114522549 }}</ref>
 
===Others Deregulations===
One study has found that FOXL2 is required for SF-1-induced ovarian AMH regulation by interactions between FOXL2 protein and SF-1, a mutated FOXL2 could not interact with SF-1 normally and thus could not regulate ovarian AMH as normal.<ref>{{cite journal | vauthors = Jin H, Won M, Park SE, Lee S, Park M, Bae J | title = FOXL2 Is an Essential Activator of SF-1-Induced Transcriptional Regulation of Anti-Müllerian Hormone in Human Granulosa Cells | journal = PLOS ONE | volume = 11 | issue = 7 | pages = e0159112 | date = 2016-07-14 | pmid = 27414805 | pmc = 4944948 | doi = 10.1371/journal.pone.0159112 }}</ref>
 
In a knockout study in mice, the granulosa cells of the ovaries failed to undergo the squamous-to-cuboidal transition which led to the arrest of folliculogenesis<ref>{{cite journal | vauthors = Schmidt D, Ovitt CE, Anlag K, Fehsenfeld S, Gredsted L, Treier AC, Treier M | title = The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance | language = en | journal = Development | volume = 131 | issue = 4 | pages = 933–42 | date = February 2004 | pmid = 14736745 | doi = 10.1242/dev.00969 }}</ref>
 
== See also ==
* [[FOX proteins]]
* [[FOX proteins]]


