Characterization of the c-Jun N-terminal kinase-BimEL signaling pathway in neuronal apoptosis.

Journal article

The c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in mediating apoptosis in the nervous system; however, the mechanisms by which JNK triggers neuronal apoptosis remain incompletely understood. Recent studies suggest that in addition to inducing transcription of pro-apoptotic genes, JNK also directly activates the cell death machinery. Here, we report that JNK catalyzed the phosphorylation of the BH3-only protein Bcl-2 interacting mediator of cell death (BimEL) at serine 65, both in vitro and in vivo. The JNK-induced phosphorylation of BimEL at serine 65 promoted the apoptotic effect of BimEL in primary cerebellar granule neurons. We also characterized the role of the JNK-BimEL signaling pathway in apoptosis that was triggered by overexpression of the p75 neurotrophin receptor (p75NTR). We found that activation of p75NTR induced the JNK-dependent phosphorylation of endogenous BimEL at serine 65 in cells. The genetic knockdown of BimEL by RNA interference or the expression of a dominant interfering form of BimEL significantly impaired the ability of activated p75NTR to induce apoptosis. Together, these results suggest that JNK-induced phosphorylation of BimEL at serine 65 mediates p75NTR-induced apoptosis. Our findings define a novel mechanism by which a death-receptor pathway directly activates the mitochondrial apoptotic machinery.

Authors: Becker, E; Howell, J; Kodama, Y; Barker, P; Bonni, A

• Publication status: Published
• Journal: Journal of neuroscience : the official journal of the Society for Neuroscience
• Volume: 24
• Issue: 40
• Pages: 8762-8770
• Publication date: 2004-10-01
• DOI: 10.1523/jneurosci.2953-04.2004
• EISSN: 1529-2401
• ISSN: 0270-6474
• Language: English
• Keywords: Serine; Receptor, Nerve Growth Factor; Receptors, Nerve Growth Factor; Humans; Apoptosis; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase Kinase 1; Animals; Neurons; Phosphorylation; Cells, Cultured; MAP Kinase Signaling System; Rats; Cell Line; PC12 Cells; Molecular Sequence Data; Amino Acid Sequence