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{{Infobox_gene}}
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'''Forkhead box protein M1''' is a [[protein]] that in humans is encoded by the ''FOXM1'' [[gene]].<ref name="pmid9032290">{{cite journal | vauthors = Ye H, Kelly TF, Samadani U, Lim L, Rubio S, Overdier DG, Roebuck KA, Costa RH | title = Hepatocyte nuclear factor 3/fork head homolog 11 is expressed in proliferating epithelial and mesenchymal cells of embryonic and adult tissues | journal = Mol. Cell. Biol. | volume = 17 | issue = 3 | pages = 1626–41  | date = March 1997 | pmid = 9032290 | pmc = 231888 | doi =  }}</ref><ref name="pmid9441747">{{cite journal | vauthors = Korver W, Roose J, Heinen K, Weghuis DO, de Bruijn D, van Kessel AG, Clevers H | title = The human TRIDENT/HFH-11/FKHL16 gene: structure, localization, and promoter characterization | journal = Genomics | volume = 46 | issue = 3 | pages = 435–42 | date = December 1997 | pmid = 9441747 | pmc =  | doi = 10.1006/geno.1997.5065 | hdl = 2066/25040 }}</ref> The [[protein]] encoded by this gene is a member of the [[FOX proteins|FOX]] family of [[transcription factor]]s.<ref name="pmid9032290" /><ref name="entrez">{{cite web | title = Entrez Gene: FOXM1 forkhead box M1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2305| accessdate = }}</ref> Its potential as a target for future cancer treatments led to it being designated the 2010 [[Molecule of the Year]].<ref>{{cite journal |author=Vincent Shen | title = 2010 Molecule of the Year | journal = BioTechniques | url = http://www.biotechniques.com/news/2010-Molecule-of-the-Year/biotechniques-311295.html }}</ref>
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = Forkhead box M1
| HGNCid = 3818
| Symbol = FOXM1
| AltSymbols =; FKHL16; FOXM1B; HFH-11; HFH11; HNF-3; INS-1; MPHOSPH2; MPP-2; MPP2; PIG29; TRIDENT
| OMIM = 602341
| ECnumber = 
| Homologene = 7318
| MGIid = 1347487
| GeneAtlas_image1 = PBB_GE_FOXM1_202580_x_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:0043565 |text = sequence-specific DNA binding}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}}
| Process = {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 2305
    | Hs_Ensembl = ENSG00000111206
    | Hs_RefseqProtein = NP_068772
    | Hs_RefseqmRNA = NM_021953
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 12
    | Hs_GenLoc_start = 2837113
    | Hs_GenLoc_end = 2856564
    | Hs_Uniprot = Q08050
    | Mm_EntrezGene = 14235
    | Mm_Ensembl = ENSMUSG00000001517
    | Mm_RefseqmRNA = NM_008021
    | Mm_RefseqProtein = NP_032047
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 6
    | Mm_GenLoc_start = 128328595
    | Mm_GenLoc_end = 128350607
    | Mm_Uniprot = Q6DI64
  }}
}}
'''Forkhead box M1''', also known as '''FOXM1''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: FOXM1 forkhead box M1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2305| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
FOXM1 is known to play a key role in [[cell cycle]] progression where endogenous FOXM1 expression peaks at [[cell cycle#S Phase|S]] and [[cell cycle#G2 phase|G2/M]] phases.<ref name="pmid18020943">{{cite journal | vauthors = Wierstra I, Alves J | title = FOXM1, a typical proliferation-associated transcription factor | journal = Biol. Chem. | volume = 388 | issue = 12 | pages = 1257–74 | date = December 2007 | pmid = 18020943 | doi = 10.1515/BC.2007.159 }}</ref> FOXM1-null mouse embryos were neonatal lethal as a result of the development of [[polyploidy|polyploid]] [[cardiac muscle|cardiomyocyte]]s and [[hepatocyte]]s, highlighting the role of FOXM1 in [[mitosis|mitotic division]]. More recently a study using [[genetically modified organism|transgenic]]/[[knockout mouse]] embryonic [[fibroblast]]s and human [[osteosarcoma]] cells (U2OS) has shown that FOXM1 regulates expression of a large array of G2/M-specific genes, such as [[PLK1|Plk1]], [[cyclin B2]], [[NEK2|Nek2]] and [[CENPF]], and plays an important role in maintenance of [[chromosome segregation|chromosomal segregation]] and genomic stability.<ref>{{cite journal | vauthors = Laoukili J, Kooistra MR, Brás A, Kauw J, Kerkhoven RM, Morrison A, Clevers H, Medema RH | title = FoxM1 is required for execution of the mitotic programme and chromosome stability | journal = Nat. Cell Biol. | volume = 7 | issue = 2 | pages = 126–36  | date = February 2005 | pmid = 15654331 | doi = 10.1038/ncb1217 }}</ref>
{{PBB_Summary
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| summary_text =  
}}


