11160861

Source:http://linkedlifedata.com/resource/pubmed/id/11160861

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Predicate	Object
rdf:type	pubmed:Citation
lifeskim:mentions	umls-concept:C0031715, umls-concept:C0162638, umls-concept:C0173879, umls-concept:C0248813, umls-concept:C0282549, umls-concept:C0332282, umls-concept:C0376515, umls-concept:C0596311, umls-concept:C1314939, umls-concept:C1330957, umls-concept:C1334474, umls-concept:C1879547
pubmed:issue	2
pubmed:dateCreated	2001-2-22
pubmed:abstractText	Paclitaxel is a novel anticancer drug that has demonstrated efficacy toward treating several malignant tumor types. Here, we demonstrate that c-Jun NH(2)-terminal kinase (JNK), but not p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2, was persistently activated by paclitaxel or other microtubule-damaging agents within human leukemia HL-60 cells. Overexpression of a dominant-negative mutant, mitogen-activated protein kinase kinase 1 (MEKK1-DN) or treatment with JNK-specific antisense oligonucleotide prevented paclitaxel-induced JNK activation, Bcl-2 phosphorylation and apoptosis. Furthermore, we found that the full-length MEKK1 was cleaved to a 91-kDa carboxyl-terminal fragment at the earlier time of apoptosis induced by microtubule-damaging agents. This cleavage, however, occurred consistently with JNK activation and Bcl-2 phosphorylation, but preceded DNA fragmentation in cells in response to paclitaxel activity. The caspase inhibitor Ac-Asp-Glu-Val-Asp-CHO (DEVD-CHO), but not Ac-Tyr-Val-Ala-Asp-CHO (Ac-YVAD-CHO), effectively blocked MEKK1 cleavage, JNK activation, Bcl-2 phosphorylation, and subsequent apoptosis. Subcellular fractionation revealed that the 91-kDa C-terminal MEKK1 fragment was translocated to cytosol. Notably, the MEKK1 fragment could be coimmunoprecipitated with anti-JNK antibodies, suggesting that a signaling complex of C-terminal MEKK1/stress-activated protein kinase/extracellular-signal regulated kinase 1/JNK formed during apoptosis induced by microtubule-damaging agents. Taken together, our results suggest that disruption of cytoarchitecture by paclitaxel triggers a novel apoptosis-signaling pathway, wherein an active DEVD-directed caspase (DEVDase) initially cleaves MEKK1to generate a proapoptotic kinase fragment that is able to activate JNK and subsequent Bcl-2 phosphorylation, finally eliciting cell death.
pubmed:language	eng
pubmed:journal	http://linkedlifedata.com/resource/pubmed/journal/0035623
pubmed:citationSubset	IM
pubmed:chemical	http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, Phytogenic, http://linkedlifedata.com/resource/pubmed/chemical/Caspases, http://linkedlifedata.com/resource/pubmed/chemical/Cysteine Proteinase Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/DEVDase, http://linkedlifedata.com/resource/pubmed/chemical/JNK Mitogen-Activated Protein..., http://linkedlifedata.com/resource/pubmed/chemical/MAP Kinase Kinase Kinase 1, http://linkedlifedata.com/resource/pubmed/chemical/MAP3K1 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinases, http://linkedlifedata.com/resource/pubmed/chemical/Oligopeptides, http://linkedlifedata.com/resource/pubmed/chemical/Paclitaxel, http://linkedlifedata.com/resource/pubmed/chemical/Peptide Fragments, http://linkedlifedata.com/resource/pubmed/chemical/Peptide Hydrolases, http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases, http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-bcl-2, http://linkedlifedata.com/resource/pubmed/chemical/aspartyl-glutamyl-valyl-aspartal
pubmed:status	MEDLINE
pubmed:month	Feb
pubmed:issn	0026-895X
pubmed:author	pubmed-author:ChuangS ESE, pubmed-author:FOXK HKH, pubmed-author:ShiahS GSG
pubmed:issnType	Print
pubmed:volume	59
pubmed:owner	NLM
pubmed:authorsComplete	Y
pubmed:pagination	254-62
pubmed:dateRevised	2011-11-2
pubmed:meshHeading	pubmed-meshheading:11160861-Antineoplastic Agents, Phytogenic, pubmed-meshheading:11160861-Apoptosis, pubmed-meshheading:11160861-Caspases, pubmed-meshheading:11160861-Cell Cycle, pubmed-meshheading:11160861-Cysteine Proteinase Inhibitors, pubmed-meshheading:11160861-Enzyme Activation, pubmed-meshheading:11160861-HL-60 Cells, pubmed-meshheading:11160861-Humans, pubmed-meshheading:11160861-JNK Mitogen-Activated Protein Kinases, pubmed-meshheading:11160861-MAP Kinase Kinase Kinase 1, pubmed-meshheading:11160861-Mitogen-Activated Protein Kinases, pubmed-meshheading:11160861-Oligopeptides, pubmed-meshheading:11160861-Paclitaxel, pubmed-meshheading:11160861-Peptide Fragments, pubmed-meshheading:11160861-Peptide Hydrolases, pubmed-meshheading:11160861-Phosphorylation, pubmed-meshheading:11160861-Protein-Serine-Threonine Kinases, pubmed-meshheading:11160861-Proto-Oncogene Proteins c-bcl-2
pubmed:year	2001
pubmed:articleTitle	Involvement of Asp-Glu-Val-Asp-directed, caspase-mediated mitogen-activated protein kinase kinase 1 Cleavage, c-Jun N-terminal kinase activation, and subsequent Bcl-2 phosphorylation for paclitaxel-induced apoptosis in HL-60 cells.
pubmed:affiliation	Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
pubmed:publicationType	Journal Article, Research Support, Non-U.S. Gov't