cAMP促肿瘤细胞存活机制研究
摘要
第二信使环腺苷酸(cyclic AMP,cAMP)是重要的胞内调节因子。其由三磷酸腺苷(ATP)通过腺苷酸环化酶(AC)催化生成,能被磷酸二酯酶(PDE)降解成5’-AMP。多种胞外刺激如:激素、生长因子、神经递质等,通过G蛋白偶联受体活化AC,使胞内cAMP浓度升高,进而调控细胞增殖、细胞凋亡等诸多细胞生命活动。cAMP下游的效应因子如PKA(protein kinase A)和cAMP反应元件结合蛋白(cAMP element-binding protein,CREB)等介导了其生物学功能的发挥。实验表明PKA及CREB在内分泌组织的肿瘤发生中起着重要作用。而且长期的研究揭示高水平的cAMP浓度能促进肿瘤的发生发展,其中一个很重要的原因是cAMP能促进肿瘤细胞存活。然而在非恶性细胞中cAMP发挥双向调节的作用,既能促进细胞死亡也能抑制细胞死亡,因细胞类型及胞外刺激剂的不同而不同。我们课题组的前期工作说明,cAMP对MAPK家族主要成员JNK、p38的抑制作用是其在非恶性细胞中双向调节细胞存活的关键机制。
一个让人不解的问题是为什么在非恶性细胞中cAMP是双向调节作用,而在肿瘤细胞中则成为单向的促存活作用?其中的分子机制仍未见报道。为回答这一科学问题,我们开展了相关研究,希望能阐明cAMP促肿瘤细胞存活的机制,为寻找新的抗肿瘤靶点奠定基础。
我们以TNF-α敏感的成纤维瘤细胞L929细胞为研究模型。首先观测了多种cAMP“激动剂”对TNF-α诱导的L929细胞死亡的影响,实验结果表明提高胞内cAMP浓度显著抑制TNF-α诱导的L929细胞坏死,证实了cAMP在肿瘤细胞中的促存活作用。而后发现JNK活性促进TNF-α诱导的L929细胞死亡,而p38活性则起拮抗作用。cAMP促L929细胞的存活机制与其显著抑制JNK的活性,而同时不抑制p38活性密切相关。进一步研究显示cAMP抑制p38通路的重要负调控机制——DLC的表达上调——在L929细胞中存在缺陷,而cAMP抑制JNK通路的重要负调控机制——cFLIPL和MKP1的表达上调——在L929细胞中却没有缺陷。因为p38抑制因子及外源过表达DLC分子均能逆转cAMP保护作用,所以是L929细胞中一个促凋亡机制的缺陷,导致了cAMP在肿瘤细胞的“净”存活效应。这为我们提出的科学问题,提供了一种可能分子机制的解释。
同时在研究中我们发现cAMP对JNK通路的抑制在其抑制TNF-α诱导L929细胞死亡方面发挥了重要作用。其中一个重要原因是cAMP通过CREB介导的转录,上调cFLIPL分子抑制MKK7活化,从而抑制JNK活性。但是除了cFLIPL,是否还有其它蛋白参与了调控MKK7分子,还不清楚。因此我们又开展了一些探索性的工作——寻找MKK7分子相互作用蛋白,以期能找到新的负向调控MKK7-JNK通路的分子,进而为更好地理解cAMP抑制JNK通路的机制奠定基础。
我们利用酵母双杂交技术,从人胎脑文库中筛选到三个未见报道的MKK7相互作用蛋白:ORF60、GNB2L1、UBA3。通过免疫共沉淀的方法确定三个蛋白均能与MKK7相互作用,免疫印迹实验表明GNB2L1能增强本底JNK磷酸化的作用,ORF60与UBA3有部分抑制JNK活性的作用。荧光素酶分析结果显示GNB2L1能增强JNK下游转录因子AP-1的转录活性,而ORF60与UBA3则不同程度的抑制AP-1的活性,与免疫印迹结果相一致。提示克隆可能与MKK7相互作用后而影响JNK通路的活性。因而,我们筛选到了新的MKK7相互作用蛋白,并具有一定的生物学功能,为今后深入研究cAMP调控MKK7-JNK通路奠定了基础,为揭示cAMP促肿瘤细胞存活机制研究提供了新思路。
The second messenger cyclic AMP (cAMP) is an important intracellular mediator, which is produced from ATP by adenylyl cyclases (AC) and can be degraded to 5’-AMP by phosphodiesterases. AC is stimulated by a variety of extracellular stimuli, such as hormones, growth factors and neurotransmitters through G-protein (Gs)-coupled membrane receptors. cAMP regulates many cellular activities, from proliferation to apoptosis, in a cell type-dependent manner. The biological functions of cAMP are mediated by its downstream effectors such as protein kinase A (PKA) and CREB (cAMP element-binding protein). PKA and CREB have been shown to contribute to the tumorgenesis of endocrine tissues. Furthermore, it has been long disclosed that cAMP elevation is associated with impaired cell death of various tumor cells. However, in non-malignant cells cAMP can either promote or suppress cell death, depending on cell type and stimulus used. The prievious studies of our group suggest that, at least in fibroblasts, the crosstalk between the cAMP signaling pathway and MAPKs JNK (c-Jun N-terminal protein kinase) /p38 pathways is the key mechanism by which cAMP plays a dual role in the regulation of cell death.
