FOXM1 (forkhead box M1)

Identity

Other names	FKHL16
	FOXM1B
	HFH-11
	HFH11
	HNF-3
	INS-1
	MPHOSPH2
	MPP-2
	MPP2
	PIG29
	TGT3
	TRIDENT
HGNC	FOXM1
Location	12p13

DNA/RNA

Description	The gene spans 25 kb and contains 10 exons.
Transcription	3.4-3.6 kb mRNA; Differential splicing of exons Va (A1) and VIIa (A2) gives rise to 3 classes of transcripts, which encode 3 different protein isoforms: FoxM1A, containing both alternative exons; FoxM1B, containing none of the alternative exons and FoxM1C, containing only exon Va.

Protein

	hFoxM1C

Description	FoxM1 belongs to a large family of forkhead transcription factors. FoxM1 protein contains 3 main regions: the N-terminal Repressor Domain (NRD). This region is followed by a conserved DNA Binding Domain called Forkhead or winged-helix domain (FKH). The C-terminal region harbors the Transcativation Domain (TAD) with several activating Cyclin-Cdk-dependent phosphorylation sites.
Expression	FoxM1 is specifically expressed in proliferating cells. Expression is negatively regulated in quiescent or terminally-differentiated cells. Both expression and transcriptional activity of FoxM1 are tightly regulated during the cell cycle. Increase in FoxM1 expression levels is initiated at the onset of S-phase and continues throughout G2-phase and Mitosis. During G1 phase, FoxM1 activity is inhibited through several mechanisms, including interaction with the cell cycle inhibitory pocket protein pRb, and through inhibition by the N-terminal auto-repressor domain of FoxM1 itself. The cell cycle-inhibitory p19ARF can also bind the C-terminal transactivation domain of FoxM1 and inactivate its transcriptional activity by targeting FoxM1 protein to the nucleolus. Transcriptional activation of FoxM1 correlates with increased phosphorylation of the protein. It occurs specifically during G2-phase of the cell cycle through direct phosphorylation of the C-terminal transactivation domain (TAD) mediated by G2-Cyclin-dependent kinases (Cdks). Cyclin-Cdk-dependent phosphorylation of the C-terminal region of FoxM1 is required to relieve auto-inhibition exerted by the N-terminal repressor domain (NRD). In addition, Cdk-dependent phosphorylation of the C-terminal TAD serves to recruit transcriptional co-activators such as the histone deacetylase p300/CREB binding protein (p300/CBP). FoxM1 transcriptional activity also requires the presence of appropriate mitogenic signals involving the Raf/MEK/MAPK signaling pathway.
Localisation	Nuclear, but can be detected in the cytoplasm upon inhibition of Raf/MEK/MAPK signaling. FoxM1 can also be targeted to the nucleolus by p19ARF.
Function	FoxM1 acts as a transcriptional activator of the G2-M-specific gene cluster in mammalian cells.
Homology	Homology with other Forkhead transcription factors in the FKH DNA Binding Domain.

Implicated in

Entity	Cancer
Disease	FoxM1 is commonly upregulated in human aggressive carcinomas originating from prostate, breast, lung, ovary, colon, pancreas, stomach, bladder, liver and kidney. FoxM1 promotes tumor progression of prostate carcinomas and lung adenocarcinomas. FoxM1 expression and activity are significantly elevated in basal cell carcinoma (BCC) skin tumors and FoxM1 expression in malignant gliomas correlates with disease staging. FoxM1 contributes to cellular transformation by the high-risk human papillomavirus-16 (HPV-16) E7 protein. Conditional deletion of the FoxM1 gene in mice reduces proliferation of lung tumors and renders hepatocytes resistant to tumor development. Down-regulation of FoxM1 reduces the invasiveness of glioma cells and decreases cell migration and cell invasion in pancreatic cancer cells.
Cytogenetics	Amplifications of the 12p13 chromosomal band, comprising the FoxM1 gene, have been reported in numerous tumors such as cervical squamous cell carcinomas, breast adenocarcinomas, nasopharyngeal carcinomas and head and neck squamous cell carcinomas.
Entity	Ageing
Disease	FoxM1 expression is affected (low) in cells from patients with progeria and FoxM1-deficient cells senesce prematurely. Inversely, increased levels of FoxM1B in regenerating liver of old transgenic mice elevate hepatocyte proliferation to levels similar to those observed in young regenerating mouse liver.