==References==
== References ==
{{reflist|2}}
{{reflist|33em}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin|33em}}
{{PBB_Further_reading
* {{cite journal | vauthors = Vaiman D, Schibler L, Oustry-Vaiman A, Pailhoux E, Goldammer T, Stevanovic M, Furet JP, Schwerin M, Cotinot C, Fellous M, Cribiu EP | title = High-resolution human/goat comparative map of the goat polled/intersex syndrome (PIS): the human homologue is contained in a human YAC from HSA3q23 | journal = Genomics | volume = 56 | issue = 1 | pages = 31–9 | date = February 1999 | pmid = 10036183 | doi = 10.1006/geno.1998.5691 }}
| citations =
* {{cite journal | vauthors = Kaestner KH, Knochel W, Martinez DE | title = Unified nomenclature for the winged helix/forkhead transcription factors | journal = Genes & Development | volume = 14 | issue = 2 | pages = 142–6 | date = January 2000 | pmid = 10702024 | doi = 10.1101/gad.14.2.142 }}
*{{cite journal | author=de Die-Smulders CE, Engelen JJ, Donk JM, Fryns JP |title=Further evidence for the location of the BPES gene at 3q2. |journal=J. Med. Genet. |volume=28 |issue= 10 |pages= 725 |year= 1991 |pmid= 1941972 |doi= }}
* {{cite journal | vauthors = Crisponi L, Deiana M, Loi A, Chiappe F, Uda M, Amati P, Bisceglia L, Zelante L, Nagaraja R, Porcu S, Ristaldi MS, Marzella R, Rocchi M, Nicolino M, Lienhardt-Roussie A, Nivelon A, Verloes A, Schlessinger D, Gasparini P, Bonneau D, Cao A, Pilia G | title = The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome | journal = Nature Genetics | volume = 27 | issue = 2 | pages = 159–66 | date = February 2001 | pmid = 11175783 | doi = 10.1038/84781 }}
*{{cite journal | author=Vaiman D, Schibler L, Oustry-Vaiman A, ''et al.'' |title=High-resolution human/goat comparative map of the goat polled/intersex syndrome (PIS): the human homologue is contained in a human YAC from HSA3q23. |journal=Genomics |volume=56 |issue= 1 |pages= 31-9 |year= 1999 |pmid= 10036183 |doi= 10.1006/geno.1998.5691 }}
* {{cite journal | vauthors = De Baere E, Dixon MJ, Small KW, Jabs EW, Leroy BP, Devriendt K, Gillerot Y, Mortier G, Meire F, Van Maldergem L, Courtens W, Hjalgrim H, Huang S, Liebaers I, Van Regemorter N, Touraine P, Praphanphoj V, Verloes A, Udar N, Yellore V, Chalukya M, Yelchits S, De Paepe A, Kuttenn F, Fellous M, Veitia R, Messiaen L | title = Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype--phenotype correlation | journal = Human Molecular Genetics | volume = 10 | issue = 15 | pages = 1591–600 | date = July 2001 | pmid = 11468277 | doi = 10.1093/hmg/10.15.1591 }}
*{{cite journal | author=Kaestner KH, Knochel W, Martinez DE |title=Unified nomenclature for the winged helix/forkhead transcription factors. |journal=Genes Dev. |volume=14 |issue= 2 |pages= 142-6 |year= 2000 |pmid= 10702024 |doi= }}
* {{cite journal | vauthors = Dollfus H, Kumaramanickavel G, Biswas P, Stoetzel C, Quillet R, Denton M, Maw M, Perrin-Schmitt F | title = Identification of a new TWIST mutation (7p21) with variable eyelid manifestations supports locus homogeneity of BPES at 3q22 | journal = Journal of Medical Genetics | volume = 38 | issue = 7 | pages = 470–2 | date = July 2001 | pmid = 11474656 | pmc = 1757180 | doi = 10.1136/jmg.38.7.470 }}
*{{cite journal | author=Crisponi L, Deiana M, Loi A, ''et al.'' |title=The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. |journal=Nat. Genet. |volume=27 |issue= 2 |pages= 159-66 |year= 2001 |pmid= 11175783 |doi= 10.1038/84781 }}
* {{cite journal | vauthors = Yamada T, Hayasaka S, Matsumoto M, Esa T, Hayasaka Y, Endo M | title = Heterozygous 17-bp deletion in the forkhead transcription factor gene, FOXL2, in a Japanese family with blepharophimosis-ptosis-epicanthus inversus syndrome | journal = Journal of Human Genetics | volume = 46 | issue = 12 | pages = 733–6 | year = 2002 | pmid = 11776388 | doi = 10.1007/s100380170009 }}
*{{cite journal | author=De Baere E, Dixon MJ, Small KW, ''et al.'' |title=Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype--phenotype correlation. |journal=Hum. Mol. Genet. |volume=10 |issue= 15 |pages= 1591-600 |year= 2001 |pmid= 11468277 |doi= }}
* {{cite journal | vauthors = Kosaki K, Ogata T, Kosaki R, Sato S, Matsuo N | title = A novel mutation in the FOXL2 gene in a patient with blepharophimosis syndrome: differential role of the polyalanine tract in the development of the ovary and the eyelid | journal = Ophthalmic Genetics | volume = 23 | issue = 1 | pages = 43–7 | date = March 2002 | pmid = 11910558 | doi = 10.1076/opge.23.1.43.2202 }}