==See also==
== Cancer link ==
 
FOXM1 gene is now known as a human [[oncogene#Proto-oncogene|proto-oncogene]].<ref name="pmid17943136">{{cite journal | vauthors = Myatt SS, Lam EW | title = The emerging roles of forkhead box (Fox) proteins in cancer | journal = Nat. Rev. Cancer | volume = 7 | issue = 11 | pages = 847–59  | date = November 2007 | pmid = 17943136 | doi = 10.1038/nrc2223 }}</ref> Abnormal upregulation of FOXM1 is involved in the oncogenesis of [[basal cell carcinoma]], the most common human cancer worldwide.<ref name="pmid12183437">{{cite journal | vauthors = Teh MT, Wong ST, Neill GW, Ghali LR, Philpott MP, Quinn AG | title = FOXM1 is a downstream target of Gli1 in basal cell carcinomas | journal = Cancer Res. | volume = 62 | issue = 16 | pages = 4773–80  | date = 15 August 2002 | pmid = 12183437 | url = http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12183437 }}</ref> FOXM1 upregulation was subsequently found in the majority of solid human cancers including liver,<ref name="pmid15082532">{{cite journal | vauthors = Kalinichenko VV, Major ML, Wang X, Petrovic V, Kuechle J, Yoder HM, Dennewitz MB, Shin B, Datta A, Raychaudhuri P, Costa RH | title = Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor | journal = Genes Dev. | volume = 18 | issue = 7 | pages = 830–50  | date = April 2004 | pmid = 15082532 | pmc = 387422 | doi = 10.1101/gad.1200704 }}</ref> breast,<ref name="pmid15958562">{{cite journal | vauthors = Wonsey DR, Follettie MT | title = Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe | journal = Cancer Res. | volume = 65 | issue = 12 | pages = 5181–9  | date = June 2005 | pmid = 15958562 | doi = 10.1158/0008-5472.CAN-04-4059 }}</ref> lung,<ref name="pmid16489016">{{cite journal | vauthors = Kim IM, Ackerson T, Ramakrishna S, Tretiakova M, Wang IC, Kalin TV, Major ML, Gusarova GA, Yoder HM, Costa RH, Kalinichenko VV | title = The Forkhead Box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer | journal = Cancer Res. | volume = 66 | issue = 4 | pages = 2153–61  | date = February 2006 | pmid = 16489016 | doi = 10.1158/0008-5472.CAN-05-3003 }}</ref> prostate,<ref name="pmid16452231">{{cite journal | vauthors = Kalin TV, Wang IC, Ackerson TJ, Major ML, Detrisac CJ, Kalinichenko VV, Lyubimov A, Costa RH | title = Increased levels of the FoxM1 transcription factor accelerate development and progression of prostate carcinomas in both TRAMP and LADY transgenic mice | journal = Cancer Res. | volume = 66 | issue = 3 | pages = 1712–20  | date = February 2006 | pmid = 16452231 | pmc = 1363687 | doi = 10.1158/0008-5472.CAN-05-3138 }}</ref> cervix of uterus,<ref name="pmid18464245">{{cite journal | vauthors = Chan DW, Yu SY, Chiu PM, Yao KM, Liu VW, Cheung AN, Ngan HY | title = Over-expression of FOXM1 transcription factor is associated with cervical cancer progression and pathogenesis | journal = J. Pathol. | volume = 215 | issue = 3 | pages = 245–52  | date = July 2008 | pmid = 18464245 | doi = 10.1002/path.2355 }}</ref> colon,<ref name="pmid16701100">{{cite journal | vauthors = Douard R, Moutereau S, Pernet P, Chimingqi M, Allory Y, Manivet P, Conti M, Vaubourdolle M, Cugnenc PH, Loric S | title = Sonic Hedgehog-dependent proliferation in a series of patients with colorectal cancer | journal = Surgery | volume = 139 | issue = 5 | pages = 665–70  | date = May 2006 | pmid = 16701100 | doi = 10.1016/j.surg.2005.10.012 }}</ref> pancreas,<ref name="pmid17804744">{{cite journal | vauthors = Wang Z, Banerjee S, Kong D, Li Y, Sarkar FH | title = Down-regulation of Forkhead Box M1 transcription factor leads to the inhibition of invasion and angiogenesis of pancreatic cancer cells | journal = Cancer Res. | volume = 67 | issue = 17 | pages = 8293–300  | date = September 2007 | pmid = 17804744 | doi = 10.1158/0008-5472.CAN-07-1265 }}</ref> and brain.<ref name="pmid16585184">{{cite journal | vauthors = Liu M, Dai B, Kang SH, Ban K, Huang FJ, Lang FF, Aldape KD, Xie TX, Pelloski CE, Xie K, Sawaya R, Huang S | title = FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells | journal = Cancer Res. | volume = 66 | issue = 7 | pages = 3593–602  | date = April 2006 | pmid = 16585184 | doi = 10.1158/0008-5472.CAN-05-2912 | citeseerx = 10.1.1.321.4506 }}</ref>
 
