Calpain small-1 modulates Akt/FoxO3A signaling and apoptosis through PP2A
Calpain small-1 modulates Akt/FoxO3A signaling and apoptosis through PP2A
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DOI：
10.1038/onc.2008.425
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发表时间：
2009-02-05
期刊：
影响因子：
8
通讯作者：
Schneider, C.
中科院分区：
文献类型：
--
作者：
Bertoli, C.;Copetti, T.;Schneider, C.
在这里，我们发现在小鼠胚胎中，FoxO3A 转录因子在钙蛋白酶小 1 (CAPNS1) 耗尽时上调。成纤维细胞 (MEF) 和人乳腺癌细胞系 MCF-7 中。饥饿时，CAPNS1 耗竭与 FoxO3A 去磷酸化和易位至细胞核的速率较高，以及 p27Kip1 和 Bim（两个 FoxO 靶基因的产物）水平急剧增加有关。值得注意的是，CAPNS1(-/-) MEF 中 FoxO3A 的消耗减少了 Bim 和细胞凋亡的诱导。冈田酸处理和蛋白磷酸酶 2A (PP2A) 催化亚基沉默均可部分减少 CAPNS1(-/-) 中饥饿诱导的 FoxO3A 激活和凋亡。成纤维细胞。 PP2A 在 CAPNS1 敲除细胞中与 Akt 结合更紧密，表明 PP2A 参与钙蛋白酶介导的 FoxO 调节。最后，我们证明PP2A调节亚基B56α和γ是钙蛋白酶的体外底物，并且钙蛋白酶在体内调节B56α稳定性，这表明钙蛋白酶在调节PP2A功能中具有直接作用。总之，我们首次报告 CAPNS1 干扰 PP2A-Akt 相互作用，从而影响 FoxO3A 依赖性细胞死亡。因此，钙蛋白酶抑制可能被用作诱导对 FoxO 激活敏感的肿瘤细胞凋亡的工具。
Here, we show that FoxO3A transcription factor is upregulated upon calpain small-1 (CAPNS1) depletion both in mouse embryonic. broblasts (MEFs) and in the human mammary carcinoma cell line MCF-7. On starvation, CAPNS1 depletion is associated with a higher rate of FoxO3A dephosphorylation and translocation to the nucleus and to a sharper increase in the levels of p27Kip1 and Bim, the products of two FoxO target genes. Notably, FoxO3A depletion in CAPNS1(-/-) MEFs reduces both the induction of Bim and apoptosis. Both okadaic acid treatment and silencing of the protein phosphatase 2A (PP2A) catalytic subunit can partially reduce starvation-induced FoxO3A activation and apoptosis in CAPNS1(-/-). broblasts. PP2A associates more tightly with Akt in CAPNS1 knockout cells, indicating that PP2A is involved in calpain-mediated FoxO regulation. Finally, we show that PP2A regulatory subunits B56 alpha and gamma are in vitro substrates of calpain, and calpain regulates B56 alpha stability in vivo, suggesting a direct role of calpain in the regulation of PP2A function. In conclusion, for the fist time we report that CAPNS1 interferes with PP2A-Akt interaction consequently affecting FoxO3A-dependent cell death. Calpain inhibition might therefore be exploited as a tool to induce apoptosis in tumors sensitive to FoxO activation.