1. Calcineurin-mediated dephosphorylation enhances the stability and transactivation of c-Myc.
- Author
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Masaki, Takahiro, Habara, Makoto, Hanaki, Shunsuke, Sato, Yuki, Tomiyasu, Haruki, Miki, Yosei, and Shimada, Midori
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PHOSPHOPROTEIN phosphatases , *DEPHOSPHORYLATION , *GENE expression , *CALCINEURIN , *TRANSCRIPTION factors - Abstract
c-Myc, a transcription factor, induces cell proliferation and is often aberrantly or highly expressed in cancers. However, molecular mechanisms underlying this aberrantly high expression remain unclear. Here, we found that intracellular Ca2+ concentration regulates c-Myc oncoprotein stability. We identified that calcineurin, a Ca2+-dependent protein phosphatase, is a positive regulator of c-Myc expression. Calcineurin depletion suppresses c-Myc targeted gene expression and c-Myc degradation. Calcineurin directly dephosphorylates Thr58 and Ser62 in c-Myc, which inhibit binding to the ubiquitin ligase Fbxw7. Mutations within the autoinhibitory domain of calcineurin, most frequently observed in cancer, may increase phosphatase activity, increasing c-Myc transcriptional activity in turn. Notably, calcineurin inhibition with FK506 decreased c-Myc expression with enhanced Thr58 and Ser62 phosphorylation in a mouse xenograft model. Thus, calcineurin can stabilize c-Myc, promoting tumor progression. Therefore, we propose that Ca2+ signaling dysfunction affects cancer-cell proliferation via increased c-Myc stability and that calcineurin inhibition could be a new therapeutic target of c-Myc-overexpressing cancers. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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