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FoxO1 – the key for the pathogenesis and therapy of acne?
Author(s) -
Melnik Bodo C.
Publication year - 2010
Publication title -
jddg: journal der deutschen dermatologischen gesellschaft
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.463
H-Index - 60
eISSN - 1610-0387
pISSN - 1610-0379
DOI - 10.1111/j.1610-0387.2010.07344.x
Subject(s) - pi3k/akt/mtor pathway , transcription factor , foxo1 , nuclear receptor , androgen receptor , signal transduction , biology , endocrinology , acne , cancer research , medicine , protein kinase b , microbiology and biotechnology , cancer , biochemistry , prostate cancer , gene , genetics
Summary Five main factors play a pivotal role in the pathogenesis of acne: androgen dependence, follicular retention hyperkeratosis, increased sebaceous lipogenesis, increased colonization with P. acnes , and inflammatory events. This paper offers a solution for the pathogenesis of acne and explains all major pathogenic factors at the genomic level by a relative deficiency of the nuclear transcription factor FoxO1. Nuclear FoxO1 suppresses androgen receptor, other important nuclear receptors and key genes of cell proliferation, lipid biosynthesis and inflammatory cytokines. Elevated growth factors during puberty and persistent growth factor signals due to Western life style stimulate the export of FoxO1 out of the nucleus into the cytoplasm via activation of the phos‐phoinositide‐3‐kinase (PI3K)/Akt pathway. By this mechanism, genes and nuclear receptors involved in acne are derepressed leading to increased androgen receptor‐mediated signal transduction, increased cell proliferation of androgen‐dependent cells, induction of sebaceous lipogenesis and upregulation of Toll‐like‐receptor‐2‐dependent inflammatory cytokines. All known acne‐inducing factors exert their action by reduction of nuclear FoxO1 levels. In contrast, retinoids, antibiotics and dietary intervention will increase the nuclear content of FoxO1, thereby normalizing increased transcription of genes involved in acne. Various receptor‐mediated growth factor signals are integrated at the level of PI3K/Akt activation which finally results in nuclear FoxO1 deficiency.