*{{cite journal | author=Dollfus H, Kumaramanickavel G, Biswas P, ''et al.'' |title=Identification of a new TWIST mutation (7p21) with variable eyelid manifestations supports locus homogeneity of BPES at 3q22. |journal=J. Med. Genet. |volume=38 |issue= 7 |pages= 470-2 |year= 2001 |pmid= 11474656 |doi= }}
* {{cite journal | vauthors = Bell R, Murday VA, Patton MA, Jeffery S | title = Two families with blepharophimosis/ptosis/epicanthus inversus syndrome have mutations in the putative forkhead transcription factor FOXL2 | journal = Genetic Testing | volume = 5 | issue = 4 | pages = 335–8 | year = 2002 | pmid = 11960581 | doi = 10.1089/109065701753617499 }}
*{{cite journal | author=Yamada T, Hayasaka S, Matsumoto M, ''et al.'' |title=Heterozygous 17-bp deletion in the forkhead transcription factor gene, FOXL2, in a Japanese family with blepharophimosis-ptosis-epicanthus inversus syndrome. |journal=J. Hum. Genet. |volume=46 |issue= 12 |pages= 733-6 |year= 2002 |pmid= 11776388 |doi= }}
* {{cite journal | vauthors = Harris SE, Chand AL, Winship IM, Gersak K, Aittomäki K, Shelling AN | title = Identification of novel mutations in FOXL2 associated with premature ovarian failure | journal = Molecular Human Reproduction | volume = 8 | issue = 8 | pages = 729–33 | date = August 2002 | pmid = 12149404 | doi = 10.1093/molehr/8.8.729 }}
*{{cite journal | author=Kosaki K, Ogata T, Kosaki R, ''et al.'' |title=A novel mutation in the FOXL2 gene in a patient with blepharophimosis syndrome: differential role of the polyalanine tract in the development of the ovary and the eyelid. |journal=Ophthalmic Genet. |volume=23 |issue= 1 |pages= 43-7 |year= 2002 |pmid= 11910558 |doi= }}
* {{cite journal | vauthors = De Baere E, Lemercier B, Christin-Maitre S, Durval D, Messiaen L, Fellous M, Veitia R | title = FOXL2 mutation screening in a large panel of POF patients and XX males | journal = Journal of Medical Genetics | volume = 39 | issue = 8 | pages = e43 | date = August 2002 | pmid = 12161610 | pmc = 1735205 | doi = 10.1136/jmg.39.8.e43 }}
*{{cite journal | author=Bell R, Murday VA, Patton MA, Jeffery S |title=Two families with blepharophimosis/ptosis/epicanthus inversus syndrome have mutations in the putative forkhead transcription factor FOXL2. |journal=Genet. Test. |volume=5 |issue= 4 |pages= 335-8 |year= 2002 |pmid= 11960581 |doi= 10.1089/109065701753617499 }}
* {{cite journal | vauthors = Ramírez-Castro JL, Pineda-Trujillo N, Valencia AV, Muñetón CM, Botero O, Trujillo O, Vásquez G, Mora BE, Durango N, Bedoya G, Ruiz-Linares A | title = Mutations in FOXL2 underlying BPES (types 1 and 2) in Colombian families | journal = American Journal of Medical Genetics | volume = 113 | issue = 1 | pages = 47–51 | date = November 2002 | pmid = 12400065 | doi = 10.1002/ajmg.10741 }}
*{{cite journal | author=Harris SE, Chand AL, Winship IM, ''et al.'' |title=Identification of novel mutations in FOXL2 associated with premature ovarian failure. |journal=Mol. Hum. Reprod. |volume=8 |issue= 8 |pages= 729-33 |year= 2003 |pmid= 12149404 |doi= }}
* {{cite journal | vauthors = Cocquet J, Pailhoux E, Jaubert F, Servel N, Xia X, Pannetier M, De Baere E, Messiaen L, Cotinot C, Fellous M, Veitia RA | title = Evolution and expression of FOXL2 | journal = Journal of Medical Genetics | volume = 39 | issue = 12 | pages = 916–21 | date = December 2002 | pmid = 12471206 | pmc = 1757225 | doi = 10.1136/jmg.39.12.916 }}
*{{cite journal | author=De Baere E, Lemercier B, Christin-Maitre S, ''et al.'' |title=FOXL2 mutation screening in a large panel of POF patients and XX males. |journal=J. Med. Genet. |volume=39 |issue= 8 |pages= e43 |year= 2002 |pmid= 12161610 |doi= }}
* {{cite journal | vauthors = De Baere E, Beysen D, Oley C, Lorenz B, Cocquet J, De Sutter P, Devriendt K, Dixon M, Fellous M, Fryns JP, Garza A, Jonsrud C, Koivisto PA, Krause A, Leroy BP, Meire F, Plomp A, Van Maldergem L, De Paepe A, Veitia R, Messiaen L | title = FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation | journal = American Journal of Human Genetics | volume = 72 | issue = 2 | pages = 478–87 | date = February 2003 | pmid = 12529855 | pmc = 379240 | doi = 10.1086/346118 }}
*{{cite journal | author=Ramírez-Castro JL, Pineda-Trujillo N, Valencia AV, ''et al.'' |title=Mutations in FOXL2 underlying BPES (types 1 and 2) in Colombian families. |journal=Am. J. Med. Genet. |volume=113 |issue= 1 |pages= 47-51 |year= 2003 |pmid= 12400065 |doi= 10.1002/ajmg.10741 }}
* {{cite journal | vauthors = Mazumdar A, Kumar R | title = Estrogen regulation of Pak1 and FKHR pathways in breast cancer cells | journal = FEBS Letters | volume = 535 | issue = 1–3 | pages = 6–10 | date = January 2003 | pmid = 12560069 | doi = 10.1016/S0014-5793(02)03846-2 }}