== Isoforms ==
 
There are three FOXM1 [[protein isoform|isoforms]], A, B and C. Isoform FOXM1A has been shown to be a gene [[Transcription (genetics)|transcriptional]] [[repressor]] whereas the remaining isoforms (B and C) are both transcriptional [[activator (genetics)|activators]]. Hence, it is not surprising that FOXM1B and C isoforms have been found to be upregulated in human cancers.<ref name="pmid18020943"/>
 
== Mechanism of oncogenesis ==
 
The exact mechanism of FOXM1 in cancer formation remains unknown. It is thought that upregulation of FOXM1 promotes oncogenesis through abnormal impact on its multiple roles in cell cycle and chromosomal/genomic maintenance. Aberrant upregulation of FOXM1 in primary human skin keratinocytes can directly induce genomic instability in the form of loss of heterozygosity (LOH) and copy number aberrations.<ref name="TEH_2010">{{cite journal | vauthors = Teh MT, Gemenetzidis E, Chaplin T, Young BD, Philpott MP | title = Upregulation of FOXM1 induces genomic instability in human epidermal keratinocytes | journal = Mol. Cancer | volume = 9 | issue =  | pages = 45 | year = 2010 | pmid = 20187950 | pmc = 2907729 | doi = 10.1186/1476-4598-9-45 }}</ref>
 
FOXM1 overexpression is involved in early events of [[carcinogenesis]] in [[head and neck]] [[squamous cell carcinoma]]. It has been shown that [[nicotine]] exposure directly activates FOXM1 activity in human oral [[keratinocytes]] and induced [[malignant transformation]].<ref name="pmid19287496">{{cite journal | vauthors = Gemenetzidis E, Bose A, Riaz AM, Chaplin T, Young BD, Ali M, Sugden D, Thurlow JK, Cheong SC, Teo SH, Wan H, Waseem A, Parkinson EK, Fortune F, Teh MT | title = FOXM1 upregulation is an early event in human squamous cell carcinoma and it is enhanced by nicotine during malignant transformation | journal = PLoS ONE | volume = 4 | issue = 3 | pages = e4849 | year = 2009 | pmid = 19287496 | pmc = 2654098 | doi = 10.1371/journal.pone.0004849 | editor1-last = Jin | editor1-first = Dong-Yan }}</ref>
 
