REGγ对p53蛋白活性调控的分子机制及其在肿瘤形成中的作用
摘要
虽然蛋白酶体激活因子REGy已经被证明能够降解哺乳动物细胞中完整的蛋白质,但是REGy的生物学功能和机理还是有很多未知之处,需要进一步的研究和探索。本文通过胞外和胞内实验证明REGy能够促进p53蛋白发生单泛素化,从而调节p53蛋白的胞内分布。当p53蛋白发生依赖于Mdm2的单泛素化后,会促进p53蛋白发生经典途径的出核和降解。p53蛋白多点的单泛素化会加强p53与Mdm2之间的相互作用,可能进一步的促进其出核和降解。同时,REGy会抑制p53蛋白四聚体的形成。这也进一步促进了p53蛋白出核,并降低了其在核内的活性。在细胞凋亡实验中,抑制REGy的表达使肿瘤细胞对抗癌药物刺激所引起的细胞凋亡变得更加敏感。通过抑制p53蛋白的表达证明REGy对细胞凋亡的调控依赖于p53蛋白。利用小鼠移植瘤模型,我们发现抑制REGy的表达会明显抑制肿瘤生长。这充分表明REGy在肿瘤发生发展中的重要作用。总之,我们的研究证明了REGy对p53蛋白活性的抑制是影响癌症发生发展的重要机理之一。
The proteasome activator REGγhas been demonstrated to mediate a shortcut to destruction of intact mammalian proteins. Yet the biological roles of REGy and underlying mechanisms are not fully understood. Here we provide evidence, in vitro and in cells, that REGy regulates p53 cellular distribution by facilitating multiple monoubiquitination of p53. While p53 get the Mdm2-dependent monoubiquitination promotes canonical nuclear export and subsequent degradation, inhibition of p53 tetramerization by REGγmay further enhance cytoplasmic relocation of p53 and reduce p53 activity in nucleus. Furthermore, multiple monoubiquitination of p53 enhances its physical interaction with Mdm2 and likely facilitates subsequent polyubiquitination of p53, suggesting a role of monoubiquitination as asignal for p53 degradation. Depletion of REGy sensitizes cells to stress-induced apoptosis, validating its critical role in the control of apoptosis likely through regulating p53 function. Using a mouse xenograft model, we show that REGy knockdown results in a significant reduction of tumor growth, suggesting an important role for REGγin tumor development. Taken together, our study demonstrates REGγ-mediated inactivation of p53 as one of the mechanisms in cancer progression.
The proteasome activator REGγhas been demonstrated to mediate a shortcut to destruction of intact mammalian proteins. Yet the biological roles of REGy and underlying mechanisms are not fully understood. Here we provide evidence, in vitro and in cells, that REGy regulates p53 cellular distribution by facilitating multiple monoubiquitination of p53. While p53 get the Mdm2-dependent monoubiquitination promotes canonical nuclear export and subsequent degradation, inhibition of p53 tetramerization by REGγmay further enhance cytoplasmic relocation of p53 and reduce p53 activity in nucleus. Furthermore, multiple monoubiquitination of p53 enhances its physical interaction with Mdm2 and likely facilitates subsequent polyubiquitination of p53, suggesting a role of monoubiquitination as asignal for p53 degradation. Depletion of REGy sensitizes cells to stress-induced apoptosis, validating its critical role in the control of apoptosis likely through regulating p53 function. Using a mouse xenograft model, we show that REGy knockdown results in a significant reduction of tumor growth, suggesting an important role for REGγin tumor development. Taken together, our study demonstrates REGγ-mediated inactivation of p53 as one of the mechanisms in cancer progression.
引文
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