The authors found that Krox-20 expression makes Schwann cells resistant to the mitogen NRG-1 and the apoptosis-inducing action of TGF-β. Rather than specifically targeting these signaling molecules, Krox-20 appears to act through a general mechanism, suppressing the activity of the JNK/c-Jun pathway. The data show that JNK/c-Jun signaling is required for both proliferative and apoptotic responses in Schwann cells. Krox-20 expression increases the expression of the scaffold protein JIP-1, a known inhibitor of JNK activity, and also decreases the level of c-Jun protein in the cell, providing two possible ways to inhibit JNK/c-Jun signals.
Surprisingly, expression of Krox-20 in cultured 3T3 fibroblasts, which are not related to Schwann cells, causes the fibroblasts to stop dividing, resist apoptosis, and express the myelin genes periaxin and P0. The ability to induce so many specialized responses in a different cell type indicates that Krox-20 is a master regulator.
By turning off a single pathway that is activated by both NRG-1 and TGF-β, Krox-20 can coordinate changes in both proliferative and apoptotic activities without affecting other processes activated by growth factors. Its position as a master regulator explains why mutations in Krox-20 often lead to severe hereditary myelination disorders. Parkinson et al. are now trying to determine whether Krox-20 acts directly or indirectly to reduce c-Jun levels and induce myelin gene expression. ▪