Complex functions of AP-1 transcription factors in differentiation and survival of PC12 cells
Complex functions of AP-1 transcription factors in differentiation and survival of PC12 cells
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DOI：
10.1128/mcb.21.13.4369-4378.2001
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发表时间：
2001-07-01
影响因子：
5.3
通讯作者：
Bohmann, D
中科院分区：
文献类型：
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作者：
Leppä, S;Eriksson, M;Bohmann, D
由丝裂原激活的蛋白激酶激活的c-jun参与了多种细胞信号反应。我们研究了JNK和c-Jun在神经元分化、细胞存活和细胞凋亡中的作用。在分化的PC12细胞中，JNK信号可诱导细胞凋亡，c-Jun介导这一反应。相反，我们发现在尚未分化的PC12细胞中，AP-1家族成员ATF-2而不是c-Jun作为凋亡的执行者。在这种情况下，c-jun的表达可以防止细胞凋亡，并触发轴突的形成。因此，c-jun在神经元分化前后具有相反的功能。这些发现提出了一种模型，在该模型中，PC12细胞中ATF-2和Jun活性之间的平衡控制着分化为神经元命运和凋亡程序之间的选择。对c-jun突变体的进一步分析表明，分化反应需要功能二聚化和DNA结合域，并受到反式激活域中磷酸化的刺激。相反，c-jun突变体不能与DNA结合或二聚化，以及缺乏JNK结合和磷酸化位点的突变体也不能诱导神经元分化，有效地保护PC12细胞免受凋亡。因此，c-jun的保护作用似乎是由一种非常规机制介导的，这种机制与其作为经典的AP-1转录因子的功能是分开的。
c-Jun activation by mitogen-activated protein kinases has been implicated in various cellular signal responses. We investigated how JNK and c-Jun contribute to neuronal differentiation, cell survival, and apoptosis. In differentiated PC12 cells, JNK signaling can induce apoptosis and c-Jun mediates this response. In contrast, we show that in PC12 cells that are not yet differentiated, the AP-1 family member ATF-2 and not c-Jun acts as an executor of apoptosis. In this context c-Jun expression protects against apoptosis and triggers neurite formation. Thus, c-Jun has opposite functions before and after neuronal differentiation. These findings suggest a model in which the balance between ATF-2 and Jun activity in PC12 cells governs the choice between differentiation towards a neuronal fate and an apoptotic program. Further analysis of c-Jun mutants showed that the differentiation response requires functional dimerization and DNA-binding domains and that it is stimulated by phosphorylation in the transactivation domain. In contrast, c-Jun mutants incompetent for DNA binding or dimerization and also mutants lacking JNK binding and phosphorylation sites that cannot elicit neuronal differentiation efficiently protect PC12 cells from apoptosis. Hence, the protective role of c-Jun appears to be mediated by an unconventional mechanism that is separable from its function as a classical AP-1 transcription factor.