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 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]
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]
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. [9]
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]
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]
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. [23] 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]
FOXproteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity. Many FOX proteins are important to embryonic development. FOX proteins also have pioneering transcription activity by being able to bind condensed chromatin during cell differentiation processes.
Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene.
Forkhead box protein P1 is a protein that in humans is encoded by the FOXP1 gene. FOXP1 is necessary for the proper development of the brain, heart, and lung in mammals. It is a member of the large FOX family of transcription factors.
High-mobility group AT-hook 2, also known as HMGA2, is a protein that, in humans, is encoded by the HMGA2 gene.
Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein encoded by the FOXO3 gene.
Cysteine-rich angiogenic inducer 61 (CYR61) or CCN family member 1 (CCN1), is a matricellular protein that in humans is encoded by the CYR61 gene.
PRKC apoptosis WT1 regulator protein, or Prostate apoptosis response-4, is a tumor-suppressor protein coded for in the human by the PAWR gene, that induces apoptosis in cancer cells, but not in normal cells.
The basal-like carcinoma is a recently proposed subtype of breast cancer defined by its gene expression and protein expression profile.
NK2 homeobox 1 (NKX2-1), also known as thyroid transcription factor 1 (TTF-1), is a protein which in humans is encoded by the NKX2-1 gene.
Epithelial cell adhesion molecule (EpCAM), also known as CD326 among other names, is a transmembrane glycoprotein mediating Ca2+-independent homotypic cell–cell adhesion in epithelia. EpCAM is also involved in cell signaling, migration, proliferation, and differentiation. Additionally, EpCAM has oncogenic potential via its capacity to upregulate c-myc, e-fabp, and cyclins A & E. Since EpCAM is expressed exclusively in epithelia and epithelial-derived neoplasms, EpCAM can be used as diagnostic marker for various cancers. It appears to play a role in tumorigenesis and metastasis of carcinomas, so it can also act as a potential prognostic marker and as a potential target for immunotherapeutic strategies.
Forkhead box protein O4 is a protein that in humans is encoded by the FOXO4 gene.
Breast cancer metastasis suppressor 1 is a protein that in humans is encoded by the BRMS1 gene.
Forkhead box protein N3 is a protein that in humans is encoded by the FOXN3 gene.
Homeobox protein Hox-C10 is a protein that in humans is encoded by the HOXC10 gene.
Transcription factor AP-2 gamma also known as AP2-gamma is a protein that in humans is encoded by the TFAP2C gene. AP2-gamma is a member of the activating protein 2 family of transcription factors.
Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the FOXO1 gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glycogenolysis by insulin signaling, and is also central to the decision for a preadipocyte to commit to adipogenesis. It is primarily regulated through phosphorylation on multiple residues; its transcriptional activity is dependent on its phosphorylation state.
Forkhead box protein A2 (FOXA2), also known as hepatocyte nuclear factor 3-beta (HNF-3B), is a transcription factor that plays an important role during development, in mature tissues and, when dysregulated or mutated, also in cancer.
In molecular biology, miR-137 is a short non-coding RNA molecule that functions to regulate the expression levels of other genes by various mechanisms. miR-137 is located on human chromosome 1p22 and has been implicated to act as a tumor suppressor in several cancer types including colorectal cancer, squamous cell carcinoma and melanoma via cell cycle control.
In molecular biology mir-708 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms. miR-708 is located on chromosome 11q14.1 and is endcoded in intron 1 of the ODZ4 gene. It is most highly expressed in the brain and eyes, and has a supposed role in endoplasmic reticular stress of the eye.
Migration inducting gene 7 is a gene that corresponds to a cysteine-rich protein localized to the cell membrane and cytoplasm. It is the first-in-class of novel proteins translated from what are thought to be long Non-coding RNAs.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
