학술논문
Divergent effects of the MEKK-1/JNK pathway on NB2a/d1 differentiation: Some activity is required for outgrowth and stabilization of neurites but overactivation inhibits both phenomena
Document Type
Academic Journal
Author
Source
Brain Research. Dec 6, 2006, Vol. 1123 Issue 1, p20, 7 p.
Subject
Language
English
ISSN
0006-8993
Abstract
To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.brainres.2006.09.036 Byline: Jason DeFuria, Po Chen, Thomas B. Shea Keywords: Stress-activated protein kinase; JNK; MEKK-1; Mitogen-activated protein kinase; Phosphorylation; Neurofilament; Axonal transport; Neuritogenesis Abstract: c-Jun N-terminal kinase (JNK), along with its upstream activator MEKK-1, is typically thought of as a stress-activated kinase that mediates apoptosis. However, additional studies indicate that the MEKK-1/JNK pathway mediates critical aspects of neuronal survival and differentiation. Herein, we demonstrate that transfection of differentiated NB2a/d1 cells with a construct expression constitutively activated (ca) MEKK-1 increases levels of phospho-dependent neurofilament (NF) immunoreactivity within perikarya, while expression of a dominant-negative (dn) form of MEKK-1 decreases it. Steady-state levels of perikaryal phospho-NF immunoreactivity are reduced and the increase resulting from expression of caMEKK-1 is prevented, by the JNK inhibitor SP600125, suggesting that JNK is a major downstream effector of MEKK-1 on NF phosphorylation. Unexpectedly, both caMEKK-1 and dnMEKK-1 inhibited neuritogenesis as well as translocation of NFs into newly elaborated neurites. The JNK inhibitor SP600125 also inhibited NF transport in a dose-dependent manner. caMEKK-1 also prevented the increase in NF transport otherwise mediated by MAP kinase. Finally, both caMEKK-1 and dnMEKK-1 prevented initial neuritogenesis. These findings indicate that the MEKK-1/JNK pathway regulates critical aspects of initial outgrowth, and subsequent stabilization of axonal neurites. Author Affiliation: Departments of Biological Sciences and Biochemistry, Center Cell Neurobiology and Neurodegeneration Research, University of Massachusetts, Lowell, Lowell, MA 01854, USA Article History: Accepted 13 September 2006