It remains unknown why cAMP can either promote or suppress cell death in non-maligant cells, but always exhibits a pro-survival role in tumor cells. Since resistance to cell death has been implicated in cancer pathogenesis, it is of great importance to elucidate the underlying mechanisms.
So we carried out work to investigate the possible mechanisms. We chose the TNF-α-sensitive fibroblastoma L929 cells as the research model. Then we found that elevation of cAMP suppressed TNF-α-induced necrotic cell death in L929 fibroblastoma cells via CREB-mediated transcription. The pro-survival role of cAMP was associated with selective unresponsiveness of L929 cells to the inhibition of p38 activation by cAMP, even though cAMP significantly inhibited the activation of JNK under the same conditions. Further exploration revealed that the induction of DLC, the major mediator of p38 inhibition by cAMP, was impaired in L929 cells. Enforced inhibition of p38 activation by using p38 specific inhibitor or ectopic expression of DLC reversed the protection of L929 cells by cAMP from TNF-α-induced cell death. These data suggest that the lack of a pro-apoptotic pathway in tumor cells leads to a net survival effect of cAMP.
On the other hand, our data suggest that cAMP suppresses TNF-α-induced cell death of L929 fibroblastoma cells via, at least partially, inhibiting the activation of JNK pathway. The induction of c-FLIPL by cAMP via CREB-mediated transcription led to the inhibition of JNK activation by targeting MKK7, the upstream kinase of JNK pathway. However, it remains unknown whether there are other negative-regulators in the regulation of JNK by cAMP. So we further designed research to screen the cellular proteins that interact with MKK7 by yeast two-hybrid assay from human fetal brain cDNA library.
We identified three new MKK7-interacting proteins by yeast two-hybrid screen. They were ORF60, GNB2L1 and UBA3. Co-immunoprecipitaion assay confirmed the specific interaction with MKK7. Furthermore, immunoblotting analysis and luciferase assay showed that GNB2L1 could enhance the activation of JNK and downstream transcriptional factor AP-1, while the overexpression of ORF60 and UBA3 could inhibit the activation of JNK and AP-1. Our finding of the three new interacting proteins of MKK7 might facilitate the studies to elucidate the complicated mechanisms by which cAMP suppresses JNK pathway and plays a pro-survival role in tumor cells.
一个让人不解的问题是为什么在非恶性细胞中cAMP是双向调节作用,而在肿瘤细胞中则成为单向的促存活作用?其中的分子机制仍未见报道。为回答这一科学问题,我们开展了相关研究,希望能阐明cAMP促肿瘤细胞存活的机制,为寻找新的抗肿瘤靶点奠定基础。
我们以TNF-α敏感的成纤维瘤细胞L929细胞为研究模型。首先观测了多种cAMP“激动剂”对TNF-α诱导的L929细胞死亡的影响,实验结果表明提高胞内cAMP浓度显著抑制TNF-α诱导的L929细胞坏死,证实了cAMP在肿瘤细胞中的促存活作用。而后发现JNK活性促进TNF-α诱导的L929细胞死亡,而p38活性则起拮抗作用。cAMP促L929细胞的存活机制与其显著抑制JNK的活性,而同时不抑制p38活性密切相关。进一步研究显示cAMP抑制p38通路的重要负调控机制——DLC的表达上调——在L929细胞中存在缺陷,而cAMP抑制JNK通路的重要负调控机制——cFLIPL和MKP1的表达上调——在L929细胞中却没有缺陷。因为p38抑制因子及外源过表达DLC分子均能逆转cAMP保护作用,所以是L929细胞中一个促凋亡机制的缺陷,导致了cAMP在肿瘤细胞的“净”存活效应。这为我们提出的科学问题,提供了一种可能分子机制的解释。
同时在研究中我们发现cAMP对JNK通路的抑制在其抑制TNF-α诱导L929细胞死亡方面发挥了重要作用。其中一个重要原因是cAMP通过CREB介导的转录,上调cFLIPL分子抑制MKK7活化,从而抑制JNK活性。但是除了cFLIPL,是否还有其它蛋白参与了调控MKK7分子,还不清楚。因此我们又开展了一些探索性的工作——寻找MKK7分子相互作用蛋白,以期能找到新的负向调控MKK7-JNK通路的分子,进而为更好地理解cAMP抑制JNK通路的机制奠定基础。
我们利用酵母双杂交技术,从人胎脑文库中筛选到三个未见报道的MKK7相互作用蛋白:ORF60、GNB2L1、UBA3。通过免疫共沉淀的方法确定三个蛋白均能与MKK7相互作用,免疫印迹实验表明GNB2L1能增强本底JNK磷酸化的作用,ORF60与UBA3有部分抑制JNK活性的作用。荧光素酶分析结果显示GNB2L1能增强JNK下游转录因子AP-1的转录活性,而ORF60与UBA3则不同程度的抑制AP-1的活性,与免疫印迹结果相一致。提示克隆可能与MKK7相互作用后而影响JNK通路的活性。因而,我们筛选到了新的MKK7相互作用蛋白,并具有一定的生物学功能,为今后深入研究cAMP调控MKK7-JNK通路奠定了基础,为揭示cAMP促肿瘤细胞存活机制研究提供了新思路。
