C JUN, C FOS AND NEURONAL PROGRAMMED CELL DEATH

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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.