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Publication Detail

Title: Taxol induces apoptosis in cortical neurons by a mechanism independent of Bcl-2 phosphorylation.

Authors: Figueroa-Masot, X A; Hetman, M; Higgins, M J; Kokot, N; Xia, Z

Published In J Neurosci, (2001 Jul 01)

Abstract: Bcl-2, an antiapoptotic protein, protects cells against many but not all forms of apoptosis. For example, Bcl-2 does not protect non-neuronal cells against taxol, a microtubule-stabilizing agent. The underlying mechanism for the ineffectiveness of Bcl-2 against taxol has been the subject of intense interest. Data from non-neuronal cells indicate that taxol-induced apoptosis requires activation of N-terminal c-Jun protein kinase (JNK) that phosphorylates and inactivates Bcl-2. This suggests the interesting possibility that the apoptotic activity of JNK may be caused by phosphorylation of Bcl-2 and inhibition of the antiapoptotic activity of Bcl-2. Here we report that taxol induces apoptosis in cortical neurons but by a mechanism significantly different from that in non-neuronal cells. In contrast to human embryonic kidney 293 cells, expression of wild-type Bcl-2 in cortical neurons protected against taxol-induced apoptosis, and taxol did not induce Bcl-2 phosphorylation. Furthermore, cortical neurons express high basal JNK activity, and taxol did not stimulate total JNK activity. However, taxol activated a subpool of JNK in the nucleus and stimulated c-Jun phosphorylation. JNK inhibition or expression of a dominant-negative c-Jun abrogated taxol-induced apoptosis in cortical neurons, suggesting a role for JNK and JNK-mediated transcription in taxol-stimulated apoptosis. Furthermore, taxol-induced apoptosis in cortical neurons required inhibition of phosphatidylinositol 3-kinase signaling. These data suggest that taxol induces apoptosis in neurons by a mechanism quite distinct from that of non-neuronal cell lines and emphasize the importance of elucidating apoptotic mechanisms specific for neurons in the CNS.

PubMed ID: 11425893 Exiting the NIEHS site

MeSH Terms: Animals; Apoptosis*; Cell Nucleus/drug effects; Cell Nucleus/metabolism; Cell Survival/drug effects; Cells, Cultured; Cerebral Cortex/cytology; Cerebral Cortex/drug effects*; Cerebral Cortex/metabolism; Enzyme Activation/drug effects; Enzyme Inhibitors/pharmacology; Gene Expression; Humans; JNK Mitogen-Activated Protein Kinases; Kidney/cytology; Kidney/drug effects; Kidney/metabolism; MAP Kinase Kinase 1; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors; Mitogen-Activated Protein Kinases/metabolism; Neurons/cytology; Neurons/drug effects*; Neurons/metabolism; Paclitaxel/pharmacology*; Phosphatidylinositol 3-Kinases/antagonists & inhibitors; Phosphatidylinositol 3-Kinases/metabolism; Phosphorylation/drug effects; Protein-Serine-Threonine Kinases/antagonists & inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2/genetics; Proto-Oncogene Proteins c-bcl-2/metabolism*; Proto-Oncogene Proteins/metabolism; Rats; Rats, Sprague-Dawley; Signal Transduction/drug effects; Transcription, Genetic; Transfection

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