PL Han - Academia.edu (original) (raw)

Papers by PL Han

Proceedings of the National Academy of Sciences, 2006

Opioid drugs produce their pharmacological effects by activating inhibitory guanine nucleotide-bi... more Opioid drugs produce their pharmacological effects by activating inhibitory guanine nucleotide-binding regulatory protein-linked μ, δ, and κ opioid receptors. One major effector for these receptors is adenylyl cyclase, which is inhibited upon receptor activation. However, little is known about which of the ten known forms of adenylyl cyclase are involved in mediating opioid actions. Here we show that all of the major behavioral effects of morphine, including locomotor activation, analgesia, tolerance, reward, and physical dependence and withdrawal symptoms, are attenuated in mice lacking adenylyl cyclase type 5 (AC5), a form of adenylyl cyclase that is highly enriched in striatum. Furthermore, the behavioral effects of selective μ or δ opioid receptor agonists are lost in AC5 −/− mice, whereas the behavioral effects of selective κ opioid receptor agonists are unaffected. These behavioral data are consistent with the observation that the ability of a μ or δ opioid receptor agonist to...

Journal of Neuroscience, 2006

Cerebral ischemic injury proceeds with excitotoxicity-induced acute neuronal death in the ischemi... more Cerebral ischemic injury proceeds with excitotoxicity-induced acute neuronal death in the ischemic core and with delayed damage processes in the penumbra. However, knowledge concerning the direct mediators that connect these two processes is limited. Here, we demonstrate that high-mobility group box 1 (HMGB1), a nonhistone DNA-binding protein, is massively released into the extracellular space immediately after ischemic insult and that it subsequently induces neuroinflammation in the postischemic brain. Short hairpin (sh)RNA-mediated HMGB1 downregulation in the postischemic brain suppressed infarct size, microglia activation, and proinflammatory marker induction, indicating that HMGB1 plays a crucial role in the inflammatory process. The proinflammatory cytokine-like function of extracellular HMGB1 was further verified in primary cortical cultures and microglial cultures. HMGB1 was found to accumulate in NMDA-treated primary cortical culture media, and supernatants collected from these cultures were found to trigger microglia activation, the hallmark of brain inflammation. Moreover, treatment with recombinant HMGB1 also induced microglial activation, but HMGB1-depleted supernatant produced by anti-HMGB1 antibody treatment or by HMGB1 shRNA expression did not, thus demonstrating the essential role of HMGB1 in microglial activation. Together, these results indicate that HMGB1 functions as a novel proinflammatory cytokine-like factor that connects excitotoxicity-induced acute damage processes and delayed inflammatory processes in the postischemic brain.

Journal of Biological Chemistry, 1997

Bcl-2 is an intracellular membrane-associated protein that prevents cell death induced by a varie... more Bcl-2 is an intracellular membrane-associated protein that prevents cell death induced by a variety of apoptotic stimuli. A mechanism by which Bcl-2 exerts an anti-cell death effect is, however, not fully understood. In the present study, Bcl-2 suppressed cell death of N18TG neuroglioma cells caused by various apoptotic stresses, including etoposide, staurosporine, anisomycin, and ultraviolet irradiation. Concomitantly, Bcl-2 disrupted a signaling cascade to the c-Jun N-terminal kinase activation induced by the apoptotic stresses. Bcl-2 also prevented the etoposide-induced stimulation of MEKK1. Furthermore, overexpression of c-Jun N-terminal kinase antagonized the death-protective function of Bcl-2. These data suggest that suppression of the c-Jun N-terminal kinase signaling pathway may be critical for Bcl-2 action.

Journal of …, 2008

Kim, K.-S., Lee, K.-W., Baek, I.-S., Lim, C.-M., Krishnan, V., Lee, J.-K., Nestler, EJ and Han, P... more Kim, K.-S., Lee, K.-W., Baek, I.-S., Lim, C.-M., Krishnan, V., Lee, J.-K., Nestler, EJ and Han, P.-L.(2008), Adenylyl cyclase-5 activity in the nucleus accumbens regulates anxiety-related behavior. Journal of Neurochemistry, 107: 105–115. doi: 10.1111/j. 1471-4159.2008. ...

Stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) is activated by a variety of c... more Stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) is activated by a variety of cellular or environmental stresses. Proper regulation of the SAPK/JNK pathway may be critical for cell survival or death under various conditions. In this study, we report the molecular cloning of novel isoforms of JIP-1, which harbor a putative phosphotyrosine interaction domain and a helix-loop-helix domain, as well as an SH3 homologous region in the C terminus. Northern analysis indicates that transcription variant jip-1 is expressed in brain and kidney and transcription variants jip-2 and jip-3 are specifically expressed in brain. In situ hybridization data showed that the hybridized jip messages were heavily concentrated in adult brain, and were particularly enriched in the cerebral cortex and hippocampus, the brain regions vulnerable to pathological states such as hypoxia-ischemia, epilepsy, and Alzheimer's disease. All the deduced protein products of the jip transcription variants appear to have a similar property in that they inhibit the SAPK/JNK stimulation when overexpressed. Inhibition of SAPK activation by overexpression of the novel isoform JIP-2a resulted in suppression of etoposide-induced cell death in a neuroglioma cell line, N18TG. These findings suggest that JIP may play an important role in regulation of the SAPK pathway that is involved in stress-induced cellular responses.

