國家衛生研究院 NHRI:Item 3990099045/7469
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    题名: Destabilization of KLF10, a tumor suppressor, relies on thr93 phosphorylation and isomerase association
    作者: Hwang, YC;Yang, CH;Lin, CH;Ch’ang, HJ;Chang, VHS;Yu, WCY
    贡献者: National Institute of Cancer Research
    摘要: KLF10 is now classified as a member of the Kr?ppel-like transcription factor family and acts as a tumor suppressor. Although KLF10 originally named as TGF-β-inducible early gene-1 and mimicking the anti-proliferative effect of TGF-β in various carcinoma cells, the transcriptional up regulatory function of KLF10 has been described for a variety of cytokines and in many diseases. Through in vivo and in vitro phosphorylation assays, we identified that KLF10 is a phosphorylated protein in cells. Using yeast-two hybrid screening and site direct mutagenesis, we also identified PIN1 as a novel KLF10 associated protein. PIN1 is a peptidyl-prolyl isomerase enzyme belonging to the parvulin family, specifically recognizes phosphorylated Ser/Thr-Pro containing substrates. Through protein-protein interaction assays, we showed that the Pro-directed Ser/Thr-Pro motif at Thr-93 in the KLF10 N-terminal region is essential for the interaction between KLF10 and PIN1. More importantly, PIN1 interacts with KLF10 in a phosphorylation-dependent manner and this interaction promotes KLF10 protein degradation in cells. Therefore, KLF10 shows shorter protein stability compared with mutant KLF10 that lacks PIN1 binding ability after cycloheximide treatments. The reversely correlated expression profile between KLF10 and PIN1 as observed in cell lines were also shown in clinic pancreatic cancer specimen. Using in vitro kinase assays and depletion assays, we were able to show that RAF-1 phosphorylates the Thr-93 of KLF10 and affect KLF10 expression level in cells. Thus these finding as a whole indicate that RAF-1 phosphorylation and PIN1 isomerization together regulates KLF10 stability and further affect the role of KLF10 in tumor progression.
    日期: 2013-12
    關聯: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2013 Dec;1833(12):3035-3045.
    Link to: http://dx.doi.org/10.1016/j.bbamcr.2013.08.010
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0167-4889&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000329596200047
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84884306913
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