Cell death is widespread during the development of the nervous system where it helps to ensure that the proper number and types of connections are formed between neurons and their targets. During development, cell death occurs when neurons fail to receive adequate survival signals from trophic factors such as nerve growth factor (NGF). Accumulating evidence suggests that trophic factor deprivation-induced death is also important in human neuronal disorders and degenerative diseases. Using NGF-dependent sympathetic neurons as a model for trophic factor deprivation-induced death, we recently uncovered a novel pro-apoptotic function for the cis/trans prolyl isomerase Pin1. Pin1 is unique among prolyl isomerases in its specificity for catalyzing isomerization at select prolines adjacent to phosphorylated Ser and Thr residues. This specificity makes it an important regulator of cell signaling pathways mediated by c-Jun N-terminal kinases (JNK) and other proline-directed protein kinases. New data presented here suggest that Pin1 functions as a proximal positive regulator of the JNK/c-Jun signaling pathway during neuronal death. In addition to Pin1, we have obtained evidence that a second proline-directed enzyme, the prolyl hydroxylase EGLN3, also functions as a pro-apoptotic regulator of the JNK/c-Jun pathway in NGF-deprived neurons. Because upregulation of EGLN3 expression during cell death may itself be regulated by c-Jun, EGLN3 may function as part of a positive feedback mechanism to ensure sufficient pro-apoptotic c-Jun activity in neurons destined to die. Preliminary results suggest that apoptosis induced by Pin1 is inhibited if EGLN3 expression is suppressed, potentially tying Pin1 and EGLN3 together in a common cell death pathway. Based on these observations, we propose a model in which Pin1 functions upstream of EGLN3 to regulate the activation of pro-apoptotic c-Jun transcription factors during cell death caused by neurotrophic factor deprivation. We will test this hypothesis using a variety of molecular genetic, pharmacological, and biochemical approaches designed to achieve three specific aims.
In specific aim 1, we will determine if Pin1 acts as a positive regulator of c-Jun/AP-1 activity during trophic factor deprivation-induced cell death.
In specific aim 2, we will determine if EGLN3 functions as part of a positive feedback mechanism that enhances c-Jun/AP-1-mediated cell death.
Specific aim 3 will test the overall hypothesis that Pin1 and EGLN3 function as part of a common pathway to activate and amplify pro- apoptotic gene expression in neurons deprived of trophic factor. Completing these aims will further our understanding of the mechanisms that lead to neuronal cell death during normal development and in nervous systems disorders where trophic factor deprivation contributes to neuronal death and dysfunction.
Trophic factor deprivation-induced cell death is critical for proper development of the nervous system and is an important contributing factor in the loss and dysfunction of neurons that accompanies stroke, spinal cord injury, and neurodegenerative disease. This project will characterize new mechanisms that regulate cell death caused by neurotrophic factor deprivation. Information gained from this project will further our understanding of normal development and could help identify new targets for therapies aimed at preventing pathological neuronal cell death.
| Lomb, David J; Desouza, Lynette A; Franklin, James L et al. (2009) Prolyl hydroxylase inhibitors depend on extracellular glucose and hypoxia-inducible factor (HIF)-2alpha to inhibit cell death caused by nerve growth factor (NGF) deprivation: evidence that HIF-2alpha has a role in NGF-promoted survival of sympathetic neur Mol Pharmacol 75:1198-209 |
| Guo, Y; Schoell, M C; Freeman, R S (2009) The von Hippel-Lindau protein sensitizes renal carcinoma cells to apoptotic stimuli through stabilization of BIM(EL). Oncogene 28:1864-74 |
