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

Gaeun Park, Sohee Baek, Jong Eun Kim, Tae Gyu Lim, Charles C. Lee, Hee Yang, Young Gyu Kang, Jun Seong Park, Martin Augustin, Michael Mrosek, Chang Yong Lee, Zigang Dong, Robert Huber, Ki Won Lee

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)473-483
Number of pages11
JournalBiochemical Pharmacology
Volume98
Issue number3
DOIs
StatePublished - Dec 1 2015

Bibliographical note

Funding Information:
This work was supported by the Leap Research Program of the National Research Foundation funded by the Bio-industry Technology Development Program (514004) funded by the Ministry of Agriculture, Food and Rural Affairs and the R&D program of MOTIE/KIAT (Establishment of Infra Structure for Anti-aging Industry Support, N0000697) of Republic of Korea.

Publisher Copyright:
© 2015 Elsevier Inc. All rights reserved.

Keywords

  • Coumestrol
  • FLT3 kinase
  • Matrix metalloproteinase 1
  • Photoaging

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