國家衛生研究院 NHRI:Item 3990099045/9917
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    題名: Metabolic stress-induced phosphorylation of KAP1 Ser473 blocks mitochondrial fusion in breast cancer cells
    作者: Cheng, CT;Kuo, CY;Ouyang, C;Li, CF;Chung, YY;Chan, D;Kung, HJ;Ann, DK
    貢獻者: Institute of Molecular and Genomic Medicine
    摘要: Mitochondrial dynamics during nutrient starvation of cancer cells likely exert profound effects on their capability for metastatic progression. Here we report that KAP1 (TRIM28), a transcriptional co-adaptor protein implicated in metastatic progression in breast cancer, is a pivotal regulator of mitochondrial fusion in glucose-starved cancer cells. Diverse metabolic stresses induced Ser473-phosphorylation of KAP1 (pS473-KAP1) in a ROS- and p38-dependent manner. Results from live cell imaging and molecular studies revealed that during the first 6-8 hr of glucose starvation mitochondria initially underwent extensive fusion, but then subsequently fragmented in a pS473-KAP1-dependent manner. Mechanistic investigations using phosphorylation-defective mutants revealed that KAP1 Ser473-phosphorylation limited mitochondrial hyperfusion in glucose-starved breast cancer cells, as driven by downregulation of the mitofusin protein MFN2, leading to reduced oxidative phosphorylation and ROS production. In clinical specimens of breast cancer, reduced expression of MFN2 corresponded to poor prognosis in patients. In a mouse xenograft model of human breast cancer, there was an association in the core region of tumors between MFN2 downregulation and the presence of highly fragmented mitochondria. Collectively, our results suggest that KAP1 Ser473 phosphorylation acts through MFN2 reduction to restrict mitochondrial hyperfusion, thereby contributing to cancer cell survival under conditions of sustained metabolic stress.
    日期: 2016-09
    關聯: Cancer Research. 2016 Sep;76(17):5006-5018.
    Link to: http://dx.doi.org/10.1158/0008-5472.can-15-2921
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0008-5472&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000382298900012
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84986904946
    顯示於類別:[龔行健] 期刊論文

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