== Role in stem cell fate ==
 
A recent report by the research group which first found that the over-expression of FOXM1 is associated with human cancer, showed that aberrant upregulation of FOXM1 in adult human epithelial stem cells induces a precancer phenotype in a 3D-organotypic tissue regeneration system - a condition similar to human hyperplasia. The authors showed that excessive expression of FOXM1 exploits the inherent self-renewal proliferation potential of stem cells by interfering with the differentiation pathway, thereby expanding the progenitor cell compartment. It was therefore hypothesized that FOXM1 induces cancer initiation through stem/progenitor cell expansion.<ref name="pmid21062979">{{cite journal | vauthors = Gemenetzidis E, Elena-Costea D, Parkinson EK, Waseem A, Wan H, Teh MT | title = Induction of human epithelial stem/progenitor expansion by FOXM1 | journal = Cancer Res. | volume = 70 | issue = 22 | pages = 9515–26 | year = 2010 | pmid = 21062979 | pmc = 3044465 | doi = 10.1158/0008-5472.CAN-10-2173 | url = http://cancerres.aacrjournals.org/content/early/2010/11/04/0008-5472.CAN-10-2173.abstract }}</ref>
 
== Role in epigenome regulations ==
 
Given the role in progenitor/stem cells expansion,<ref name="pmid21062979"/> FOXM1 has been shown to modulate the [[epigenome]]. It was found that overexpression of FOXM1 "brain washes" normal cells to adopt cancer-like [[epigenome]]. A number of new [[epigenetic biomarkers]] influenced by FOXM1 were identified from the study and these were thought to represent [[epigenetic]] signature of early cancer development which has potential for early cancer diagnosis and prognosis.<ref name="pmid22461910">{{cite journal | vauthors = Teh MT, Gemenetzidis E, Patel D, Tariq R, Nadir A, Bahta AW, Waseem A, Hutchison IL | title = FOXM1 induces a global methylation signature that mimics the cancer epigenome in head and neck squamous cell carcinoma | journal = PLoS ONE | volume = 7 | issue = 3 | pages = e34329 | year = 2012 | pmid = 22461910 | pmc = 3312909 | doi = 10.1371/journal.pone.0034329 }}</ref>
 
== Interactions ==
 
FOXM1 has been shown to [[Protein-protein interaction|interact]] with [[FZR1 (gene)|Cdh1]].<ref name=pmid18758239>{{cite journal | vauthors = Laoukili J, Alvarez-Fernandez M, Stahl M, Medema RH | title = FoxM1 is degraded at mitotic exit in a Cdh1-dependent manner | journal = Cell Cycle | volume = 7 | issue = 17 | pages = 2720–6  | date = Sep 2008 | pmid = 18758239 | doi = 10.4161/cc.7.17.6580 }}</ref>
 
== See also ==
* [[FOX proteins]]
* [[FOX proteins]]


