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Flt3 is a target of coumestrol in protecting against UVB-induced skin photoaging.

Abstract：

:While skin aging is a naturally occurring process by senescence, exposure to ultraviolet (UV) radiation accelerates wrinkle formation and sagging of skin. UV induces skin aging by degrading collagen via activating matrix metalloproteinases (MMPs). In this study, we show that coumestrol, a metabolite of the soybean isoflavone daidzein, has a preventive effect on skin photoaging in three-dimensional human skin equivalent model. Coumestrol inhibited UVB-induced MMP-1 expression and activity. Whole human kinase profiling assay identified FLT3 kinase as a novel target protein of coumestrol in UVB-induced signaling pathway in skin. Coumestrol suppresses FLT3 kinase activity, and subsequently, Ras/MEK/ERK and Akt/p70 ribosomal S6 kinase pathway. This suppresses AP-1 activity and in turn, diminishes MMP-1 gene transcription. Using X-ray crystallography, the binding of coumestrol to FLT3 was defined and implied ATP-competitive inhibition. Residues Lys644 and Phe830 showed local changes to accommodate coumestrol in the ATP-binding pocket. 4-APIA, a pharmacological inhibitor of FLT3, inhibited MMP-1 expression and induced signal transduction changes similar to coumestrol. Taken together, coumestrol inhibits UVB-induced MMP-1 expression by suppressing FLT3 kinase activity. These findings suggest that coumestrol is a novel dietary compound with potential application in preventing and improving UVB-associated skin aging.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Park G,Baek S,Kim JE,Lim TG,Lee CC,Yang H,Kang YG,Park JS,Augustin M,Mrosek M,Lee CY,Dong Z,Huber R,Lee KW

doi

10.1016/j.bcp.2015.08.104

subject

Has Abstract

pub_date

2015-12-01 00:00:00

pages

473-83

issue

3

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(15)00549-3

journal_volume

98

pub_type

杂志文章

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