Abstract
The forkhead box (FOX) proteins are transcription factors that play complex and important roles in processes from development and organogenesis to regulation of metabolism and the immune system. There are 50 FOX genes in the human genome and 44 in the mouse, divided into 19 subfamilies. All human FOX genes have close mouse orthologues, with one exception: the mouse has a single Foxd4, whereas the human gene has undergone a recent duplication to a total of seven (FOXD4 and FOXD4L1 → FOXD4L6). Evolutionarily ancient family members can be found as far back as the fungi and metazoans. The DNA-binding domain, the forkhead domain, is an example of the winged-helix domain, and is very well conserved across the FOX family and across species, with a few notable exceptions in which divergence has created new functionality. Mutations in FOX genes have been implicated in at least four familial human diseases, and differential expression may play a role in a number of other pathologies -- ranging from metabolic disorders to autoimmunity. Furthermore, FOX genes are differentially expressed in a large number of cancers; their role can be either as an oncogene or tumour suppressor, depending on the family member and cell type. Although some drugs that target FOX gene expression or activity, notably proteasome inhibitors, appear to work well, much more basic research is needed to unlock the complex interplay of upstream and downstream interactions with FOX family transcription factors.
Highlights
Gene expression is controlled at multiple levels, including modulation of transcriptional activity, mRNA processing, and post-translational modification of proteins
The forkhead box (FOX) gene family encodes proteins that regulate the transcription of genes participating in a number of functions — including development of various organs, regulation of senescence or proliferation, and metabolic homeostasis
The winged helix/forkhead nomenclature committee defined the FOX family as all genes/ proteins having sequence homology to the canonical winged helix/forkhead DNA-binding domain; subclasses FOXA to FOXO were defined based on a phylogenetic analysis of the forkhead domain.[7]
Summary
Gene expression is controlled at multiple levels, including modulation of transcriptional activity, mRNA processing, and post-translational modification of proteins. The first FOX gene to be discovered was forkhead ( fkh) in Drosophila, which, when mutated, gives the insect a fork-headed appearance.[1]. Another group characterised FOXA1 in the rat.[2] In 1990, Weigel et al discovered that these two proteins shared a similar. The winged helix/forkhead nomenclature committee defined the FOX family as all genes/ proteins having sequence homology to the canonical winged helix/forkhead DNA-binding domain; subclasses FOXA to FOXO were defined based on a phylogenetic analysis of the forkhead domain (other domains were highly divergent, and alignment was unclear between subclasses).[7] Since the family has been expanded to include subclasses FOXP to FOXS. The variety of possible phosphorylation, acetylation, methylation and O-linked glycosylation has been dubbed the FOXO code.[14]
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