Biology:FOXM1

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Short description: Protein-coding gene in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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] and brain.[15]

Isoforms

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.[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.[16]

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.[17]

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.[18]

Role in epigenome regulations

Given the role in progenitor/stem cells expansion,[18] FOXM1 has been shown to modulate the epigenome. It was found that overexpression of FOXM1 "brain washes" normal cells to adopt cancer-like epigenome.[19] 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.[19]

Interactions

FOXM1 has been shown to interact with Cdh1.[20]

See also

References

  1. ↑ 1.0 1.1 "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. March 1997. doi:10.1128/MCB.17.3.1626. PMID 9032290. 
  2. ↑ "The human TRIDENT/HFH-11/FKHL16 gene: structure, localization, and promoter characterization". Genomics 46 (3): 435–42. December 1997. doi:10.1006/geno.1997.5065. PMID 9441747. 
  3. ↑ "Entrez Gene: FOXM1 forkhead box M1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2305. 
  4. ↑ Vincent Shen. "2010 Molecule of the Year". BioTechniques. http://www.biotechniques.com/news/2010-Molecule-of-the-Year/biotechniques-311295.html. Retrieved 18 February 2011. 
  5. ↑ 5.0 5.1 "FOXM1, a typical proliferation-associated transcription factor". Biol. Chem. 388 (12): 1257–74. December 2007. doi:10.1515/BC.2007.159. PMID 18020943. 
  6. ↑ "FoxM1 is required for execution of the mitotic programme and chromosome stability". Nat. Cell Biol. 7 (2): 126–36. February 2005. doi:10.1038/ncb1217. PMID 15654331. 
  7. ↑ "The emerging roles of forkhead box (Fox) proteins in cancer". Nat. Rev. Cancer 7 (11): 847–59. November 2007. doi:10.1038/nrc2223. PMID 17943136. 
  8. ↑ "FOXM1 is a downstream target of Gli1 in basal cell carcinomas". Cancer Res. 62 (16): 4773–80. 15 August 2002. PMID 12183437. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12183437. 
  9. ↑ "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. April 2004. doi:10.1101/gad.1200704. PMID 15082532. 
  10. ↑ "Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe". Cancer Res. 65 (12): 5181–9. June 2005. doi:10.1158/0008-5472.CAN-04-4059. PMID 15958562. 
  11. ↑ "The Forkhead Box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer". Cancer Res. 66 (4): 2153–61. February 2006. doi:10.1158/0008-5472.CAN-05-3003. PMID 16489016. 
  12. ↑ "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. February 2006. doi:10.1158/0008-5472.CAN-05-3138. PMID 16452231. 
  13. ↑ "Over-expression of FOXM1 transcription factor is associated with cervical cancer progression and pathogenesis". J. Pathol. 215 (3): 245–52. July 2008. doi:10.1002/path.2355. PMID 18464245. 
  14. ↑ "Sonic Hedgehog-dependent proliferation in a series of patients with colorectal cancer". Surgery 139 (5): 665–70. May 2006. doi:10.1016/j.surg.2005.10.012. PMID 16701100. 
  15. ↑ "FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells". Cancer Res. 66 (7): 3593–602. April 2006. doi:10.1158/0008-5472.CAN-05-2912. PMID 16585184. 
  16. ↑ "Upregulation of FOXM1 induces genomic instability in human epidermal keratinocytes". Mol. Cancer 9: 45. 2010. doi:10.1186/1476-4598-9-45. PMID 20187950. 
  17. ↑ Jin, Dong-Yan, ed (2009). "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. PMID 19287496. Bibcode: 2009PLoSO...4.4849G. 
  18. ↑ 18.0 18.1 "Induction of human epithelial stem/progenitor expansion by FOXM1". Cancer Res. 70 (22): 9515–26. 2010. doi:10.1158/0008-5472.CAN-10-2173. PMID 21062979. 
  19. ↑ 19.0 19.1 "FOXM1 induces a global methylation signature that mimics the cancer epigenome in head and neck squamous cell carcinoma". PLOS ONE 7 (3): e34329. 2012. doi:10.1371/journal.pone.0034329. PMID 22461910. Bibcode: 2012PLoSO...734329T. 
  20. ↑ "FoxM1 is degraded at mitotic exit in a Cdh1-dependent manner". Cell Cycle 7 (17): 2720–6. Sep 2008. doi:10.4161/cc.7.17.6580. PMID 18758239. 

External links

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




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