*{{cite journal | author=Cocquet J, Pailhoux E, Jaubert F, ''et al.'' |title=Evolution and expression of FOXL2. |journal=J. Med. Genet. |volume=39 |issue= 12 |pages= 916-21 |year= 2003 |pmid= 12471206 |doi=  }}
* {{cite journal | vauthors = Fokstuen S, Antonarakis SE, Blouin JL | title = FOXL2-mutations in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES); challenges for genetic counseling in female patients | journal = American Journal of Medical Genetics. Part A | volume = 117A | issue = 2 | pages = 143–6 | date = March 2003 | pmid = 12567411 | doi = 10.1002/ajmg.a.10024 }}
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
* {{cite journal | vauthors = Dollfus H, Stoetzel C, Riehm S, Lahlou Boukoffa W, Bediard Boulaneb F, Quillet R, Abu-Eid M, Speeg-Schatz C, Francfort JJ, Flament J, Veillon F, Perrin-Schmitt F | title = Sporadic and familial blepharophimosis -ptosis-epicanthus inversus syndrome: FOXL2 mutation screen and MRI study of the superior levator eyelid muscle | journal = Clinical Genetics | volume = 63 | issue = 2 | pages = 117–20 | date = February 2003 | pmid = 12630957 | doi = 10.1034/j.1399-0004.2003.00011.x }}
*{{cite journal | author=De Baere E, Beysen D, Oley C, ''et al.'' |title=FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation. |journal=Am. J. Hum. Genet. |volume=72 |issue= 2 |pages= 478-87 |year= 2003 |pmid= 12529855 |doi= }}
* {{cite journal | vauthors = Udar N, Yellore V, Chalukya M, Yelchits S, Silva-Garcia R, Small K | title = Comparative analysis of the FOXL2 gene and characterization of mutations in BPES patients | journal = Human Mutation | volume = 22 | issue = 3 | pages = 222–8 | date = September 2003 | pmid = 12938087 | doi = 10.1002/humu.10251 }}
*{{cite journal | author=Mazumdar A, Kumar R |title=Estrogen regulation of Pak1 and FKHR pathways in breast cancer cells. |journal=FEBS Lett. |volume=535 |issue= 1-3 |pages= 6-10 |year= 2003 |pmid= 12560069 |doi= }}
* {{cite journal | vauthors = Crisponi L, Uda M, Deiana M, Loi A, Nagaraja R, Chiappe F, Schlessinger D, Cao A, Pilia G | title = FOXL2 inactivation by a translocation 171 kb away: analysis of 500 kb of chromosome 3 for candidate long-range regulatory sequences | journal = Genomics | volume = 83 | issue = 5 | pages = 757–64 | date = May 2004 | pmid = 15081106 | doi = 10.1016/j.ygeno.2003.11.010 }}
*{{cite journal | author=Fokstuen S, Antonarakis SE, Blouin JL |title=FOXL2-mutations in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES); challenges for genetic counseling in female patients. |journal=Am. J. Med. Genet. A |volume=117 |issue= 2 |pages= 143-6 |year= 2003 |pmid= 12567411 |doi= 10.1002/ajmg.a.10024 }}
* {{cite journal | vauthors = L'Hôte D, Georges A, Todeschini AL, Kim JH, Benayoun BA, Bae J, Veitia RA | title = Discovery of novel protein partners of the transcription factor FOXL2 provides insights into its physiopathological roles | journal = Human Molecular Genetics | volume = 21 | issue = 14 | pages = 3264–74 | date = July 2012 | pmid = 22544055 | doi = 10.1093/hmg/dds170 }}
*{{cite journal | author=Dollfus H, Stoetzel C, Riehm S, ''et al.'' |title=Sporadic and familial blepharophimosis -ptosis-epicanthus inversus syndrome: FOXL2 mutation screen and MRI study of the superior levator eyelid muscle. |journal=Clin. Genet. |volume=63 |issue= 2 |pages= 117-20 |year= 2003 |pmid= 12630957 |doi= }}
* {{cite journal | vauthors = Georges A, L'Hôte D, Todeschini AL, Auguste A, Legois B, Zider A, Veitia RA | title = The transcription factor FOXL2 mobilizes estrogen signaling to maintain the identity of ovarian granulosa cells | journal = eLife | volume = 3 | date = November 2014 | pmid = 25369636 | doi = 10.7554/eLife.04207 | pmc=4356143}}
*{{cite journal | author=Udar N, Yellore V, Chalukya M, ''et al.'' |title=Comparative analysis of the FOXL2 gene and characterization of mutations in BPES patients. |journal=Hum. Mutat. |volume=22 |issue= 3 |pages= 222-8 |year= 2003 |pmid= 12938087 |doi= 10.1002/humu.10251 }}
* {{cite journal | vauthors = Elzaiat M, Todeschini AL, Caburet S, Veitia RA | title = The genetic make-up of ovarian development and function: the focus on the transcription factor FOXL2 | journal = Clinical Genetics | volume = 91 | issue = 2 | pages = 173–182 | date = February 2017 | pmid = 27604691 | doi = 10.1111/cge.12862 }}
*{{cite journal | author=Crisponi L, Uda M, Deiana M, ''et al.'' |title=FOXL2 inactivation by a translocation 171 kb away: analysis of 500 kb of chromosome 3 for candidate long-range regulatory sequences. |journal=Genomics |volume=83 |issue= 5 |pages= 757-64 |year= 2004 |pmid= 15081106 |doi= 10.1016/j.ygeno.2003.11.010 }}
}}
{{refend}}
{{refend}}


