FOXM1

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]

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
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12p13.33 Start 2,857,681 bp[1] End 2,877,155 bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6 F3|6 62.98 cM Start 128,362,967 bp[2] End 128,376,146 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • DNA binding • sequence-specific DNA binding • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • GO:0001948 protein binding • protein kinase binding • RNA polymerase II regulatory region sequence-specific DNA binding • GO:0001078, GO:0001214, GO:0001206 DNA-binding transcription repressor activity, RNA polymerase II-specific • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component • cell nucleus • nucleoplasm Biological process • positive regulation of double-strand break repair • negative regulation of cell aging • regulation of Ras protein signal transduction • negative regulation of transcription from RNA polymerase II promoter • regulation of reactive oxygen species metabolic process • transcription from RNA polymerase II promoter • transcription, DNA-templated • regulation of cell cycle • cellular response to DNA damage stimulus • regulation of cell proliferation • G2/M transition of mitotic cell cycle • regulation of cell growth • positive regulation of cell proliferation • negative regulation of stress-activated MAPK cascade • negative regulation of transcription, DNA-templated • regulation of cell cycle arrest • DNA repair • positive regulation of transcription from RNA polymerase II promoter • 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
Entrez	2305	14235
Ensembl	ENSG00000111206	ENSMUSG00000001517
UniProt	Q08050	O08696
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: 128.36 – 128.38 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

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

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

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.[9]

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.[20]

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.[21]

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.[22]

Role in epigenome regulations

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. 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

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

See also

• FOX proteins

References

1. GRCh38: Ensembl release 89: ENSG00000111206 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000001517 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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.
6. 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.
7. "Entrez Gene: FOXM1 forkhead box M1".
8. Vincent Shen. "2010 Molecule of the Year". BioTechniques. Archived from the original on 24 July 2011. Retrieved 18 February 2011.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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 (2009). Jin D (ed.). "FOXM1 upregulation is an early event in human squamous cell carcinoma and it is enhanced by nicotine during malignant transformation". PLoS ONE. 4 (3): e4849. doi:10.1371/journal.pone.0004849. PMC 2654098. PMID 19287496.
22. Gemenetzidis E, Elena-Costea D, Parkinson EK, Waseem A, Wan H, Teh MT (2010). "Induction of human epithelial stem/progenitor expansion by FOXM1". Cancer Res. 70 (22): 9515–26. doi:10.1158/0008-5472.CAN-10-2173. PMC 3044465. PMID 21062979.
23. 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.
24. Laoukili J, Alvarez-Fernandez M, Stahl M, Medema RH (September 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.

External links

• FOXM1+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.