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(Top) 1 Function 2 Cancer link 3 Isoforms 4 Mechanism of oncogenesis 5 Role in stem cell fate 6 Role in epigenome regulations 7 Interactions 8 See also 9 References 10 External links

FOXM1

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FOXM1

Available structures

PDB

Ortholog search: PDBe RCSB

List of PDB id codes

3G73

Identifiers

Aliases

FOXM1, FKHL16, FOXM1B, HFH-11, HFH11, HNF-3, INS-1, MPHOSPH2, MPP-2, MPP2, PIG29, TGT3, TRIDENT, forkhead box M1, FOXM1A, FOXM1C

External IDs

OMIM: 602341; MGI: 1347487; HomoloGene: 7318; GeneCards: FOXM1; OMA:FOXM1 - orthologs

Gene location (Human)

Chr.

Chromosome 12 (human)^[1]

Band

12p13.33

Start

2,857,680 bp^[1]

End

2,877,174 bp^[1]

Gene location (Mouse)

Chr.

Chromosome 6 (mouse)^[2]

Band

6 F3|6 62.98 cM

Start

128,339,930 bp^[2]

End

128,353,109 bp^[2]

RNA expression pattern

Bgee

Human

Mouse (ortholog)

Top expressed in

ventricular zone

ganglionic eminence

gonad

sperm

mucosa of transverse colon

left testis

stromal cell of endometrium

right testis

testicle

rectum

Top expressed in

genital tubercle

tail of embryo

ventricular zone

secondary oocyte

zygote

otic vesicle

primary oocyte

otic placode

yolk sac

seminiferous tubule

More reference expression data

BioGPS

More reference expression data

Gene ontology

Molecular function

DNA binding

sequence-specific DNA binding

DNA-binding transcription factor activity

protein binding

protein kinase binding

RNA polymerase II transcription regulatory region sequence-specific DNA binding

DNA-binding transcription repressor activity, RNA polymerase II-specific

DNA-binding transcription factor activity, RNA polymerase II-specific

Cellular component

nucleus

nucleoplasm

Biological process

positive regulation of double-strand break repair

regulation of Ras protein signal transduction

negative regulation of transcription by RNA polymerase II

regulation of reactive oxygen species metabolic process

transcription by RNA polymerase II

transcription, DNA-templated

regulation of cell cycle

cellular response to DNA damage stimulus

regulation of cell population proliferation

G2/M transition of mitotic cell cycle

regulation of cell growth

positive regulation of cell population proliferation

negative regulation of stress-activated MAPK cascade

negative regulation of transcription, DNA-templated

DNA repair

positive regulation of transcription by RNA polymerase II

DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator

regulation of transcription, DNA-templated

anatomical structure morphogenesis

cell differentiation

cell cycle

positive regulation of transcription, DNA-templated

Sources:Amigo / QuickGO

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

NM_001243088
NM_001243089
NM_021953
NM_202002
NM_202003

NM_008021

RefSeq (protein)

NP_001230017
NP_001230018
NP_068772
NP_973731
NP_973732

n/a

Location (UCSC)

Chr 12: 2.86 – 2.88 Mb

Chr 6: 128.34 – 128.35 Mb

PubMed search

^[3]

^[4]

Wikidata

View/Edit Human

View/Edit Mouse

Forkhead box protein M1 is a protein that in humans is encoded by the FOXM1 gene.^[5]^[6] The protein encoded by this gene is a member of the FOX family of transcription factors.^[5]^[7] Its potential as a target for future cancer treatments led to it being designated the 2010 Molecule of the Year.^[8]

Function[edit]

FOXM1 is known to play a key role in cell cycle progression where endogenous FOXM1 expression peaks at S and G2/M phases.^[9] 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.^[10]

Cancer link[edit]

FOXM1 gene is now known as a human proto-oncogene.^[11] Abnormal upregulation of FOXM1 is involved in the oncogenesis of basal cell carcinoma, the most common human cancer worldwide.^[12] FOXM1 upregulation was subsequently found in the majority of solid human cancers including liver,^[13] breast,^[14] lung,^[15] prostate,^[16] cervix of uterus,^[17] colon,^[18] and brain.^[19]

Isoforms[edit]

There are three FOXM1 isoforms in humans, 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.^[9]

Mechanism of oncogenesis[edit]

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.^[20]

FOXM1 overexpression is involved in early events of carcinogenesisinhead and neck squamous cell carcinoma. It has been shown that nicotine exposure directly activates FOXM1 activity in human oral keratinocytes and induced malignant transformation.^[21]

Role in stem cell fate[edit]

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.^[22]

Role in epigenome regulations[edit]

Given the role in progenitor/stem cells expansion,^[22] FOXM1 has been shown to modulate the epigenome. It was found that overexpression of FOXM1 "brain washes" normal cells to adopt cancer-like epigenome.^[23] 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.^[23]

Interactions[edit]

FOXM1 has been shown to interact with Cdh1.^[24]

References[edit]

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000111206 – Ensembl, May 2017

^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000001517 – Ensembl, May 2017

^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

^ ^a ^b 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. doi:10.1128/MCB.17.3.1626. PMC 231888. PMID 9032290.

^ 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. S2CID 25093788.

^ "Entrez Gene: FOXM1 forkhead box M1".

^ Vincent Shen. "2010 Molecule of the Year". BioTechniques. Archived from the original on 24 July 2011. Retrieved 18 February 2011.

^ ^a ^b 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. S2CID 19721737.

^ Laoukili J, Kooistra MR, Brás A, Kauw J, Kerkhoven RM, Morrison A, Clevers H, Medema RH (February 2005). "FoxM1 is required for execution of the mitotic programme and chromosome stability". Nat. Cell Biol. 7 (2): 126–36. doi:10.1038/ncb1217. PMID 15654331. S2CID 11732068.

^ Myatt SS, Lam EW (November 2007). "The emerging roles of forkhead box (Fox) proteins in cancer". Nat. Rev. Cancer. 7 (11): 847–59. doi:10.1038/nrc2223. PMID 17943136. S2CID 1330189.

^ Teh MT, Wong ST, Neill GW, Ghali LR, Philpott MP, Quinn AG (15 August 2002). "FOXM1 is a downstream target of Gli1 in basal cell carcinomas". Cancer Res. 62 (16): 4773–80. PMID 12183437.

^ Kalinichenko VV, Major ML, Wang X, Petrovic V, Kuechle J, Yoder HM, Dennewitz MB, Shin B, Datta A, Raychaudhuri P, Costa RH (April 2004). "Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor". Genes Dev. 18 (7): 830–50. doi:10.1101/gad.1200704. PMC 387422. PMID 15082532.

^ 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.

^ 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.

^ Kalin TV, Wang IC, Ackerson TJ, Major ML, Detrisac CJ, Kalinichenko VV, Lyubimov A, Costa RH (February 2006). "Increased levels of the FoxM1 transcription factor accelerate development and progression of prostate carcinomas in both TRAMP and LADY transgenic mice". Cancer Res. 66 (3): 1712–20. doi:10.1158/0008-5472.CAN-05-3138. PMC 1363687. PMID 16452231.

^ Chan DW, Yu SY, Chiu PM, Yao KM, Liu VW, Cheung AN, Ngan HY (July 2008). "Over-expression of FOXM1 transcription factor is associated with cervical cancer progression and pathogenesis". J. Pathol. 215 (3): 245–52. doi:10.1002/path.2355. PMID 18464245. S2CID 30137454.

^ 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.

^ 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.