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FLASH GENE

Symbol

FOXM1

contributors: mct/pgu - updated : 16-09-2022

HGNC name	forkhead box M1
HGNC id	3818

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	12p13.33      Physical location : 2.966.849 - 2.986.303
Synonym name	M-phase phosphoprotein 2
	forkhead (Drosophila)-like 16
	trident
	transcription factor-like 16
	HNF-3/fork-head homolog 11
	hepatocyte nuclear factor 3 forkhead homolog 11
	winged-helix factor from INS-1 cells
Synonym symbol(s)	HNF3, FKHL16, FOXM1B, HFH-11, HFH11, HNF-3, INS-1, MPHOSPH2, MPP-2, MPP2, PIG29, TGT3, WIN, MPP2, PIG29, TRIDENT

DNA

TYPE	functioning gene
STRUCTURE	19.47 kb     10 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

text	at least three classes of transcripts

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_202002 10 - 3641 NP_973731 - 801 - 2007 18020943 isoform 1 NM_021953 9 - 3527 NP_068772 - 763 - 2007 18020943 cyclin/Cdk-binding LXL-motif is required for its interaction with CDK2, CDC2, and CDKN1B activated by cyclin B/Cdk (cyclin-dependent kinase) 1 FOXM1b, HFH-11B, isoform 2 NM_202003 8 - 3487 NP_973732 - 748 - 2007 18020943 interacts with the coactivator and histone acetyltransferase PCAF transactivates the c-myc promoter by binding directly to its TATA-boxes FOXM1c, isoform 3 predominantly overexpressed in oesophageal squamous cell carcinoma (ESCC) cell lines CCND1/CDK4 increases the transcriptional activity of FOXM1c without phosphorylating FOXM1c NM_001243088 8 - 3506 NP_001230017 - 748 - 2007 18020943 NM_001243089 8 - 3503 NP_001230018 - 747 - 2007 18020943

EXPRESSION

Type

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine large intestine colon     Endocrine neuroendocrine pituitary     highly Lymphoid/Immune thymus         Reproductive female system ovary     highly   female system uterus cervix   highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Lymphoid

cells

System Cell Pubmed Species Stage Rna symbol Reproductive spermatid

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo

cell cycle

cell cycle, M

Text	mesenchymal epithelial cells

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a forkhead (FH, winged helix) domain
	two loops-wings on the C terminal side of helix-turn-helix domain
	a cyclin/Cdk-binding LXL-motif

HOMOLOGY

interspecies	homolog to murine Trident
	homolog to Drosophila homeo forkhead DNA binding domain

Homologene

FAMILY

HNF-3, FKH family of transcriptional activators

CATEGORY

transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm
	intracellular,nucleus,nucleoplasm
	intracellular,nucleus,chromatin/chromosome

basic FUNCTION	important positive regulator of DNA replication and mitosis in a variety of cell types
	proliferation-associated transcription factor, stimulating proliferation by promoting both G1/S- and G2/M-transition and implicated in tumorigenesis
	embryonic transcriptional regulator, involved in cell proliferation
	critical for surfactant homeostasis and lung maturation before birth and is required for adaptation to air breathing
	has critical functions in tumor development and progression
	regulate, variously, proliferation and/or spindle formation during the G2/M transition of the cell cycle
	functions in SHH-induced neuroproliferation are restricted to the regulation of the G2/M transition in cerebellar granule neuron precursors, most probably through transcriptional effects on target genes such as those coding for B-type cyclins
	a typical proliferation-associated transcription factor that stimulates proliferation by promoting S-phase entry as well as M-phase entry and is involved in proper execution of mitosis
	regulates genes that control G1/S-transition, S-phase progression, G2/M-transition and M-phase progression
	having two different transactivation mechanisms, the regulation of its transcriptional activity by proliferation versus anti-proliferation signals and its function in normal cell cycle progression and tumorigenesis
	key regulator of oxidative stress that contributes to malignant transformation and tumor cell survival
	transcriptionally active during a DNA-damage-induced G2 arrest and is essential for checkpoint recovery
	critical involvement in maintenance of stem cell pluripotency
	in cancer cells the interaction between FOXM1 and NPM1 is necessary for sustaining the level and localization of FOXM1 and it may be required for cancer progression
	expression of FOXM1 in macrophages is required for pulmonary inflammation, recruitment of macrophages into tumor sites and lung tumor growth
	is required for KRAS signaling in distal lung epithelium and provides a mechanism integrating Kras and canonical WNT/CTNNB1 signaling during lung development
	is required for differentiation and maintenance of epithelial cells lining conducting airways.
	regulates genes critical for allergen-induced lung inflammation and goblet cell metaplasia
	is a critical regulator of the G1/S and G2/M cell cycle transitions, as well as of the mitotic spindle assembly
	FOXM1 controls the cell cycle through its association with CDC25A
	is required for lung fibrosis and epithelial-to-mesenchymal transition
	promoted EMT in breast cancer cells by stimulating the transcription of EMT-related genes such as SNAI2
	strongly activates promoters of G2/M phase genes and weakly activates those induced in S phase
	is an essential effector of G2/M-phase transition, mitosis and the DNA damage response
	function for FOXM1 in interkinetic nuclear migration in the developing telencephalon and anxiety-related behavior
	FZR1-FOXM1-APC axis functions as a key regulator of muscle development and regeneration

