Ras-Signaling Pathways: Positive and Negative Regulation of Tau Expression in PC12 Cells

Abstract: Tau is a microtubule-associated protein whose promoter is activated during the first phase of nerve growth factor-induced PC12 cell differentiation, whereas levels of its mRNA are accumulating throughout differentiation. In this study, we have followed the signal transduction cascades regulating tau induction. Using dominant negative Ras-expressing PC12 cells, we show that ras regulates tau expression during the first 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 activity 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 the 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.