Molecular cloning of multiple splicing variants of JIP-1 preferentially expressed in brain

Stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) is activ ated by a variety of cellular or environmental stresses. Proper regulation of the SAPK/JNK pathway may be critical for cell survival or death under va rious conditions. In this study, we report the molecular cloning of novel i soforms of JIP-1, which harbor a putative phosphotyrosine interaction domai n 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 i s 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 brai n regions vulnerable to pathological states such as hypoxia-ischemia, epile psy, and Alzheimer's disease. All the deduced protein products of the jip t ranscription variants appear to have a similar property in that they inhibi t the SAPK/JNK stimulation when overexpressed. Inhibition of SAPK activatio n by overexpression of the novel isoform JIP-2a resulted in suppression of etoposide-induced cell death in a neuroglioma cell line, N18TG. These findi ngs suggest that JIP may play an important role in regulation of the SAPK p athway that is involved in stress-induced cellular responses.