Forkhead box genes

Forkhead box genes characterize a specific DNA section (forkhead box) that can be detected in many genes. The DNA domain of the Fox proteins has hardly changed during evolution. Therefore, the nucleotide sequences of the genes coding for this domain have remained the same and the corresponding gene section is referred to as a forkhead box.

All genes with this nucleotide sequence belong to the family of forkhead box genes (FOX genes). The proteins encoded by these gene segments are called Fox proteins and are important transcription factors. Fox proteins regulate proliferation, differentiation and the lifespan of cells. In addition, they play an important role in embryonic development.

The Fox proteins are divided into subclasses from Fox-A to Fox-R (analogous to the coding genes).

Fox-P3 is a protein that is important for the generation and function of regulatory T cells. In humans, Fox-P3 is highly specific for CD4+/CD25+ T cells. In the nucleus of regulatory T cells (Tregs), it ensures that those genes are read that are essential for the function of these cells. Other T cells, which may be pathogen-specific or self-reactive, generally do not possess this transcription factor. Therefore, the protein Fox-p3 can also be used as a "marker" to distinguish regulatory from normal T cells.

Fox O1 is a protein that serves as a central switch in insulin regulation and glucose and lipid metabolism. FoxO1 inhibits key transcription factors of lipid synthesis. Furthermore, Fox O1 inhibits the androgen receptor. FoxO1 is inhibited in sebocytes by insulin-like-growth-factor 1 (IGF-1) IGF-1 (Mirdamadi Y et al. 2015). In acne, this regulatory circuit ultimately leads to an induction of sebocytic lipogenesis.

FOXN1 is a DNA-binding transcription factor that has a significant impact on the regulation of keratin expression. This transcription factor regulates the development, differentiation, and function of thymic epithelial cells (TECs) in both prenatal and postnatal thymus. FOXN1 acts as a master regulator in the development of the TEC lineage. It regulates the differentiation of immature TECs into functional cortical TECs (cTECs) and medullary TECs (mTECs). FOXN1-associated diseases include:

T-cell immunodeficiency with congenital alopecia and nail dystrophy (TINAD) (autosomal recessive primary immunodeficiency/ congenital thymic aplasia and a severe T-cell immunodeficiency ).

T-cell lymphopenia infantile with or without nail dystrophy (TLIND) (T-cell immunodeficiency, congenital alopecia and nail dystrophy and T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant/OMIM: 618806).

In spinocellular carcinoma of the skin, various genes are switched off by promoter hypermethylation, such as the FOXE1 gene. The protein encoded by this gene, the FoxE1 protein, is a 371 amino acid protein located in the cell nucleus. As a transcription factor, this protein controls, among other things, the transcription of certain genes in the thyroid, such as the gene expression of the gene for the enzyme thyreoperoxidase. Furthermore, FOXE1 encodes a transcription factor that plays a role in cell growth and differentiation. Hypermethylation of FOXE1 leads to its inactivity and has already been observed in pancreatic carcinoma and breast carcinoma. Furthermore, methylation of the promoter region FOXE1 was shown to be more abundant in spinocellular carcinomas of the skin than in healthy skin.

Role of Fox in acne: The activity of FoxO1 is inhibited by IGF-1 as well as insulin. In the presence of low IGF-1 and insulin secretion, FoxO1 suppresses the activity of the androgen receptor (AR) and other transcription factors of lipid biosynthesis (PPARgamma, LXRalpha, SREbP1). IGF-1/insulin-induced inactivation of FoxO1 increases the activity of androgen signaling and sebocytic lipid biosynthesis. This effect plays a significant role in the pathogenesis of acne.

1. Gavin MA et al (2007) Foxp3-dependent programme of regulatory T cell ifferentiation. Nature 445: 771-775
2. Mirdamadi Y et al (2015) Insulin and insulin-like growth factor-1 can modulate thephosphoinositide-3-kinase/Akt/FoxO1
   pathway in SZ95 sebocytes in vitro.
   Mol cell endocrinol 415:32-44.
3. Tuteja G et al (2007) Forkhead transcription factors I. Cell 130: 1160.e1-1160.e2
4. Venza I et al (2010) FOXE1 is a target for aberrant methylation in cutaneous squamous cell carcinoma. Br J Dermatol 162: 1093-1097