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

Park, G., Baek, S., Kim, J.-E., Lim, T.-g., Lee, C. C., Yang, H., et al. (2015). Flt3 is a target of coumestrol in protecting against UVB-induced skin photoaging. BIOCHEMICAL PHARMACOLOGY, 98(3), 473-483. doi:10.1016/j.bcp.2015.08.104.

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 Creators:
Park, Gaeun1, Author
Baek, Sohee2, Author              
Kim, Jong-Eun1, Author
Lim, Tae-gyu1, Author
Lee, Charles C.1, Author
Yang, Hee1, Author
Kang, Young-Gyu1, Author
Park, Jun Seong1, Author
Augustin, Martin1, Author
Mrosek, Michael1, Author
Lee, Chang Yong1, Author
Dong, Zigang1, Author
Huber, Robert2, Author              
Lee, Ki Won1, Author
Affiliations:
1external, ou_persistent22              
2Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565155              

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Free keywords: ULTRAVIOLET-B IRRADIATION; RECEPTOR TYROSINE KINASE; HUMAN DERMAL FIBROBLASTS; PROTEIN-KINASE; MATRIX METALLOPROTEINASES; MOLECULAR MECHANISMS; PATHWAY; CELLS; ACTIVATION; PHYTOESTROGENSCoumestrol; Photoaging; Matrix metalloproteinase 1; FLT3 kinase;
 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. (C) 2015 Elsevier Inc. All rights reserved.

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Language(s): eng - English
 Dates: 2015
 Publication Status: Published in print
 Pages: 11
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000366150200012
DOI: 10.1016/j.bcp.2015.08.104
 Degree: -

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Title: BIOCHEMICAL PHARMACOLOGY
Source Genre: Journal
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Publ. Info: THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND : PERGAMON-ELSEVIER SCIENCE LTD
Pages: - Volume / Issue: 98 (3) Sequence Number: - Start / End Page: 473 - 483 Identifier: ISSN: 0006-2952