Proceedings of the National Academy of Sciences, 2006

Opioid drugs produce their pharmacological effects by activating inhibitory guanine nucleotide-bi... more Opioid drugs produce their pharmacological effects by activating inhibitory guanine nucleotide-binding regulatory protein-linked μ, δ, and κ opioid receptors. One major effector for these receptors is adenylyl cyclase, which is inhibited upon receptor activation. However, little is known about which of the ten known forms of adenylyl cyclase are involved in mediating opioid actions. Here we show that all of the major behavioral effects of morphine, including locomotor activation, analgesia, tolerance, reward, and physical dependence and withdrawal symptoms, are attenuated in mice lacking adenylyl cyclase type 5 (AC5), a form of adenylyl cyclase that is highly enriched in striatum. Furthermore, the behavioral effects of selective μ or δ opioid receptor agonists are lost in AC5 −/− mice, whereas the behavioral effects of selective κ opioid receptor agonists are unaffected. These behavioral data are consistent with the observation that the ability of a μ or δ opioid receptor agonist to...

Journal of Neuroscience, 2006

Cerebral ischemic injury proceeds with excitotoxicity-induced acute neuronal death in the ischemi... more Cerebral ischemic injury proceeds with excitotoxicity-induced acute neuronal death in the ischemic core and with delayed damage processes in the penumbra. However, knowledge concerning the direct mediators that connect these two processes is limited. Here, we demonstrate that high-mobility group box 1 (HMGB1), a nonhistone DNA-binding protein, is massively released into the extracellular space immediately after ischemic insult and that it subsequently induces neuroinflammation in the postischemic brain. Short hairpin (sh)RNA-mediated HMGB1 downregulation in the postischemic brain suppressed infarct size, microglia activation, and proinflammatory marker induction, indicating that HMGB1 plays a crucial role in the inflammatory process. The proinflammatory cytokine-like function of extracellular HMGB1 was further verified in primary cortical cultures and microglial cultures. HMGB1 was found to accumulate in NMDA-treated primary cortical culture media, and supernatants collected from these cultures were found to trigger microglia activation, the hallmark of brain inflammation. Moreover, treatment with recombinant HMGB1 also induced microglial activation, but HMGB1-depleted supernatant produced by anti-HMGB1 antibody treatment or by HMGB1 shRNA expression did not, thus demonstrating the essential role of HMGB1 in microglial activation. Together, these results indicate that HMGB1 functions as a novel proinflammatory cytokine-like factor that connects excitotoxicity-induced acute damage processes and delayed inflammatory processes in the postischemic brain.

Journal of Biological Chemistry, 1997

Bcl-2 is an intracellular membrane-associated protein that prevents cell death induced by a varie... more Bcl-2 is an intracellular membrane-associated protein that prevents cell death induced by a variety of apoptotic stimuli. A mechanism by which Bcl-2 exerts an anti-cell death effect is, however, not fully understood. In the present study, Bcl-2 suppressed cell death of N18TG neuroglioma cells caused by various apoptotic stresses, including etoposide, staurosporine, anisomycin, and ultraviolet irradiation. Concomitantly, Bcl-2 disrupted a signaling cascade to the c-Jun N-terminal kinase activation induced by the apoptotic stresses. Bcl-2 also prevented the etoposide-induced stimulation of MEKK1. Furthermore, overexpression of c-Jun N-terminal kinase antagonized the death-protective function of Bcl-2. These data suggest that suppression of the c-Jun N-terminal kinase signaling pathway may be critical for Bcl-2 action.

Journal of …, 2008

Kim, K.-S., Lee, K.-W., Baek, I.-S., Lim, C.-M., Krishnan, V., Lee, J.-K., Nestler, EJ and Han, P... more Kim, K.-S., Lee, K.-W., Baek, I.-S., Lim, C.-M., Krishnan, V., Lee, J.-K., Nestler, EJ and Han, P.-L.(2008), Adenylyl cyclase-5 activity in the nucleus accumbens regulates anxiety-related behavior. Journal of Neurochemistry, 107: 105–115. doi: 10.1111/j. 1471-4159.2008. ...

Stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) is activated by a variety of c... more Stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) is activated by a variety of cellular or environmental stresses. Proper regulation of the SAPK/JNK pathway may be critical for cell survival or death under various conditions. In this study, we report the molecular cloning of novel isoforms of JIP-1, which harbor a putative phosphotyrosine interaction domain and a helix-loop-helix domain, as well as an SH3 homologous region in the C terminus. Northern analysis indicates that transcription variant jip-1 is expressed in brain and kidney and transcription variants jip-2 and jip-3 are specifically expressed in brain. In situ hybridization data showed that the hybridized jip messages were heavily concentrated in adult brain, and were particularly enriched in the cerebral cortex and hippocampus, the brain regions vulnerable to pathological states such as hypoxia-ischemia, epilepsy, and Alzheimer's disease. All the deduced protein products of the jip transcription variants appear to have a similar property in that they inhibit the SAPK/JNK stimulation when overexpressed. Inhibition of SAPK activation by overexpression of the novel isoform JIP-2a resulted in suppression of etoposide-induced cell death in a neuroglioma cell line, N18TG. These findings suggest that JIP may play an important role in regulation of the SAPK pathway that is involved in stress-induced cellular responses.