External links

	Nomenclature
HGNC	FOXM1   3818
Entrez_Gene	FOXM1  2305  forkhead box M1
	Cards
Atlas	FOXM1ID40631ch12p13
GeneCards	FOXM1
Ensembl	FOXM1 [Search_View]   ENSG00000111206 [Gene_View]
Genatlas	FOXM1
GeneLynx	FOXM1
eGenome	FOXM1
euGene	2305
	Genomic and cartography
GoldenPath	FOXM1  -  12p13   chr12:2837110-2856564 -  12p13   [Description]    (hg18-Mar_2006)
Ensembl	FOXM1 - 12p13 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	FOXM1
	Gene and transcription
Genbank	AK291206 [ ENTREZ ]
Genbank	AK313845 [ ENTREZ ]
Genbank	AY542306 [ ENTREZ ]
Genbank	BC006192 [ ENTREZ ]
Genbank	BC006529 [ ENTREZ ]
RefSeq	NM_021953 [ SRS ]    NM_021953 [ ENTREZ ]
RefSeq	NM_202002 [ SRS ]    NM_202002 [ ENTREZ ]
RefSeq	NM_202003 [ SRS ]    NM_202003 [ ENTREZ ]
RefSeq	AC_000055 [ SRS ]    AC_000055 [ ENTREZ ]
RefSeq	AC_000144 [ SRS ]    AC_000144 [ ENTREZ ]
RefSeq	NC_000012 [ SRS ]    NC_000012 [ ENTREZ ]
RefSeq	NT_009759 [ SRS ]    NT_009759 [ ENTREZ ]
RefSeq	NW_001838049 [ SRS ]    NW_001838049 [ ENTREZ ]
RefSeq	NW_925295 [ SRS ]    NW_925295 [ ENTREZ ]
AceView	FOXM1 AceView - NCBI
Unigene	Hs.239 [ SRS ]    Hs.239 [ NCBI ]     HS239 [ spliceNest ]
Fast-db	519 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	Q08050 [ SRS]    Q08050 [ EXPASY ]     Q08050 [ INTERPRO ]     Q08050 [ UNIPROT ]
Prosite	PS00657 FORK_HEAD_1 [ SRS ]    PS00657 FORK_HEAD_1 [ Expasy ]
Prosite	PS00658 FORK_HEAD_2 [ SRS ]    PS00658 FORK_HEAD_2 [ Expasy ]
Prosite	PS50039 FORK_HEAD_3 [ SRS ]    PS50039 FORK_HEAD_3 [ Expasy ]
Interpro	IPR001766 TF_Fork_head [ SRS ]    IPR001766 TF_Fork_head [ EBI ]
Interpro	IPR011991 Wing_hlx_DNA_bd [ SRS ]    IPR011991 Wing_hlx_DNA_bd [ EBI ]
CluSTr	Q08050
Pfam	PF00250 Fork_head [ SRS ]    PF00250 Fork_head [ Sanger ]    pfam00250 [ NCBI-CDD ]
Smart	SM00339 FH [EMBL]
Prodom	PD000425 TF_Fork_head[INRA-Toulouse]
Prodom	Q08050 FOXM1_HUMAN [ Domain structure ]   Q08050 FOXM1_HUMAN  [ sequences sharing at least 1 domain ]
Blocks	Q08050
HPRD	03823
	Protein Interaction databases
DIP	Q08050
IntAct	Q08050
	Polymorphism : SNP, mutations, diseases
OMIM	602341    [ map ]
GENECLINICS	602341
SNP	FOXM1 [dbSNP-NCBI]
SNP	NM_021953 [SNP-NCI]
SNP	NM_202002 [SNP-NCI]
SNP	NM_202003 [SNP-NCI]
SNP	FOXM1 [GeneSNPs - Utah]  FOXM1] [HGBASE - SRS]
HAPMAP	FOXM1 [HAPMAP]
COSMIC	FOXM1 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	FOXM1
	General knowledge
Family Browser	FOXM1 [UCSC Family Browser]
SOURCE	NM_021953
SOURCE	NM_202002
SOURCE	NM_202003
SMD	Hs.239
SAGE	Hs.239
GO	transcription factor activity [Amigo]  transcription factor activity
GO	protein binding [Amigo]  protein binding
GO	nucleus [Amigo]  nucleus
GO	transcription [Amigo]  transcription
GO	regulation of transcription, DNA-dependent [Amigo]  regulation of transcription, DNA-dependent
GO	sequence-specific DNA binding [Amigo]  sequence-specific DNA binding
PubGene	FOXM1
TreeFam	FOXM1
CTD	2305 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	FOXM1 Related clones (RZPD - Berlin)
	PubMed
PubMed	30 Pubmed reference(s) in LocusLink

