Keramaris Elizabeth, Ruzhynsky Vladamir A, Callaghan Steve M, Wong Estelle, Davis Roger J, Flavell Richard, Slack Ruth S, Park David S
Department of Cellular Molecular Medicine, Neuroscience East, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada, the.
Department of Biochemistry and Molecular Biology, Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
J Biol Chem. 2008 Jan 4;283(1):405-415. doi: 10.1074/jbc.M701552200. Epub 2007 Nov 5.
Retinoblastoma-deficient mice show massive neuronal damage and deficits in both CNS and PNS tissue. Previous work in the field has shown that death is regulated through distinct processes where CNS tissue undergoes death regulated by the tumor suppressor p53 and the apoptosome component, APAF1. Death in the PNS, however, is independent of p53 and reliant on the death protease, caspase 3. In the present study, we more carefully delineated the common and distinct mechanisms of death regulation by examining the stress-activated kinases, JNK2 and 3, the conserved Bcl-2 member Bax, and the relationship among these elements including p53. By use of genetic modeling, we show that death in various regions of the CNS and DRGs of the PNS is reliant on Bax. In the CNS, Bax acts downstream of p53. The relevance of the JNKs is more complex, however. Surprisingly, JNK3 deficiency by itself does not inhibit c-Jun phosphorylation and instead, aggravates death in both CNS and PNS tissue. However, JNK2/3 double deficiency blocks death due to Rb loss in both the PNS and CNS. Importantly, the relationships between JNKs, p53, and Bax exhibit regional differences. In the medulla region of the hindbrain in the CNS, JNK2/3 deficiency blocks p53 activation. Moreover, Bax deficiency does not affect c-Jun phosphorylation. This indicates that a JNK-p53-Bax pathway is central in the hindbrain. However, in the diencephalon regions of the forebrain (thalamus), Bax deficiency blocks c-Jun activation, indicating that a Bax-JNK pathway of death is more relevant. In the DRGs of the PNS, a third pathway is present. In this case, a JNK-Bax pathway, independent of p53, regulates damage. Accordingly, our results show that a death regulator Bax is common to death in both PNS and CNS tissue. However, it is regulated by or itself regulates different effectors including the JNKs and p53 depending upon the specific region of the nervous system.
视网膜母细胞瘤缺陷小鼠的中枢神经系统（CNS）和外周神经系统（PNS）组织均出现大量神经元损伤和功能缺陷。该领域先前的研究表明，细胞死亡是通过不同的过程进行调控的，其中CNS组织的死亡受肿瘤抑制因子p53和凋亡小体成分APAF1的调控。然而，PNS中的细胞死亡独立于p53，依赖于死亡蛋白酶caspase 3。在本研究中，我们通过研究应激激活激酶JNK2和JNK3、保守的Bcl-2家族成员Bax以及包括p53在内的这些元件之间的关系，更仔细地描绘了细胞死亡调控的共同和不同机制。通过基因建模，我们表明CNS的各个区域以及PNS的背根神经节（DRG）中的细胞死亡依赖于Bax。在CNS中，Bax在p53的下游起作用。然而，JNKs的相关性更为复杂。令人惊讶的是，单独的JNK3缺陷并不抑制c-Jun磷酸化，反而会加重CNS和PNS组织中的细胞死亡。然而，JNK2/3双缺陷可阻止PNS和CNS中由于Rb缺失导致的细胞死亡。重要的是，JNKs、p53和Bax之间的关系存在区域差异。在CNS中脑桥的延髓区域，JNK2/3缺陷会阻止p53激活。此外，Bax缺陷并不影响c-Jun磷酸化。这表明JNK-p53-Bax通路在延髓中起核心作用。然而，在前脑的间脑区域（丘脑），Bax缺陷会阻止c-Jun激活，这表明Bax-JNK细胞死亡通路更为相关。在PNS的DRG中，存在第三条通路。在这种情况下，独立于p53的JNK-Bax通路调节损伤。因此，我们的结果表明，死亡调节因子Bax在PNS和CNS组织的细胞死亡中是共同存在的。然而，根据神经系统的特定区域，它受不同效应器（包括JNKs和p53）的调控或自身调控这些效应器。