== External links ==
== External links ==
* {{MeshName|FOXL2+protein,+human}}
* {{MeshName|FOXL2+protein,+human}}
*[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=bpes  GeneReviews/NCBI/NIH/UW entry on Blepharophimosis, Ptosis, and Epicanthus Inversus]
{{Transcription factors|g3}}


{{protein-stub}}
[[Category:Forkhead transcription factors]]
{{Transcription factors}}
[[Category:Transcription factors]]

Latest revision as of 11:50, 5 March 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
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View/Edit Human

Forkhead box protein L2 is a protein that in humans is encoded by the FOXL2 gene.[1][2]

Function

FOXL2 is a forkhead transcription factor. The protein contains a fork-head DNA-binding domain and plays a role in ovarian development and function.[2] FoxL2 is a marker for ovarian differentiation, and is required for granulosa cell differentiation. In addition, the foxl2 protein will prevent the formation of testes by suppressing expression of SOX9.[3]

In postnatal ovaries FOXL2 regulates granulosa cell differentiation and also supports the growth of the pre-ovulatory follicles during adult life.[4]

Regulation

FOXL2 has several post-translational modifications that modulate its stability, subcellular localization and pro-apoptotic activity.[5] By a yeast-two-hybrid screening, 10 novel protein partners of FOXL2 are discovered. The interactions were confirmed by co-immunoprecipitation experiments between FOXL2 and CXXC4 (IDAX), CXXC5 (RINF/WID), CREM, GMEB1 (P96PIF), NR2C1 (TR2), SP100, RPLP1, BAF (BANF1), XRCC6 (KU70) and SIRT1.[6]

Clinical significance

Sex determination

This protein is involved in sex determination. Female missing the FOXL2 gene appear male. FOXL2 knockout in mature mouse ovaries cause them to develop into testes, however oocytes are still formed.[7]

Blepharophimosis-ptosis-epicanthus inversus syndrome

Mutations in this gene are a cause of blepharophimosis syndrome and/or premature ovarian failure 3.[2] Predicting the occurrence of POF based on the nature of the missense mutations in FOXL2 was a medical challenge. However, a correlation between the transcriptional activity of FOXL2 variants and the type of BPES has been founded.[8] Moreover by studying the effects of natural and artificial mutations in the forkhead domain of FOXL2, a clear correlation between the orientation of amino-acid side chains in the DNA-binding domain and transcriptional activity is founded, providing the first (in silico) predictive tool of the effects of FOXL2 missense mutations.[9]

Adult Granulosa Cell Tumors AGCT

A missense mutation in the FOXL2 gene C134W is found in adult granulosa cell tumors, but not in other ovarian cancers nor in juvenile granulosa cell tumors.[4]

Endometriosis

In addition to ovarian expression of FOXL2, there has been recent studies to suggest that overexpression of FOXL2 has been implicated in endometriosis in addition to activin A.[10]

Others Deregulations

One study has found that FOXL2 is required for SF-1-induced ovarian AMH regulation by interactions between FOXL2 protein and SF-1, a mutated FOXL2 could not interact with SF-1 normally and thus could not regulate ovarian AMH as normal.[11]