Bibliography

The winged-helix transcription factor Trident is expressed in cycling cells.

Korver W, Roose J, Clevers H

Nucleic acids research. 1997 ; 25 (9) : 1715-1719.

PMID 9108152

The human TRIDENT/HFH-11/FKHL16 gene: structure, localization, and promoter characterization.

Korver W, Roose J, Heinen K, Weghuis DO, de Bruijn D, van Kessel AG, Clevers H

Genomics. 1997 ; 46 (3) : 435-442.

PMID 9441747

Hepatocyte nuclear factor 3/fork head homolog 11 is expressed in proliferating epithelial and mesenchymal cells of embryonic and adult tissues.

Ye H, Kelly TF, Samadani U, Lim L, Rubio S, Overdier DG, Roebuck KA, Costa RH

Molecular and cellular biology. 1997 ; 17 (3) : 1626-1641.

PMID 9032290

Interaction of the fork head domain transcription factor MPP2 with the human papilloma virus 16 E7 protein: enhancement of transformation and transactivation.

Lˆºscher-Firzlaff JM, Westendorf JM, Zwicker J, Burkhardt H, Henriksson M, Mˆºller R, Pirollet F, Lˆºscher B

Oncogene. 1999 ; 18 (41) : 5620-5630.

PMID 10523841

Mitotic misregulation and human aging.

Ly DH, Lockhart DJ, Lerner RA, Schultz PG

Science (New York, N.Y.). 2000 ; 287 (5462) : 2486-2492.

PMID 10741968

Increased levels of forkhead box M1B transcription factor in transgenic mouse hepatocytes prevent age-related proliferation defects in regenerating liver.

Wang X, Quail E, Hung NJ, Tan Y, Ye H, Costa RH

Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (20) : 11468-11473.

PMID 11572993

FOXM1 is a downstream target of Gli1 in basal cell carcinomas.

Teh MT, Wong ST, Neill GW, Ghali LR, Philpott MP, Quinn AG

Cancer research. 2002 ; 62 (16) : 4773-4780.

PMID 12183437

Increased hepatic Forkhead Box M1B (FoxM1B) levels in old-aged mice stimulated liver regeneration through diminished p27Kip1 protein levels and increased Cdc25B expression.

Wang X, Krupczak-Hollis K, Tan Y, Dennewitz MB, Adami GR, Costa RH

The Journal of biological chemistry. 2002 ; 277 (46) : 44310-44316.

PMID 12221098

Growth hormone stimulates proliferation of old-aged regenerating liver through forkhead box m1b.

Krupczak-Hollis K, Wang X, Dennewitz MB, Costa RH

Hepatology (Baltimore, Md.). 2003 ; 38 (6) : 1552-1562.

PMID 14647066

Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor.

Kalinichenko VV, Major ML, Wang X, Petrovic V, Kuechle J, Yoder HM, Dennewitz MB, Shin B, Datta A, Raychaudhuri P, Costa RH

Genes & development. 2004 ; 18 (7) : 830-850.

PMID 15082532

Forkhead box M1B transcriptional activity requires binding of Cdk-cyclin complexes for phosphorylation-dependent recruitment of p300/CBP coactivators.

Major ML, Lepe R, Costa RH

Molecular and cellular biology. 2004 ; 24 (7) : 2649-2661.

PMID 15024056

Identification and validation of commonly overexpressed genes in solid tumors by comparison of microarray data.

Pilarsky C, Wenzig M, Specht T, Saeger HD, Grˆºtzmann R

Neoplasia (New York, N.Y.). 2004 ; 6 (6) : 744-750.

PMID 15720800

FoxM1 is required for execution of the mitotic programme and chromosome stability.

