Abstract
The complex multifactorial pathogenesis of acne vulgaris, the most common skin disease, may be explained at the level of genomic regulation. A recent hypothesis suggested that a relative nuclear defi ciency of the metabolic sensor and nuclear transcription factor FoxO1 appears to play a key role in the pathogenesis of acne vulgaris. FoxO1 has been identified as an important regulator of androgen receptor, cell proliferation, apoptosis, lipogenesis, oxidative stress regulation, innate and acquired immunity, all important aspects involved in the pathogenesis of acne. It is the intention of this review article to provide further evidence for the potential function of the PI3K/Akt/FoxO1 signaling pathway for other types of acne and acne-like eruptions. Apparently unrelated acneigenic stimuli like hyperglycemic food, insulinotropic milk and dairy product consumption, smoking, psychological stress, fibroblast growth factor receptor-2 mutations in Apert syndrome and acneiform nevus, chloracne, and antidepressant-induced acne are all associated with upregulated PI3K/Akt-signaling known to result in a nuclear deficiency of FoxO1. Reduced nuclear levels of FoxO1 may increase the expression of important acne target genes and derepress nuclear receptors, suggested to be involved in the clinical manifestation of acne. Accumulating indirect evidence supports the role of growth factor- and growth factorlike acneigenic stimuli in posttranslational modifi cation of nuclear FoxO1 and strenghtens the hypothesis of a nuclear FoxO1 deficiency as the possible underlying cause of acne vulgaris and clinical acne variants. This review intends to stimulate future research activities on the promising PI3K/Akt/FoxO1 signaling pathway which may be most helpful to unravel the pathogenesis of acne.
Highlights
The complex multifactorial pathogenesis of acne vulgaris, the most common skin disease, may be explained at the level of genomic regulation
The Forkhead Box O1 (FoxO1) Transcription Factor. It is the purpose of this review to support the hypothetical concept that the nuclear transcription factor FoxO1, a member of the class O subfamily of forkhead box (FoxO) transcription factors may be involved in the pathogenesis of acne vulgaris and other acne variants
All major factors in acne pathogenesis, i.e., androgen receptor (AR)-mediated signal transduction, increased proliferation of keratinocytes, augmented lipogenesis, upregulation of tolllike receptor-2 (TLR2) signaling with local activation of innate and adaptive immune responses has been linked to a nuclear deficiency of FoxO1 [1]
Summary
Factors leading to acne [1]. It will be shown that various growth factor- and growth factor-like signals like insulin and insulin-like growth factor-1 (IGF-1) which are perceived by distinct cell membrane receptors are intergrated at the level of phosphoinositol-3 kinase (PI3K)/Akt activation (Figure 1). The activated kinase Akt (protein kinase B) translocates into the nucleus where Akt phosphorylates the nuclear FoxO1 protein. Phosphorylated FoxO1 is exported from the nucleus into the cytoplasm thereby derepressing target genes and activating nuclear receptors involved in acne pathogenesis (Figure 1) [1,2,3]. Received July 27, 2010; Accepted September 13, 2010; Published September 13, 2010 J Clin Exp Dermatol Res 1:101. doi:10.4172/2155-9554.1000101
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