In a knockout study in mice, the granulosa cells of the ovaries failed to undergo the squamous-to-cuboidal transition which led to the arrest of folliculogenesis[12]

See also

References

  1. ↑ de Die-Smulders CE, Engelen JJ, Donk JM, Fryns JP (October 1991). "Further evidence for the location of the BPES gene at 3q2". Journal of Medical Genetics. 28 (10): 725. doi:10.1136/jmg.28.10.725. PMC 1017067. PMID 1941972.
  2. ↑ 2.0 2.1 2.2 "Entrez Gene: FOXL2 forkhead box L2".
  3. ↑ Yang YJ, Wang Y, Li Z, Zhou L, Gui JF (April 2017). "Sequential, Divergent, and Cooperative Requirements of Foxl2a and Foxl2b in Ovary Development and Maintenance of Zebrafish". Genetics. 205 (4): 1551–1572. doi:10.1534/genetics.116.199133. PMC 5378113. PMID 28193729.
  4. ↑ 4.0 4.1 Leung DT, Fuller PJ, Chu S (March 2016). "Impact of FOXL2 mutations on signaling in ovarian granulosa cell tumors". The International Journal of Biochemistry & Cell Biology. 72: 51–4. doi:10.1016/j.biocel.2016.01.003. PMID 26791928.
  5. ↑ Georges A, Benayoun BA, Marongiu M, Dipietromaria A, L'Hôte D, Todeschini AL, Auer J, Crisponi L, Veitia RA (Oct 2011). "SUMOylation of the Forkhead transcription factor FOXL2 promotes its stabilization/activation through transient recruitment to PML bodies". PLOS ONE. 6 (10): e25463. doi:10.1371/journal.pone. PMC 3192040. PMID 22022399.
  6. ↑ L'Hôte D, Georges A, Todeschini AL, Kim JH, Benayoun BA, Bae J, Veitia RA (July 2012). "Discovery of novel protein partners of the transcription factor FOXL2 provides insights into its physiopathological roles". Human Molecular Genetics. 21 (14): 3264–74. doi:10.1093/hmg/dds170. PMID 22544055.
  7. ↑ Uhlenhaut NH, Jakob S, Anlag K, Eisenberger T, Sekido R, Kress J, Treier AC, Klugmann C, Klasen C, Holter NI, Riethmacher D, Schütz G, Cooney AJ, Lovell-Badge R, Treier M (December 2009). "Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation". Cell. 139 (6): 1130–42. doi:10.1016/j.cell.2009.11.021. PMID 20005806. Lay summary – Nature News.
  8. ↑ Dipietromaria A, Benayoun BA, Todeschini AL, Rivals I, Bazin C, Veitia RA (September 2009). "Towards a functional classification of pathogenic FOXL2 mutations using transactivation reporter systems". Human Molecular Genetics. 18 (17): 3324–33. doi:10.1093/hmg/ddp273. PMID 19515849.
  9. ↑ Todeschini AL, Dipietromaria A, L'hôte D, Boucham FZ, Georges AB, Pandaranayaka PJ, Krishnaswamy S, Rivals I, Bazin C, Veitia RA (September 2011). "Mutational probing of the forkhead domain of the transcription factor FOXL2 provides insights into the pathogenicity of naturally occurring mutations". Human Molecular Genetics. 20 (17): 3376–85. doi:10.1093/hmg/ddr244. PMID 21632871.
  10. ↑ Governini L, Carrarelli P, Rocha AL, Leo VD, Luddi A, Arcuri F, Piomboni P, Chapron C, Bilezikjian LM, Petraglia F (October 2014). "FOXL2 in human endometrium: hyperexpressed in endometriosis". Reproductive Sciences. 21 (10): 1249–55. doi:10.1177/1933719114522549. PMID 24520083.
  11. ↑ Jin H, Won M, Park SE, Lee S, Park M, Bae J (2016-07-14). "FOXL2 Is an Essential Activator of SF-1-Induced Transcriptional Regulation of Anti-Müllerian Hormone in Human Granulosa Cells". PLOS ONE. 11 (7): e0159112. doi:10.1371/journal.pone.0159112. PMC 4944948. PMID 27414805.
  12. ↑ Schmidt D, Ovitt CE, Anlag K, Fehsenfeld S, Gredsted L, Treier AC, Treier M (February 2004). "The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance". Development. 131 (4): 933–42. doi:10.1242/dev.00969. PMID 14736745.