Laoukili J, Kooistra MR, Brˆ°s A, Kauw J, Kerkhoven RM, Morrison A, Clevers H, Medema RH

Nature cell biology. 2005 ; 7 (2) : 126-136.

PMID 15654331

Raf/MEK/MAPK signaling stimulates the nuclear translocation and transactivating activity of FOXM1c.

Ma RY, Tong TH, Cheung AM, Tsang AC, Leung WY, Yao KM

Journal of cell science. 2005 ; 118 (Pt 4) : 795-806.

PMID 15671063

Conventional and array-based comparative genomic hybridization analysis of nasopharyngeal carcinomas from the Mediterranean area.

Rodriguez S, Khabir A, Keryer C, Perrot C, Drira M, Ghorbel A, Jlidi R, Bernheim A, Valent A, Busson P

Cancer genetics and cytogenetics. 2005 ; 157 (2) : 140-147.

PMID 15721635

Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase.

Wang IC, Chen YJ, Hughes D, Petrovic V, Major ML, Park HJ, Tan Y, Ackerson T, Costa RH

Molecular and cellular biology. 2005 ; 25 (24) : 10875-10894.

PMID 16314512

Increased levels of the FoxM1 transcription factor accelerate development and progression of prostate carcinomas in both TRAMP and LADY transgenic mice.

Kalin TV, Wang IC, Ackerson TJ, Major ML, Detrisac CJ, Kalinichenko VV, Lyubimov A, Costa RH

Cancer research. 2006 ; 66 (3) : 1712-1720.

PMID 16452231

The Forkhead Box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer.

Kim IM, Ackerson T, Ramakrishna S, Tretiakova M, Wang IC, Kalin TV, Major ML, Gusarova GA, Yoder HM, Costa RH, Kalinichenko VV

Cancer research. 2006 ; 66 (4) : 2153-2161.

PMID 16489016

FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells.

Liu M, Dai B, Kang SH, Ban K, Huang FJ, Lang FF, Aldape KD, Xie TX, Pelloski CE, Xie K, Sawaya R, Huang S

Cancer research. 2006 ; 66 (7) : 3593-3602.

PMID 16585184

Despite its strong transactivation domain, transcription factor FOXM1c is kept almost inactive by two different inhibitory domains.

Wierstra I, Alves J

Biological chemistry. 2006 ; 387 (7) : 963-976.

PMID 16913846

FoxM1: at the crossroads of ageing and cancer.

Laoukili J, Stahl M, Medema RH

Biochimica et biophysica acta. 2007 ; 1775 (1) : 92-102.

PMID 17014965

An N-terminal inhibitory domain modulates activity of FoxM1 during cell cycle.

Park HJ, Wang Z, Costa RH, Tyner A, Lau LF, Raychaudhuri P

Oncogene. 2008 ; 27 (12) : 1696-1704.

PMID 17891172

Chk2 mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes.

Tan Y, Raychaudhuri P, Costa RH

Molecular and cellular biology. 2007 ; 27 (3) : 1007-1016.

PMID 17101782

Down-regulation of Forkhead Box M1 transcription factor leads to the inhibition of invasion and angiogenesis of pancreatic cancer cells.

Wang Z, Banerjee S, Kong D, Li Y, Sarkar FH

Cancer research. 2007 ; 67 (17) : 8293-8300.

PMID 17804744

FOXM1, a typical proliferation-associated transcription factor.

Wierstra I, Alves J

Biological chemistry. 2007 ; 388 (12) : 1257-1274.

PMID 18020943

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

Search in all EBI   NCBI

Contributor(s)

Written	02-2008	Jamila Laoukili, Monica Alvarez Fernandez, René H Medema
		Department of Human Genetics, Academic Medical Center, Amsterdam, The Netherlands (JL); Department of Medical Oncology, University Medical Center Utrecht, The Netherlands (MAF, RHM)

Citation

This paper should be referenced as such :

Laoukili J, Alvarez Fernandez M, Medema RH . FOXM1 (forkhead box M1). Atlas Genet Cytogenet Oncol Haematol. February 2008 . URL : http://AtlasGeneticsOncology.org/Genes/FOXM1ID40631ch12p13.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Aug 11 21:13:59 2008