MLK3 is a direct target of biochanin A, which plays a role in solar UV-induced COX-2 expression in human keratinocytes

Tae Gyu Lim, Jong Eun Kim, Sung Keun Jung, Yan Li, Ann M. Bode, Jun Seong Park, Myeong Hun Yeom, Zigang Dong, Ki Won Lee

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Solar UV (sUV) is an important environmental carcinogen. Recent studies have shown that sUV is associated with numerous human skin disorders, such as wrinkle formation and inflammation. In this study, we found that the isoflavone, biochanin A, inhibited the expression of sUV-induced COX-2, which is a well-characterized sUV-induced enzyme, in both human HaCaT keratinocytes and JB6 P+ mouse skin epidermal cells. Several studies have demonstrated the beneficial effects of biochanin A. However, its direct molecular target is unknown. We found that biochanin A inhibited sUV-induced phosphorylation of MKK4/JNK/c-Jun and MKK3/6/p38/MSK1. Mixed-lineage kinase 3 (MLK3) is an upstream kinase of MKK4 and MKK3/6. Thus, we evaluated the effect of biochanin A on MLK3. We found that sUV-induced MLK3 phosphorylation was not affected, whereas MLK3 kinase activity was significantly suppressed by biochanin A. Furthermore, direct binding of biochanin A in the MLK3 ATP-binding pocket was detected using pull-down assays. Computer modeling supported our observation that MLK3 is a novel target of biochanin A. These results suggest that biochanin A exerts chemopreventive effects by suppressing sUV-induced COX-2 expression mediated through MLK3 inhibition.

Original languageEnglish (US)
Pages (from-to)896-903
Number of pages8
JournalBiochemical Pharmacology
Volume86
Issue number7
DOIs
StatePublished - Aug 30 2013

Keywords

  • Biochanin A
  • Cyclooxygenase-2
  • Mixed-lineage kinase 3
  • Solar UV

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