Apoptosis plays important roles in the developing nervous system and in the maintenance of homeostasis in adult brains. Aberrations in the regulation of apoptosis contribute to pathogenesis of neurodegenerative diseases, including hereditary sensory and autonomic neuropathy, ALS, Huntington's Disease, Parkinson's Disease, and Alzheimer's Disease. One major mechanism to control cell death is by transcriptional regulation of members in the Bcl-2 family. For instance, p53 induces neuronal apoptosis by up-regulating Bax and inhibiting Bcl-xL expression. In contrast, homeodomain transcription factor Brn3a antagonizes p53 and promotes the expression of Bcl-2 and Bcl-xL. While these results suggest that p53 and Brn3a may control the delicate balance of neuronal death and survival, it remains unclear if these two molecules interact directly or if they are regulated through a common signaling mechanism. Our data favor the latter model and indicate that homeodomain interacting protein kinase 2 (HIPK2) induces neuronal apoptosis by exerting opposing effects on p53 and Brn3a. Expression of HIPK2 in sensory neurons activates apoptosis through up-regulation of p53 target gene Bax and suppression of Brn3a target Bcl-xL. Consistent with these data, HIPK2-induced apoptosis can be partially inhibited by Brn3a, Bcl-xL and Bcl-w. Furthermore, the effect of HIPK2 is much attenuated in p53 -/- neurons and is completely abolished in BaX/neurons. HIPK2 is abundantly present in the nervous system and the subcellular localization of HIPK2 in sensory neurons appears to coincide with the stages when neurons receive neurotrophins from the target tissue, suggesting that the activity of HIPK2 may be regulated through neurotrophin signaling pathways. These results lead us to hypothesize that HIPK2 is a key component that regulates the neuronal death during development and in stress-induced pathological conditions. To test this hypothesis further, we propose to investigate the upstream signaling pathways that regulate HIPK2 activity. In particular, we will focus on the roles of JNK pathway in HIPK2 functions (Aim 1). To determine the in vivo functions of HIPK2, we have deleted the HIPK2 gene and will investigate the neurological phenotype of HIPK2 / mutants in developmentally programmed cell death and in injury-induced apoptosis paradigms (Aim 2). Finally, we will study the detailed mechanisms of HIPK2-induced, p53-dependent regulation of Bax and related pro-apoptotic genes. We will also determine if HIPK2-mediated activation of additional targets, such as p53-related molecule p73, contributes to neuronal apoptosis. Our long-term goal is to elucidate HIPK2-induced signaling pathways in neuronal apoptosis. Discoveries from this project will contribute to future design of HIPK2 inhibitors that can promote neuronal survival in neurodegenerative diseases ? ?
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