c-Myc是一种转录因子，促进细胞增殖，在癌症中常常异常或高度表达。然而，导致这种异常高表达的分子机制尚不清楚。在本研究中，我们发现细胞内Ca2+浓度调节c-Myc的致癌蛋白稳定性。我们确定了依赖于Ca2+的蛋白磷酸酶calcineurin是c-Myc表达的正调控因子。calcineurin的耗尽抑制了c-Myc靶基因表达和c-Myc的降解。calcineurin直接对c-Myc中的Thr58和Ser62进行去磷酸化，抑制其与泛素连接酶Fbxw7的结合。在calcineurin的自抑制结构域内观察到的突变体，最常见于癌症中，可能增加磷酸酶活性，从而增加c-Myc的转录活性。值得注意的是，使用FK506抑制calcineurin在小鼠异种移植模型中降低了c-Myc的表达，并增强了Thr58和Ser62的磷酸化。因此，calcineurin可以稳定c-Myc，促进肿瘤进展。因此，我们提出Ca2+信号功能障碍通过增加c-Myc稳定性影响癌细胞增殖，而calcineurin的抑制可能成为抑制c-Myc过表达癌症的新治疗靶点。© 2023. Springer Nature Limited.

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.© 2023. Springer Nature Limited.