==References==
== References ==
{{reflist|2}}
{{Reflist|2}}
 
==Further reading==
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal  | author=Laoukili J, Stahl M, Medema RH |title=FoxM1: at the crossroads of ageing and cancer. |journal=Biochim. Biophys. Acta |volume=1775 |issue= 1 |pages= 92-102 |year= 2007 |pmid= 17014965 |doi= 10.1016/j.bbcan.2006.08.006 }}
*{{cite journal  | author=Westendorf JM, Rao PN, Gerace L |title=Cloning of cDNAs for M-phase phosphoproteins recognized by the MPM2 monoclonal antibody and determination of the phosphorylated epitope. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=91 |issue= 2 |pages= 714-8 |year= 1994 |pmid= 8290587 |doi=  }}
*{{cite journal  | author=Ye H, Kelly TF, Samadani U, ''et al.'' |title=Hepatocyte nuclear factor 3/fork head homolog 11 is expressed in proliferating epithelial and mesenchymal cells of embryonic and adult tissues. |journal=Mol. Cell. Biol. |volume=17 |issue= 3 |pages= 1626-41 |year= 1997 |pmid= 9032290 |doi=  }}
*{{cite journal  | author=Yao KM, Sha M, Lu Z, Wong GG |title=Molecular analysis of a novel winged helix protein, WIN. Expression pattern, DNA binding property, and alternative splicing within the DNA binding domain. |journal=J. Biol. Chem. |volume=272 |issue= 32 |pages= 19827-36 |year= 1997 |pmid= 9242644 |doi=  }}
*{{cite journal  | author=Korver W, Roose J, Heinen K, ''et al.'' |title=The human TRIDENT/HFH-11/FKHL16 gene: structure, localization, and promoter characterization. |journal=Genomics |volume=46 |issue= 3 |pages= 435-42 |year= 1998 |pmid= 9441747 |doi= 10.1006/geno.1997.5065 }}
*{{cite journal  | author=Lüscher-Firzlaff JM, Westendorf JM, Zwicker J, ''et al.'' |title=Interaction of the fork head domain transcription factor MPP2 with the human papilloma virus 16 E7 protein: enhancement of transformation and transactivation. |journal=Oncogene |volume=18 |issue= 41 |pages= 5620-30 |year= 1999 |pmid= 10523841 |doi= 10.1038/sj.onc.1202967 }}
*{{cite journal  | author=Waris G, Siddiqui A |title=Interaction between STAT-3 and HNF-3 leads to the activation of liver-specific hepatitis B virus enhancer 1 function. |journal=J. Virol. |volume=76 |issue= 6 |pages= 2721-9 |year= 2002 |pmid= 11861839 |doi=  }}
*{{cite journal  | author=Teh MT, Wong ST, Neill GW, ''et al.'' |title=FOXM1 is a downstream target of Gli1 in basal cell carcinomas. |journal=Cancer Res. |volume=62 |issue= 16 |pages= 4773-80 |year= 2002 |pmid= 12183437 |doi=  }}
*{{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  | author=Wang X, Bhattacharyya D, Dennewitz MB, ''et al.'' |title=Rapid hepatocyte nuclear translocation of the Forkhead Box M1B (FoxM1B) transcription factor caused a transient increase in size of regenerating transgenic hepatocytes. |journal=Gene Expr. |volume=11 |issue= 3-4 |pages= 149-62 |year= 2004 |pmid= 14686788 |doi=  }}
*{{cite journal  | author=Major ML, Lepe R, Costa RH |title=Forkhead box M1B transcriptional activity requires binding of Cdk-cyclin complexes for phosphorylation-dependent recruitment of p300/CBP coactivators. |journal=Mol. Cell. Biol. |volume=24 |issue= 7 |pages= 2649-61 |year= 2004 |pmid= 15024056 |doi=  }}
*{{cite journal  | author=Beausoleil SA, Jedrychowski M, Schwartz D, ''et al.'' |title=Large-scale characterization of HeLa cell nuclear phosphoproteins. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue= 33 |pages= 12130-5 |year= 2004 |pmid= 15302935 |doi= 10.1073/pnas.0404720101 }}
*{{cite journal  | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
*{{cite journal  | author=Laoukili J, Kooistra MR, Brás A, ''et al.'' |title=FoxM1 is required for execution of the mitotic programme and chromosome stability. |journal=Nat. Cell Biol. |volume=7 |issue= 2 |pages= 126-36 |year= 2005 |pmid= 15654331 |doi= 10.1038/ncb1217 }}
*{{cite journal  | author=Wonsey DR, Follettie MT |title=Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe. |journal=Cancer Res. |volume=65 |issue= 12 |pages= 5181-9 |year= 2005 |pmid= 15958562 |doi= 10.1158/0008-5472.CAN-04-4059 }}
*{{cite journal  | author=Wang IC, Chen YJ, Hughes D, ''et al.'' |title=Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase. |journal=Mol. Cell. Biol. |volume=25 |issue= 24 |pages= 10875-94 |year= 2006 |pmid= 16314512 |doi= 10.1128/MCB.25.24.10875-10894.2005 }}
*{{cite journal  | author=Kim IM, Ackerson T, Ramakrishna S, ''et al.'' |title=The Forkhead Box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer. |journal=Cancer Res. |volume=66 |issue= 4 |pages= 2153-61 |year= 2006 |pmid= 16489016 |doi= 10.1158/0008-5472.CAN-05-3003 }}
*{{cite journal  | author=Lüscher-Firzlaff JM, Lilischkis R, Lüscher B |title=Regulation of the transcription factor FOXM1c by Cyclin E/CDK2. |journal=FEBS Lett. |volume=580 |issue= 7 |pages= 1716-22 |year= 2006 |pmid= 16504183 |doi= 10.1016/j.febslet.2006.02.021 }}
*{{cite journal  | author=Liu M, Dai B, Kang SH, ''et al.'' |title=FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells. |journal=Cancer Res. |volume=66 |issue= 7 |pages= 3593-602 |year= 2006 |pmid= 16585184 |doi= 10.1158/0008-5472.CAN-05-2912 }}
*{{cite journal  | author=Douard R, Moutereau S, Pernet P, ''et al.'' |title=Sonic Hedgehog-dependent proliferation in a series of patients with colorectal cancer. |journal=Surgery |volume=139 |issue= 5 |pages= 665-70 |year= 2006 |pmid= 16701100 |doi= 10.1016/j.surg.2005.10.012 }}
}}
{{refend}}