Further reading

  • Vaiman D, Schibler L, Oustry-Vaiman A, Pailhoux E, Goldammer T, Stevanovic M, Furet JP, Schwerin M, Cotinot C, Fellous M, Cribiu EP (February 1999). "High-resolution human/goat comparative map of the goat polled/intersex syndrome (PIS): the human homologue is contained in a human YAC from HSA3q23". Genomics. 56 (1): 31–9. doi:10.1006/geno.1998.5691. PMID 10036183.
  • Kaestner KH, Knochel W, Martinez DE (January 2000). "Unified nomenclature for the winged helix/forkhead transcription factors". Genes & Development. 14 (2): 142–6. doi:10.1101/gad.14.2.142. PMID 10702024.
  • Crisponi L, Deiana M, Loi A, Chiappe F, Uda M, Amati P, Bisceglia L, Zelante L, Nagaraja R, Porcu S, Ristaldi MS, Marzella R, Rocchi M, Nicolino M, Lienhardt-Roussie A, Nivelon A, Verloes A, Schlessinger D, Gasparini P, Bonneau D, Cao A, Pilia G (February 2001). "The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome". Nature Genetics. 27 (2): 159–66. doi:10.1038/84781. PMID 11175783.
  • De Baere E, Dixon MJ, Small KW, Jabs EW, Leroy BP, Devriendt K, Gillerot Y, Mortier G, Meire F, Van Maldergem L, Courtens W, Hjalgrim H, Huang S, Liebaers I, Van Regemorter N, Touraine P, Praphanphoj V, Verloes A, Udar N, Yellore V, Chalukya M, Yelchits S, De Paepe A, Kuttenn F, Fellous M, Veitia R, Messiaen L (July 2001). "Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype--phenotype correlation". Human Molecular Genetics. 10 (15): 1591–600. doi:10.1093/hmg/10.15.1591. PMID 11468277.
  • Dollfus H, Kumaramanickavel G, Biswas P, Stoetzel C, Quillet R, Denton M, Maw M, Perrin-Schmitt F (July 2001). "Identification of a new TWIST mutation (7p21) with variable eyelid manifestations supports locus homogeneity of BPES at 3q22". Journal of Medical Genetics. 38 (7): 470–2. doi:10.1136/jmg.38.7.470. PMC 1757180. PMID 11474656.
  • Yamada T, Hayasaka S, Matsumoto M, Esa T, Hayasaka Y, Endo M (2002). "Heterozygous 17-bp deletion in the forkhead transcription factor gene, FOXL2, in a Japanese family with blepharophimosis-ptosis-epicanthus inversus syndrome". Journal of Human Genetics. 46 (12): 733–6. doi:10.1007/s100380170009. PMID 11776388.
  • Kosaki K, Ogata T, Kosaki R, Sato S, Matsuo N (March 2002). "A novel mutation in the FOXL2 gene in a patient with blepharophimosis syndrome: differential role of the polyalanine tract in the development of the ovary and the eyelid". Ophthalmic Genetics. 23 (1): 43–7. doi:10.1076/opge.23.1.43.2202. PMID 11910558.
  • Bell R, Murday VA, Patton MA, Jeffery S (2002). "Two families with blepharophimosis/ptosis/epicanthus inversus syndrome have mutations in the putative forkhead transcription factor FOXL2". Genetic Testing. 5 (4): 335–8. doi:10.1089/109065701753617499. PMID 11960581.
  • Harris SE, Chand AL, Winship IM, Gersak K, Aittomäki K, Shelling AN (August 2002). "Identification of novel mutations in FOXL2 associated with premature ovarian failure". Molecular Human Reproduction. 8 (8): 729–33. doi:10.1093/molehr/8.8.729. PMID 12149404.
  • De Baere E, Lemercier B, Christin-Maitre S, Durval D, Messiaen L, Fellous M, Veitia R (August 2002). "FOXL2 mutation screening in a large panel of POF patients and XX males". Journal of Medical Genetics. 39 (8): e43. doi:10.1136/jmg.39.8.e43. PMC 1735205. PMID 12161610.