The second messenger cyclic AMP (cAMP) is an important intracellular mediator, which is produced from ATP by adenylyl cyclases (AC) and can be degraded to 5’-AMP by phosphodiesterases. AC is stimulated by a variety of extracellular stimuli, such as hormones, growth factors and neurotransmitters through G-protein (Gs)-coupled membrane receptors. cAMP regulates many cellular activities, from proliferation to apoptosis, in a cell type-dependent manner. The biological functions of cAMP are mediated by its downstream effectors such as protein kinase A (PKA) and CREB (cAMP element-binding protein). PKA and CREB have been shown to contribute to the tumorgenesis of endocrine tissues. Furthermore, it has been long disclosed that cAMP elevation is associated with impaired cell death of various tumor cells. However, in non-malignant cells cAMP can either promote or suppress cell death, depending on cell type and stimulus used. The prievious studies of our group suggest that, at least in fibroblasts, the crosstalk between the cAMP signaling pathway and MAPKs JNK (c-Jun N-terminal protein kinase) /p38 pathways is the key mechanism by which cAMP plays a dual role in the regulation of cell death.
It remains unknown why cAMP can either promote or suppress cell death in non-maligant cells, but always exhibits a pro-survival role in tumor cells. Since resistance to cell death has been implicated in cancer pathogenesis, it is of great importance to elucidate the underlying mechanisms.
So we carried out work to investigate the possible mechanisms. We chose the TNF-α-sensitive fibroblastoma L929 cells as the research model. Then we found that elevation of cAMP suppressed TNF-α-induced necrotic cell death in L929 fibroblastoma cells via CREB-mediated transcription. The pro-survival role of cAMP was associated with selective unresponsiveness of L929 cells to the inhibition of p38 activation by cAMP, even though cAMP significantly inhibited the activation of JNK under the same conditions. Further exploration revealed that the induction of DLC, the major mediator of p38 inhibition by cAMP, was impaired in L929 cells. Enforced inhibition of p38 activation by using p38 specific inhibitor or ectopic expression of DLC reversed the protection of L929 cells by cAMP from TNF-α-induced cell death. These data suggest that the lack of a pro-apoptotic pathway in tumor cells leads to a net survival effect of cAMP.
On the other hand, our data suggest that cAMP suppresses TNF-α-induced cell death of L929 fibroblastoma cells via, at least partially, inhibiting the activation of JNK pathway. The induction of c-FLIPL by cAMP via CREB-mediated transcription led to the inhibition of JNK activation by targeting MKK7, the upstream kinase of JNK pathway. However, it remains unknown whether there are other negative-regulators in the regulation of JNK by cAMP. So we further designed research to screen the cellular proteins that interact with MKK7 by yeast two-hybrid assay from human fetal brain cDNA library.
We identified three new MKK7-interacting proteins by yeast two-hybrid screen. They were ORF60, GNB2L1 and UBA3. Co-immunoprecipitaion assay confirmed the specific interaction with MKK7. Furthermore, immunoblotting analysis and luciferase assay showed that GNB2L1 could enhance the activation of JNK and downstream transcriptional factor AP-1, while the overexpression of ORF60 and UBA3 could inhibit the activation of JNK and AP-1. Our finding of the three new interacting proteins of MKK7 might facilitate the studies to elucidate the complicated mechanisms by which cAMP suppresses JNK pathway and plays a pro-survival role in tumor cells.
引文
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