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首页> 外文期刊>Cellular Signalling >Cytotoxic T lymphocyte antigen-2 alpha induces apoptosis of murine T-lymphoma cells and cardiac fibroblasts and is regulated by cAMP/PKA
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Cytotoxic T lymphocyte antigen-2 alpha induces apoptosis of murine T-lymphoma cells and cardiac fibroblasts and is regulated by cAMP/PKA

机译：细胞毒性T淋巴细胞抗原2α诱导鼠T淋巴瘤细胞和心脏成纤维细胞凋亡，并受cAMP / PKA调节

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The mechanism of cAMP-promoted apoptosis is not well defined. In wild-type (WT) murine S49 lymphoma cells, cAMP promotes apoptosis in a protein kinase A (PKA)-dependent manner. We find that treatment of WT S49 cells with 8-CPT-cAMP prominently increases the expression (as determined by DNA microarray analysis, real-time PCR and immunblotting) of cytotoxic T lymphocyte antigen-2α (CTLA-2α), a cathepsin L-like cysteine protease inhibitor. By contrast, CTLA-2α expression is only slightly increased by 8-CPT-cAMP treatment of D-S49 cells, which lack cAMP/PKA-promoted apoptosis. Raising endogenous cAMP (by use of forskolin or inhibition of phosphodiesterase [PDE] 4) or a PKA-selective, but not an Epac-selective, cAMP analogue, increases CTLA-2α mRNA expression; PKA, and not Epac, thus mediates the increase in CTLA-2α expression. An adenoviral CLTA-2α (Ad-CTLA-2α) construct induces apoptosis and enhances cAMP-promoted apoptosis in WT S49 cells but such cells do not have an increase in cathepsin L activity nor does a cathepsin L inhibitor alter cAMP-promoted apoptosis. 8-CPT-cAMP also increases CTLA-2α expression and induces apoptosis in murine cardiac fibroblasts; knockdown of CTLA-2α expression by siRNA blocks 8-CPT-cAMP-promoted apoptosis. Thus, cAMP increases CTLA-2α expression in murine lymphoma and cardiac fibroblasts and this increase in CTLA-2α contributes to cAMP/PKA-promoted apoptosis by mechanisms that are independent of the ability of CTLA-2α to inhibit cathepsin L.
机译：cAMP促进细胞凋亡的机制尚不清楚。在野生型（WT）鼠S49淋巴瘤细胞中，cAMP以蛋白激酶A（PKA）依赖性方式促进细胞凋亡。我们发现用8-CPT-cAMP处理WT S49细胞可显着增加细胞毒性T淋巴细胞抗原2α（CTLA-2α），组织蛋白酶L-的表达（通过DNA芯片分析，实时PCR和免疫印迹测定）像半胱氨酸蛋白酶抑制剂。相比之下，通过8-CPT-cAMP处理D-S49细胞（仅缺少cAMP / PKA促进的细胞凋亡），CTLA-2α表达仅略有增加。提高内源性cAMP（通过使用福司可林或抑制磷酸二酯酶[PDE] 4）或PKA选择性而不是Epac选择性cAMP类似物可增加CTLA-2αmRNA表达。因此，PKA而非Epac介导CTLA-2α表达的增加。腺病毒CLTA-2α（Ad-CTLA-2α）构建体在WT S49细胞中诱导凋亡并增强cAMP促进的细胞凋亡，但是这种细胞的组织蛋白酶L活性没有增加，组织蛋白酶L抑制剂也没有改变cAMP促进的细胞凋亡。 8-CPT-cAMP还可增加鼠心肌成纤维细胞中CTLA-2α的表达并诱导细胞凋亡。 siRNA抑制CTLA-2α表达可阻断8-CPT-cAMP促进的细胞凋亡。因此，cAMP增加了鼠淋巴瘤和心脏成纤维细胞中CTLA-2α的表达，而CTLA-2α的这种增加通过独立于CTLA-2α抑制组织蛋白酶L的能力的机制促进了cAMP / PKA促进的细胞凋亡。

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