  • Ramírez-Castro JL, Pineda-Trujillo N, Valencia AV, Muñetón CM, Botero O, Trujillo O, Vásquez G, Mora BE, Durango N, Bedoya G, Ruiz-Linares A (November 2002). "Mutations in FOXL2 underlying BPES (types 1 and 2) in Colombian families". American Journal of Medical Genetics. 113 (1): 47–51. doi:10.1002/ajmg.10741. PMID 12400065.
  • Cocquet J, Pailhoux E, Jaubert F, Servel N, Xia X, Pannetier M, De Baere E, Messiaen L, Cotinot C, Fellous M, Veitia RA (December 2002). "Evolution and expression of FOXL2". Journal of Medical Genetics. 39 (12): 916–21. doi:10.1136/jmg.39.12.916. PMC 1757225. PMID 12471206.
  • De Baere E, Beysen D, Oley C, Lorenz B, Cocquet J, De Sutter P, Devriendt K, Dixon M, Fellous M, Fryns JP, Garza A, Jonsrud C, Koivisto PA, Krause A, Leroy BP, Meire F, Plomp A, Van Maldergem L, De Paepe A, Veitia R, Messiaen L (February 2003). "FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation". American Journal of Human Genetics. 72 (2): 478–87. doi:10.1086/346118. PMC 379240. PMID 12529855.
  • Mazumdar A, Kumar R (January 2003). "Estrogen regulation of Pak1 and FKHR pathways in breast cancer cells". FEBS Letters. 535 (1–3): 6–10. doi:10.1016/S0014-5793(02)03846-2. PMID 12560069.
  • Fokstuen S, Antonarakis SE, Blouin JL (March 2003). "FOXL2-mutations in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES); challenges for genetic counseling in female patients". American Journal of Medical Genetics. Part A. 117A (2): 143–6. doi:10.1002/ajmg.a.10024. PMID 12567411.
  • Dollfus H, Stoetzel C, Riehm S, Lahlou Boukoffa W, Bediard Boulaneb F, Quillet R, Abu-Eid M, Speeg-Schatz C, Francfort JJ, Flament J, Veillon F, Perrin-Schmitt F (February 2003). "Sporadic and familial blepharophimosis -ptosis-epicanthus inversus syndrome: FOXL2 mutation screen and MRI study of the superior levator eyelid muscle". Clinical Genetics. 63 (2): 117–20. doi:10.1034/j.1399-0004.2003.00011.x. PMID 12630957.
  • Udar N, Yellore V, Chalukya M, Yelchits S, Silva-Garcia R, Small K (September 2003). "Comparative analysis of the FOXL2 gene and characterization of mutations in BPES patients". Human Mutation. 22 (3): 222–8. doi:10.1002/humu.10251. PMID 12938087.
  • Crisponi L, Uda M, Deiana M, Loi A, Nagaraja R, Chiappe F, Schlessinger D, Cao A, Pilia G (May 2004). "FOXL2 inactivation by a translocation 171 kb away: analysis of 500 kb of chromosome 3 for candidate long-range regulatory sequences". Genomics. 83 (5): 757–64. doi:10.1016/j.ygeno.2003.11.010. PMID 15081106.
  • L'Hôte D, Georges A, Todeschini AL, Kim JH, Benayoun BA, Bae J, Veitia RA (July 2012). "Discovery of novel protein partners of the transcription factor FOXL2 provides insights into its physiopathological roles". Human Molecular Genetics. 21 (14): 3264–74. doi:10.1093/hmg/dds170. PMID 22544055.
  • Georges A, L'Hôte D, Todeschini AL, Auguste A, Legois B, Zider A, Veitia RA (November 2014). "The transcription factor FOXL2 mobilizes estrogen signaling to maintain the identity of ovarian granulosa cells". eLife. 3. doi:10.7554/eLife.04207. PMC 4356143. PMID 25369636.
  • Elzaiat M, Todeschini AL, Caburet S, Veitia RA (February 2017). "The genetic make-up of ovarian development and function: the focus on the transcription factor FOXL2". Clinical Genetics. 91 (2): 173–182. doi:10.1111/cge.12862. PMID 27604691.

External links

Retrieved from "https://www.wikidoc.org/index.php?title=Forkhead_box_L2&oldid=1532257"