Identification of novel small molecules that elevate Klotho expression

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dc.contributor.authorKing, Gwendalyn D.
dc.contributor.authorChen, CiDi
dc.contributor.authorHuang, Mickey M.
dc.contributor.authorZeldich, Ella
dc.contributor.authorBrazee, Patricia L.
dc.contributor.authorSchyman, Eli R.
dc.contributor.authorRobin, Maxime
dc.contributor.authorCuny, Gregory D.
dc.contributor.authorGlicksman, Marcie A.
dc.contributor.authorAbraham, Carmela R.
dc.date.accessioned2020-03-10T17:31:27Z
dc.date.available2020-03-10T17:31:27Z
dc.date.issued2013-06
dc.description.abstractThe absence of Klotho (KL) from mice causes the development of disorders associated with human aging and decreased longevity, whereas increased expression prolongs lifespan. With age, KL protein levels decrease, and keeping levels consistent may promote healthier aging and be disease-modifying. Using the KL promoter to drive expression of luciferase, we conducted a high-throughput screen to identify compounds that activate KL transcription. Hits were identified as compounds that elevated luciferase expression at least 30%. Following validation for dose-dependent activation and lack of cytotoxicity, hit compounds were evaluated further in vitro by incubation with opossum kidney and Z310 rat choroid plexus cells, which express KL endogenously. All compounds elevated KL protein compared with control. To determine whether increased protein resulted in an in vitro functional change, we assayed FGF23 (fibroblast growth factor 23) signalling. Compounds G–I augmented ERK (extracellular-signal-regulated kinase) phosphorylation in FGFR (fibroblast growth factor receptor)-transfected cells, whereas co-transfection with KL siRNA (small interfering RNA) blocked the effect. These compounds will be useful tools to allow insight into the mechanisms of KL regulation. Further optimization will provide pharmacological tools for in vivo studies of KL.
dc.identifier.citationCopyright 2012 Biochemical Journal. This is a post-print version of a published paper that is available at: http://www.biochemj.org/content/441/1/453.abstract. Recommended citation: King, Gwendalyn D., CiDi Chen, Mickey M. Huang, Ella Zeldich, Patricia L. Brazee, Eli R. Schuman, Maxime Robin, Gregory D. Cuny, Marcie A. Glicksman, and Carmela R. Abraham. "Identification of novel small molecules that elevate Klotho expression." Biochemical Journal 441, no. 1 (2012): 453-461. doi: 10.1042/BJ20101909. This item has been deposited in accordance with publisher copyright and licensing terms and with author's permission.
dc.identifier.urihttps://hdl.handle.net/10657/5954
dc.language.isoen_US
dc.publisherBiochemical Journal
dc.subjectchoroid plexus
dc.subjectfibroblast growth factor 23 (FGF23)
dc.subjecthigh-throughput screen
dc.subjectKidney
dc.subjectklotho
dc.subjectlongevity
dc.titleIdentification of novel small molecules that elevate Klotho expression
dc.typeArticle

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