Activation of MLK2-mediated signaling cascades by polyglutamine-expanded huntingtin.

We previously reported that expression of polyglutamine-expanded huntingtin induces apoptosis via c-Jun amino-terminal kinase (JNK) activation in HN33 cells (Liu, Y. F. (1998) J. Biol. Chem. 273, 28873-28822). Extending this study, we now demonstrate a role of mixed-lineage kinase 2 (MLK2), a JNK activator, in polyglutamine-expanded huntingtin-mediated neuronal toxicity. We ...
find that normal huntingtin interacts with MLK2, whereas the polyglutamine expansion interferes with this interaction. Similar to the expression of polyglutamine-expanded huntingtin, expression of MLK2 also induces JNK activation and apoptosis in HN33 cells. Co-expression of dominant negative MLK2 significantly attenuates neuronal apoptosis induced by the mutated huntingtin. Furthermore, over-expression of the N terminus of normal huntingtin partially rescues the neuronal toxicity induced by MLK2. Our results suggest that activation of MLK2-mediated signaling cascades may be partially involved in neuronal death induced by polyglutamine-expanded huntingtin.
Mesh Terms:
Animals, Cell Line, Enzyme Activation, Glutathione Transferase, MAP Kinase Kinase Kinases, Mutagenesis, Nerve Tissue Proteins, Nuclear Proteins, Peptides, Rats, Recombinant Fusion Proteins, Signal Transduction
J. Biol. Chem.
Date: Jun. 23, 2000
Download Curated Data For This Publication
4221
Switch View:
  • Interactions 2