== External links ==
== External links ==
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{{NLM content}}
{{NLM content}}
{{protein-stub}}
 
{{Transcription factors}}
{{Transcription factors|g3}}
[[Category:Transcription factors]]
 
{{WikiDoc Sources}}
{{DEFAULTSORT:Foxm1}}
[[Category:Forkhead transcription factors]]

Latest revision as of 05:55, 7 December 2018

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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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Wikidata
View/Edit Human

Forkhead box protein M1 is a protein that in humans is encoded by the FOXM1 gene.[1][2] The protein encoded by this gene is a member of the FOX family of transcription factors.[1][3] Its potential as a target for future cancer treatments led to it being designated the 2010 Molecule of the Year.[4]

Function

FOXM1 is known to play a key role in cell cycle progression where endogenous FOXM1 expression peaks at S and G2/M phases.[5] FOXM1-null mouse embryos were neonatal lethal as a result of the development of polyploid cardiomyocytes and hepatocytes, highlighting the role of FOXM1 in mitotic division. More recently a study using transgenic/knockout mouse embryonic fibroblasts and human osteosarcoma cells (U2OS) has shown that FOXM1 regulates expression of a large array of G2/M-specific genes, such as Plk1, cyclin B2, Nek2 and CENPF, and plays an important role in maintenance of chromosomal segregation and genomic stability.[6]

Cancer link

FOXM1 gene is now known as a human proto-oncogene.[7] Abnormal upregulation of FOXM1 is involved in the oncogenesis of basal cell carcinoma, the most common human cancer worldwide.[8] FOXM1 upregulation was subsequently found in the majority of solid human cancers including liver,[9] breast,[10] lung,[11] prostate,[12] cervix of uterus,[13] colon,[14] pancreas,[15] and brain.[16]

Isoforms

There are three FOXM1 isoforms, A, B and C. Isoform FOXM1A has been shown to be a gene transcriptional repressor whereas the remaining isoforms (B and C) are both transcriptional activators. Hence, it is not surprising that FOXM1B and C isoforms have been found to be upregulated in human cancers.[5]

Mechanism of oncogenesis

The exact mechanism of FOXM1 in cancer formation remains unknown. It is thought that upregulation of FOXM1 promotes oncogenesis through abnormal impact on its multiple roles in cell cycle and chromosomal/genomic maintenance. Aberrant upregulation of FOXM1 in primary human skin keratinocytes can directly induce genomic instability in the form of loss of heterozygosity (LOH) and copy number aberrations.[17]

FOXM1 overexpression is involved in early events of carcinogenesis in head and neck squamous cell carcinoma. It has been shown that nicotine exposure directly activates FOXM1 activity in human oral keratinocytes and induced malignant transformation.[18]

Role in stem cell fate

A recent report by the research group which first found that the over-expression of FOXM1 is associated with human cancer, showed that aberrant upregulation of FOXM1 in adult human epithelial stem cells induces a precancer phenotype in a 3D-organotypic tissue regeneration system - a condition similar to human hyperplasia. The authors showed that excessive expression of FOXM1 exploits the inherent self-renewal proliferation potential of stem cells by interfering with the differentiation pathway, thereby expanding the progenitor cell compartment. It was therefore hypothesized that FOXM1 induces cancer initiation through stem/progenitor cell expansion.[19]

