C JUN, C FOS AND NEURONAL PROGRAMMED CELL DEATH

细胞程序性死亡是一种公认的发育现象 这是通过细胞凋亡过程发生的。 最近的证据有力地表明 PCD也会导致病理状况。 几行 有证据表明，PCD是由一种特定的 基因程序导致蛋白质杀死细胞。 我们已经确定 在交感神经元中表达增加的几个基因 经历PCD以响应神经营养因子NGF的剥夺， 以及许多表达减少的基因。 我们提供了证据 c-Jun，一种由诱导基因编码的转录因子， 是神经元PCD所必需的。 我们还提供了证据， 暗示Fos家族是细胞凋亡所必需的;在缺乏NGF的 神经元，某些Fos家族成员，即，c-fos和fos B被诱导， 而其他的潜在抑制性家族成员，即，FRA-1和FRA-2， 被压抑了 这些结果使我们推测神经元PCD依赖于 在某些基因，即，c-jun和镇压 其他基因，即，FRA-1和FRA-2。 因为（i）归纳f c-jun是 最早可检测的遗传事件，（ii）c-Jun与每个Fos相互作用 家庭成员，和（iii）c-Jun已被牵连具体作为 我们目前的工作假设是， 诱导c-jun，调节c-Jun的活性， c-Jun的作用，构成了生物化学和遗传学的关键部分。 导致神经元死亡的级联反应。 我们建议集中攻击 评估这个假设。 我们将进一步明确jun和Fos家族成员的角色， 神经元死亡的分子遗传学方法。 我们将 分析这些基因在mRNA蛋白水平上的表达， 可能的转录后调节。 我们将研究 蛋白质：Jun和Fos家族成员之间的蛋白质相互作用， 直接鉴定与c-Jun相互作用的c-Jun蛋白。我们将 评估是否有保护神经元免受NGF剥夺的药物，即， cAMP类似物和钾去极化，通过激活CREB-2， 这些试剂激活并调节c-Jun的转录因子。 我们将确定细胞凋亡过程中的生化变化， c-Jun，以确定c-Jun作用的“下游”机制。 我们将 确定导致激活的分子和细胞机制， c-jun;这项调查将导致“上游”的时间级联 通过评估氧化应激和c-Jun的作用， 磷酸化 这些研究将提供相当深入的了解， 和Fos家族成员在神经元PCD中的作用及其整体机制 神经元PCD 鉴于越来越多的证据表明神经元PCD在 神经系统的病理状况，即，中风，神经毒性， 和神经退行性疾病，这些见解可能会导致策略， 在这些情况下进行干预，以防止或延缓死亡。

Programmed cell death (PCD) is a well-recognized developmental phenomenon that occurs by a process of apoptosis. Recent evidence strongly suggests that PCD also contributes to pathological conditions. Several lines of evidence have indicated that PCD results from the expression of a specific genetic program leading to proteins that kill the cell. We have identified several genes whose expression in increased in sympathetic neurons undergoing PCD in response to deprivation of the neurotrophic factor, NGF, and many genes whose expression is decreased. We have presented evidence that c-Jun, a transcription factor encoded by the one of the induced genes, is required for neuronal PCD. We have also presented evidence that implicate the Fos family as being necessary for apoptosis; in NGF-deprived neurons, certain Fos family members, i.e., c-fos and fos B, are induced, while other, potentially inhibitory family members, i.e., fra-1 and fra-2, are repressed. These results led us to theorize that neuronal PCD depends upon both the activation of certain genes, i.e., c-jun, and the repression of other genes, i.e., fra-1 and fra-2. Since (i) the induction f c-jun is the earliest detectable genetic event, (ii) c-Jun interacts with each Fos family member, and (iii) c-Jun has been implicated specifically as necessary for death, our current working hypothesis is that events that induce c-jun, modulate the activity of c-Jun, and that emanate from the actions of c-Jun, constitute critical portions of a biochemical and genetic cascade that results in neuronal death. We propose a focused attack aimed at evaluating this hypothesis. We shall further define the roles of the jun and Fos family members in neuronal death by using several molecular genetic approaches. We shall analyze athe expression of these genes at athe protein level to investigate possible post-transcriptional regulation. We shall examine the protein:protein interactions among the Jun and Fos family members to identify directly athe proteins that interact with c-Jun. We shall evaluate whether agents that protect neurons from NGF deprivation, i.e., cAMP analogs and potassium depolarization, do so by activating CREB-2, a transcription factor that these agents activate and that modulates c-Jun. We shall determine the biochemical changes during apoptosis that depend on c-Jun, to identify 'downstream" mechanisms of c-Jun action. We shall identify the molecular and cellular mechanisms leading to the activation of c-jun; this investigation will lead "upstream" in the temporal cascade of events by evaluating the roles of oxidative stress and c-Jun phosphorylation. These studies will provide considerable insight into the role of the Jun and Fos family members in neuronal PCD and athe overall mechanism of neuronal PCD. Given the increasing evidence for a role of neuronal PCD in pathological conditions of the nervous system, i.e., stroke, neurotoxicity, and neurodegenerative disease, these insights may lead to strategies to intervene pharmacologically to prevent or retard death in these conditions.