FOXM1
Encyclopedia
Forkhead box protein M1 is a protein
that in humans is encoded by the FOXM1 gene
. The protein
encoded by this gene is a member of the FOX
family of transcription factor
s. FOXM1 has been awarded the Molecule of the Year 2010 for its growing potential as a target for cancer diagnosis and therapies.
progression where endogenous FOXM1 expression peaks at S and G2/M phases. FOXM1-null mouse embryos were neonatal lethal as a result of the development of polyploid
cardiomyocyte
s and hepatocyte
s, highlighting the role of FOXM1 in mitotic division
. More recently a study using transgenic
/knockout mouse
embryonic fibroblast
s 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.
, the most common human cancer worldwide. FOXM1 upregulation was subsequently found in the majority of solid human cancers including liver, breast, lung, prostate, cervix of uterus, colon, pancreas, and brain.
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.
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.
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
.
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.
with CDH1
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the FOXM1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. The protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
encoded by this gene is a member of the FOX
FOX proteins
FOX proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity...
family of transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s. FOXM1 has been awarded the Molecule of the Year 2010 for its growing potential as a target for cancer diagnosis and therapies.
Function
FOXM1 is known to play a key role in cell cycleCell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
progression where endogenous FOXM1 expression peaks at S and G2/M phases. FOXM1-null mouse embryos were neonatal lethal as a result of the development of polyploid
Polyploidy
Polyploid is a term used to describe cells and organisms containing more than two paired sets of chromosomes. Most eukaryotic species are diploid, meaning they have two sets of chromosomes — one set inherited from each parent. However polyploidy is found in some organisms and is especially common...
cardiomyocyte
Cardiac muscle
Cardiac muscle is a type of involuntary striated muscle found in the walls and histologic foundation of the heart, specifically the myocardium. Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle...
s and hepatocyte
Hepatocyte
A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...
s, highlighting the role of FOXM1 in mitotic division
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
. More recently a study using transgenic
Genetically modified organism
A genetically modified organism or genetically engineered organism is an organism whose genetic material has been altered using genetic engineering techniques. These techniques, generally known as recombinant DNA technology, use DNA molecules from different sources, which are combined into one...
/knockout mouse
Knockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...
embryonic fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
s and human osteosarcoma
Osteosarcoma
Osteosarcoma is an aggressive cancerous neoplasm arising from primitive transformed cells of mesenchymal origin that exhibit osteoblastic differentiation and produce malignant osteoid...
cells (U2OS) has shown that FOXM1, regulates expression of a large array of G2/M-specific genes, such as Plk1
PLK1
Serine/threonine-protein kinase PLK1, also known as polo-like kinase 1 or serine/threonine-protein kinase 13 , is an enzyme that in humans is encoded by the PLK1 gene.- Structure :...
, cyclin B2
Cyclin B2
G2/mitotic-specific cyclin-B2 is a protein that in humans is encoded by the CCNB2 gene.-Interactions:Cyclin B2 has been shown to interact with TGF beta receptor 2.-Further reading:...
, Nek2
NEK2
Serine/threonine-protein kinase Nek2 is an enzyme that in humans is encoded by the NEK2 gene.-Interactions:NEK2 has been shown to interact with MAPK1 and NDC80.-Further reading:...
and CENPF
CENPF
Centromere protein F is a protein that in humans is encoded by the CENPF gene.-Further reading:...
, and plays an important role in maintenance of chromosomal segregation
Chromosome segregation
Chromosome segregation is a step in cell reproduction or division, where chromosomes pair off with their similar homologous chromosome. In mitosis, a complete copy of each one is made. In meiosis, one chromosome from each pair migrates to opposite ends of the cell and the genes are split to make a...
and genomic stability.
Cancer link
FOXM1 gene is now known as a human proto-oncogene. Abnormal upregulation of FOXM1 is involved in the oncogenesis of basal cell carcinomaBasal cell carcinoma
Basal-cell carcinoma is the most common type of skin cancer. It rarely metastasizes or kills. However, because it can cause significant destruction and disfigurement by invading surrounding tissues, it is still considered malignant. Statistically, approximately 3 out of 10 Caucasians may develop a...
, the most common human cancer worldwide. FOXM1 upregulation was subsequently found in the majority of solid human cancers including liver, breast, lung, prostate, cervix of uterus, colon, pancreas, and brain.
There are three FOXM1 isoforms
Protein isoform
A protein isoform is any of several different forms of the same protein. Different forms of a protein may be produced from related genes, or may arise from the same gene by alternative splicing. A large number of isoforms are caused by single-nucleotide polymorphisms or SNPs, small genetic...
, A, B and C. Isoform FOXM1A has been shown to be a gene transcriptional
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
repressor
Repressor
In molecular genetics, a repressor is a DNA-binding protein that regulates the expression of one or more genes by binding to the operator and blocking the attachment of RNA polymerase to the promoter, thus preventing transcription of the genes. This blocking of expression is called...
whereas the remaining isoforms (B and C) are both transcriptional activators
Activator (genetics)
An activator is a DNA-binding protein that regulates one or more genes by increasing the rate of transcription. The activator may increase transcription by virtue of a connected domain which assists in the formation of the RNA polymerase holoenzyme, or may operate through a coactivator. A...
. Hence, it is not surprising that FOXM1B and C isoforms have been found to be upregulated in human cancers.
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.
FOXM1 overexpression is involved in early events of carcinogenesis
Carcinogenesis
Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...
in head and neck squamous cell carcinoma
Squamous cell carcinoma
Squamous cell carcinoma , occasionally rendered as "squamous-cell carcinoma", is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of malignant cells deriving from epithelium, or showing particular cytological or tissue architectural characteristics of...
. It has been shown that nicotine
Nicotine
Nicotine is an alkaloid found in the nightshade family of plants that constitutes approximately 0.6–3.0% of the dry weight of tobacco, with biosynthesis taking place in the roots and accumulation occurring in the leaves...
exposure directly activates FOXM1 activity in human oral keratinocytes and induced malignant transformation
Malignant transformation
Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor....
.
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.
Interactions
FOXM1 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with CDH1
CDH1 (gene)
Cadherin-1 also known as CAM 120/80 or epithelial cadherin or uvomorulin is a protein that in humans is encoded by the CDH1 gene. CDH1 has also been designated as CD324 . It is a tumor suppressor gene.- Function :Cadherin-1 is a classical member of the cadherin superfamily...
.