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.
Liu
Y F
YF
Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, USA. yafliu@lynx.neu.edu
Dorow
D
D
Marshall
J
J
D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D005982:Glutathione Transferase / Q000235:genetics; D000071058:Huntingtin Protein; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D016296:Mutagenesis; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D015398:Signal Transduction
C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011993:Recombinant Fusion Proteins; C097188:polyglutamine; D005982:Glutathione Transferase; D020930:MAP Kinase Kinase Kinases