CELLULAR PROCESS

nucleotide, transcription

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

FOXM1-LDHA signaling functioned as a stimulator of glycolysis and promoted Gastric cancer progression

a component

INTERACTION

DNA

binding

RNA

small molecule

protein	direct transcriptional activator of SFTPA, SFTPB
	AKT1 and FOXM1 are downstream targets of NOTCH1 signaling
	NPM1 interacts with FOXM1 and their interaction is required for sustaining the level and localization of FOXM1
	MYBL2 is required as a pioneer factor to enable FOXM1 binding to G2/M gene promoters
	FOXM1 transcription factor is a key downstream target of activated KRAS(G12D)
	FOXM1 directly bound to and increased transcriptional activity of the AXIN2 promoter region
	its downregulation is required for contact inhibition by regulating expression of cyclin A and polo-like kinase 1
	binds and regulates a group of genes which are mainly involved in controlling late cell cycle events in the G(2) and M phases
	FOXM1 directly regulates CDC25A gene transcription via direct promoter binding and indirect activation of E2F-dependent pathways
	endogenously bind to and stimulate the promoter of SNAI2 that is crucial for EMT progression
	bound to cell cycle-regulated genes with peak expression in both S phase and G2/M phases
	KLF1 binds to the FOXM1 gene promoter in blood cells
	is a direct target gene of MEIS2 and is required for MEIS2 to upregulate mitotic genes
	IRF1 is a transcriptional target of FOXM1c and a FOXM1c-binding site is in the IRF1 promoter region
	partnering role of EPS8 with FOXM1 in the regulation of cancer cell proliferation
	FOXM1, a master regulator of cell division, binds directly to the promoter region of PSMB4 and regulates the PSMB4 expression in the mRNA level
	MELK enhances tumorigenesis, migration, invasion and metastasis of Esophageal squamous cell carcinoma (ESCC) cells via activation of FOXM1 signaling pathway

cell & other

REGULATION

activated by

Cdk activity which is required for activation of FOXM1

induced by

RAS, requiring reactive oxygene species

inhibited by

DACH1 (DACH1 displaced FOXM1 from the known target gene promoters including CDC25B, Survivin, CENPA, and CENPB)

repressed by

TP53

Other	reactivated in proliferating epithelial and mesenchymal cells by proliferative signals or oxidative stress
	is dynamically modified by SUMO1 but not by SUMO2/3 at multiple sites, and SUMOylation attenuates FOXM1 activity and causes mitotic delay in cytotoxic drug response

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional   deletion     from respiratory epithelium did not influence branching lung morphogenesis or epithelial proliferation, but impaired lung sacculation, delayed type I cell differentiation, and reduced expression of surfactant-associated proteins, causing respiratory failure after birth tumoral     --over   overexpressed in OCSCC tumoral     --over   overexpression of FOXM1, XIAP, and BIRC5 contributes to the development of drug-resistance and is associated with poor clinical outcome in breast cancer patients

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed respiratory lung   provide novel strategies for diagnosis, prevention, and treatment of respiratory distress syndrome in preterm infants cancer hemopathy   curcumin together with FOXM1 targeting agents may be effective for acute myeloid leukemia therapy cancer     targeting FOXM1 increases apoptosis and inhibits tumor growth cancer reproductive uterus FOXM1-PSMB4 axis could be a potential target for the treatment of cervical cancer

ANIMAL & CELL MODELS