RAS-SIGNALING PATHWAYS - POSITIVE AND NEGATIVE REGULATION OF TAU-EXPRESSION IN PC12 CELLS

Tau is a microtubule-associated protein whose promoter is activated du ring the first phase of nerve growth factor-induced PC12 cell differen tiation, whereas levels of its mRNA are accumulating throughout differ entiation. In this study, we have followed the signal transduction cas cades regulating tau induction. Using dominant negative Ras-expressing PC12 cells, we show that ras regulates tau expression during the firs t phase of PC12 cell differentiation. The ERK and JNK cascades, which are downstream of Ras, have opposing effects on tau promoter activity: ERK induces tau promoter activity, JNK inhibits it. Tau promoter acti vity in PC12 cells is correlated with a short-term activation of ERK, which declines after a few hours and is followed by an activation of t he inhibitory JNK cascade 76 h later. These observations suggest that the induction and inhibition of tau promoter are mediated by alternate ERK and JNK activities, which may underlie a mechanism to turn on and off genes during PC12 cell differentiation.