Involvement of calcineurin in apoptosis induced by microtubule dysfunction

紫杉醇与微管结合并诱导各种癌细胞凋亡。几条证据表明，紫杉醇通过激活c-Jun N-末端激酶（JNK）和激活的JNK伴随的B细胞白血病/淋巴瘤-2（Bcl-2）磷酸化诱导细胞凋亡。钙调神经磷酸酶是一种丝氨酸/苏氨酸蛋白磷酸酶，据报道参与Bcl-2的去磷酸化。我们发现人膀胱癌T24细胞对紫杉醇具有耐药性。紫杉醇和环孢素A（CsA）或FK 506，钙调磷酸酶抑制剂的组合治疗，导致钙调磷酸酶活性的损失和Bcl-2的磷酸化增强。CsA或FK 506处理细胞后，Bcl-2蛋白和mRNA的表达均显著降低。有趣的是，在CsA或FK 506存在下，低剂量紫杉醇诱导T24细胞凋亡。这些结果表明，钙调神经磷酸酶具有抗凋亡浓度的紫杉醇在CsA或FK 506的存在下。这些结果表明，钙调神经磷酸酶通过Bcl-2的去磷酸化和诱导Bcl-2的基因表达具有抗凋亡作用。在神经元中，tau蛋白与微管结合并调节轴突中微管的功能。我们发现Ca^<2+>、钙调蛋白依赖性蛋白激酶II（CaM激酶II）在微管蛋白结合位点磷酸化tau并抑制tau与微管的结合。这些结果可能表明，CaM激酶II参与细胞凋亡通过磷酸化的tau蛋白。

Taxol binds to microtubules and induces apoptosis of various cancer cells. Several lines of evidence indicate that taxol induces apoptosis through activation of c-Jun N-terminal kinase (JNK) and the concomitant phosphorylation of B-cell leukemia/lymphoma-2 (Bcl-2) by the activated JNK. Calcineurin is a serine/threonine protein phosphatase and has been reported to be involved in dephosphorylation of Bcl-2. We found that T24 cells derived from human urinary bladder cancer were resistant to taxol. A combination treatment with taxol and cyclosporin A (CsA) or FK506, calcineurin inhibitors, resulted in loss of calcineurin activity and enhancement of phosphorylation of Bcl-2. In addition, treatment of the cells with CsA or FK506 significantly decreased the expression of Bcl-2 at both the protein and mRNA levels. Interestingly, apoptosis of T24 cells was induced by low of taxol in the presence of CsA or FK506. These results suggest that calcineurin has antiapoptotic concentration of taxol in the presence of CsA or FK506. These results suggest that calcineurin has antiapoptotic actions via the dephosphorylation of Bcl-2 and the induction of the gene expression of Bcl-2. In neurons, tau protein binds to microtubules and regulates the microtubule functions in axons. We found that Ca^<2+>, calmodulin-dependent protein kinase II (CaM kinase II) phosphorylated tau at tubulin binding sites and inhibited the binding of tau to microtubules. These results may suggest that CaM kinase II is involved in apoptosis via the phosphorylation of tau.