uPAR and cathepsin B downregulation induces apoptosis by targeting calcineurin A to BAD via Bcl-2 in glioma.
uPAR and cathepsin B downregulation induces apoptosis by targeting calcineurin A to BAD via Bcl-2 in glioma.
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DOI：
10.1007/s11060-011-0727-x
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发表时间：
2012-03
影响因子：
3.9
通讯作者：
Rao, Jasti S.
中科院分区：
文献类型：
--
作者：
Malla, Rama Rao;Gopinath, Sreelatha;Gondi, Christopher S.;Alapati, Kiranmai;Dinh, Dzung H.;Tsung, Andrew J.;Rao, Jasti S.
组织蛋白酶B和尿激酶型纤溶酶原激活物受体（uPAR）被认为在胶质瘤侵袭中起关键作用。钙调神经磷酸酶是神经细胞凋亡的关键调节因子之一，但其作用机制尚不清楚。因此，我们研究了胶质瘤中uPAR和组织蛋白酶B转录下调后钙调神经磷酸酶的亚细胞定位。在本研究中，uPAR和组织蛋白酶B的有效下调增加了钙调神经磷酸酶A从线粒体向胞质的移位，降低了pBAD（S136）的表达及其与14-3-3-ATP的相互作用，并增加了BAD与Bcl-Xl的相互作用。共同消耗uPAR和组织蛋白酶B诱导线粒体BAD和caspase 3易位以及PARP激活、细胞色素c和SMAC释放。这些作用可被FK 506（10 μM）抑制，FK 506是一种钙调神经磷酸酶的特异性抑制剂。钙调神经磷酸酶A与Bcl-2共定位，也与Bcl-2共免疫沉淀。这种相互作用随着uPAR和组织蛋白酶B以及Bcl-2抑制剂HA 14-1（20 μg/mL）的共同消耗而降低。当uPAR和组织蛋白酶B下调时，在体内也观察到钙调神经磷酸酶A与Bcl-2的改变的定位和相互作用。总之，下调uPAR和组织蛋白酶B通过Bcl-2将钙调磷酸酶A靶向BAD诱导胶质瘤细胞凋亡。
Cathepsin B and urokinase plasminogen activator receptor (uPAR) are postulated to play key roles in glioma invasion. Calcineurin is one of the key regulators of mitochondrial-dependent apoptosis, but its mechanism is poorly understood. Hence, we studied subcellular localization of calcineurin after transcriptional downregulation of uPAR and cathepsin B in glioma. In the present study, efficient downregulation of uPAR and cathepsin B increased the translocation of calcineurin A from the mitochondria to the cytosol, decreased pBAD (S136) expression and its interaction with 14-3-3ζ, and increased the interaction of BAD with Bcl-Xl. Co-depletion of uPAR and cathepsin B induced mitochondrial translocation of BAD and caspase 3 as well as PARP activation, cytochrome c and SMAC release. These effects were inhibited by FK506 (10 μM), a specific inhibitor of calcineurin. Calcineurin A was co-localized and also co-immunoprecipitated with Bcl-2. This interaction decreased with co-depletion of uPAR and cathepsin B and also with Bcl-2 inhibitor, HA 14-1 (20 μg/mL). Altered localization and interaction of calcineurin A with Bcl-2 was also observed in vivo when uPAR and cathepsin B were downregulated. In conclusion, downregulation of uPAR and cathepsin B induced apoptosis by targeting calcineurin A to BAD via Bcl-2 in glioma.
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DOI：
10.1016/j.bbamcr.2008.10.015
发表时间：
2009-06
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Rong YP;Barr P;Yee VC;Distelhorst CW
通讯作者：
Distelhorst CW
影响因子：
3.7
作者：
Malla R;Gopinath S;Alapati K;Gondi CS;Gujrati M;Dinh DH;Mohanam S;Rao JS
通讯作者：
Rao JS
影响因子：
4.8
作者：
Asai, A;Qiu, JH;Kirino, T
通讯作者：
Kirino, T
影响因子：
3.6
作者：
Masters, SC;Yang, HZ;Fu, H
通讯作者：
Fu, H
影响因子：
3.7
作者：
Gopinath S;Malla RR;Gondi CS;Alapati K;Fassett D;Klopfenstein JD;Dinh DH;Gujrati M;Rao JS
通讯作者：
Rao JS