Zeini Miriam, Través Paqui G, López-Fontal Raquel, Pantoja Cristina, Matheu Ander, Serrano Manuel, Boscá Lisardo, Hortelano Sonsoles
Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
J Immunol. 2006 Sep 1;177(5):3327-36. doi: 10.4049/jimmunol.177.5.3327.
NO is an important bioactive molecule involved in a variety of physio- and pathological processes, including apoptosis induction. The proapoptotic activity of NO involves the rise in the tumor suppressor p53 and the accumulation and targeting of proapoptotic members of the Bcl-2 family, in particular Bax and the release of cytochrome c from the mitochondria. However, the exact mechanism by which NO induces p53 activation has not been fully elucidated. In this study, we describe that NO induces p19(ARF) through a transcriptional mechanism. This up-regulation of p19(ARF) activates p53, leading to apoptosis. The importance of p19(ARF) on NO-dependent apoptosis was revealed by the finding that various cell types from alternate reading frame-knockout mice exhibit a diminished response to NO-mediated apoptosis when compared with normal mice. Moreover, the biological relevance of alternative reading frame to p53 apoptosis was confirmed in in vivo models of apoptosis. Together, these results demonstrate that NO-dependent apoptosis requires, in part, the activation of p19(ARF).
一氧化氮（NO）是一种重要的生物活性分子，参与多种生理和病理过程，包括诱导细胞凋亡。NO的促凋亡活性涉及肿瘤抑制因子p53的升高以及Bcl-2家族促凋亡成员（特别是Bax）的积累和靶向作用，以及细胞色素c从线粒体的释放。然而，NO诱导p53激活的确切机制尚未完全阐明。在本研究中，我们描述了NO通过转录机制诱导p19（ARF）。p19（ARF）的这种上调激活了p53，导致细胞凋亡。与正常小鼠相比，来自可变阅读框敲除小鼠的各种细胞类型对NO介导的细胞凋亡反应减弱，这一发现揭示了p19（ARF）在NO依赖性细胞凋亡中的重要性。此外，在体内细胞凋亡模型中证实了可变阅读框与p53凋亡的生物学相关性。总之，这些结果表明，NO依赖性细胞凋亡部分需要p19（ARF）的激活。