Role in epigenome regulations

Given the role in progenitor/stem cells expansion,[19] FOXM1 has been shown to modulate the epigenome. It was found that overexpression of FOXM1 "brain washes" normal cells to adopt cancer-like epigenome. A number of new epigenetic biomarkers influenced by FOXM1 were identified from the study and these were thought to represent epigenetic signature of early cancer development which has potential for early cancer diagnosis and prognosis.[20]

Interactions

FOXM1 has been shown to interact with Cdh1.[21]

See also

References

  1. ↑ 1.0 1.1 Ye H, Kelly TF, Samadani U, Lim L, Rubio S, Overdier DG, Roebuck KA, Costa RH (March 1997). "Hepatocyte nuclear factor 3/fork head homolog 11 is expressed in proliferating epithelial and mesenchymal cells of embryonic and adult tissues". Mol. Cell. Biol. 17 (3): 1626–41. PMC 231888. PMID 9032290.
  2. ↑ Korver W, Roose J, Heinen K, Weghuis DO, de Bruijn D, van Kessel AG, Clevers H (December 1997). "The human TRIDENT/HFH-11/FKHL16 gene: structure, localization, and promoter characterization". Genomics. 46 (3): 435–42. doi:10.1006/geno.1997.5065. hdl:2066/25040. PMID 9441747.
  3. ↑ "Entrez Gene: FOXM1 forkhead box M1".
  4. ↑ Vincent Shen. "2010 Molecule of the Year". BioTechniques.
  5. ↑ 5.0 5.1 Wierstra I, Alves J (December 2007). "FOXM1, a typical proliferation-associated transcription factor". Biol. Chem. 388 (12): 1257–74. doi:10.1515/BC.2007.159. PMID 18020943.
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  10. ↑ Wonsey DR, Follettie MT (June 2005). "Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe". Cancer Res. 65 (12): 5181–9. doi:10.1158/0008-5472.CAN-04-4059. PMID 15958562.
  11. ↑ Kim IM, Ackerson T, Ramakrishna S, Tretiakova M, Wang IC, Kalin TV, Major ML, Gusarova GA, Yoder HM, Costa RH, Kalinichenko VV (February 2006). "The Forkhead Box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer". Cancer Res. 66 (4): 2153–61. doi:10.1158/0008-5472.CAN-05-3003. PMID 16489016.
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  14. ↑ Douard R, Moutereau S, Pernet P, Chimingqi M, Allory Y, Manivet P, Conti M, Vaubourdolle M, Cugnenc PH, Loric S (May 2006). "Sonic Hedgehog-dependent proliferation in a series of patients with colorectal cancer". Surgery. 139 (5): 665–70. doi:10.1016/j.surg.2005.10.012. PMID 16701100.
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  16. ↑ Liu M, Dai B, Kang SH, Ban K, Huang FJ, Lang FF, Aldape KD, Xie TX, Pelloski CE, Xie K, Sawaya R, Huang S (April 2006). "FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells". Cancer Res. 66 (7): 3593–602. CiteSeerX 10.1.1.321.4506. doi:10.1158/0008-5472.CAN-05-2912. PMID 16585184.
  17. ↑ Teh MT, Gemenetzidis E, Chaplin T, Young BD, Philpott MP (2010). "Upregulation of FOXM1 induces genomic instability in human epidermal keratinocytes". Mol. Cancer. 9: 45. doi:10.1186/1476-4598-9-45. PMC 2907729. PMID 20187950.
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  20. ↑ Teh MT, Gemenetzidis E, Patel D, Tariq R, Nadir A, Bahta AW, Waseem A, Hutchison IL (2012). "FOXM1 induces a global methylation signature that mimics the cancer epigenome in head and neck squamous cell carcinoma". PLoS ONE. 7 (3): e34329. doi:10.1371/journal.pone.0034329. PMC 3312909. PMID 22461910.
  21. ↑ Laoukili J, Alvarez-Fernandez M, Stahl M, Medema RH (Sep 2008). "FoxM1 is degraded at mitotic exit in a Cdh1-dependent manner". Cell Cycle. 7 (17): 2720–6. doi:10.4161/cc.7.17.6580. PMID 18758239.

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