Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.
Department of Biochemistry, Joint Faculty of Veterinary Science, Yamaguchi University, 1677-1 Yoshida, Yamaguchi, 753-8511, Japan.
Sci Rep. 2019 Sep 4;9(1):12779. doi: 10.1038/s41598-019-48976-7.
The Calcineurin/NFAT (nuclear factor of activated T cells) pathway plays an essential role in the tumorigenic and metastatic properties in breast cancer. The molecular mechanism of the antiproliferative effect of calcineurin inhibition, however, is poorly understood. We found that calcineurin inhibition delayed cell cycle progression at G1/S, and promoted cyclin D1 degradation by inhibiting dephosphorylation at T286. Importantly, overexpression of cyclin D1 partially rescued delayed G1/S progression, thereby revealing cyclin D1 as a key factor downstream of calcineurin inhibition. Cyclin D1 upregulation is observed in human invasive breast cancers, and our findings indicate that dysregulation of T286 phosphorylation could play a role in this phenomenon. We therefore propose that targeting site specific phosphorylation of cyclin D1 could be a potential strategy for clinical intervention of invasive breast cancer.
钙调神经磷酸酶/NFAT（激活 T 细胞的核因子）通路在乳腺癌的致瘤和转移特性中发挥着重要作用。然而，钙调神经磷酸酶抑制的抗增殖作用的分子机制尚不清楚。我们发现钙调神经磷酸酶抑制作用可延迟 G1/S 期细胞周期进程，并通过抑制 T286 的去磷酸化来促进细胞周期蛋白 D1 的降解。重要的是，cyclin D1 的过表达部分挽救了 G1/S 期的延迟进展，从而揭示了 cyclin D1 是钙调神经磷酸酶抑制作用的关键下游因子。在人类浸润性乳腺癌中观察到 cyclin D1 的上调，我们的研究结果表明，T286 磷酸化的失调可能在这种现象中起作用。因此，我们提出靶向 cyclin D1 的特定位点磷酸化可能是浸润性乳腺癌临床干预的一种潜在策略。
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