• Interaction

    AccNo. 45217 Score 0.49
    Name PM_11160861
    Kd 1.0

    Peptide

    AccNo. 45095
    Name YVAD
    Sequence YVAD
    45095_small
    Internalized no
    Is Motif no

    Interactor

    AccNo. 44717
    Name unknown

    Experiment

    AccNo. 45058
    Classification incorrect?
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    Voting_motivation
    CA CVD DM APO ANG MI BD
    0.78 0.81 0.38 0.79 0.23 0.33 0.51 Vote
    plus plus plus plus plus plus plus Yes
    minus minus minus minus minus minus minus No
    Name PM_11160861
    Detection unspecified method, MI:0686
    Source Pubmed Text Id 11160861
    Journal Mol Pharmacol. 2001 Feb;59(2):254-62.
    Title 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.
    Authors Shiah SG, Chuang SE, Kuo ML
    Text 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.
    Mesh Terms Antineoplastic Agents, Phytogenic/pharmacology; Apoptosis; Caspases/metabolism; Cell Cycle/drug effects; Cysteine Proteinase Inhibitors/pharmacology; Enzyme Activation/drug effects; HL-60 Cells; Humans; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase Kinase 1; Mitogen-Activated Protein Kinases/metabolism; Oligopeptides/pharmacology; Paclitaxel/pharmacology; Peptide Fragments/metabolism; Peptide Hydrolases/physiology; Phosphorylation/drug effects; Protein-Serine-Threonine Kinases/metabolism; Proto-Oncogene Proteins c-bcl-2/metabolism
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