NUCLEAR HORMONE-RECEPTOR ANTAGONISM WITH AP-1 BY INHIBITION OF THE JNK PATHWAY

The activity of c-Tun, the major component of the transcription factor AP-1, is potentiated by amino-terminal phosphorylation on serines 63 and 73 (Ser-63/73). This phosphorylation is mediated by the Tun amino- terminal kinase (INK) and required to recruit the transcriptional coac tivator CREB-binding protein (CBP). AP-1 function is antagonized by ac tivated members of the steroid/thyroid hormone receptor superfamily. R ecently, a competition for CBP has been proposed as a mechanism for th is antagonism. Here we present evidence that hormone-activated nuclear receptors prevent c-Tun phosphorylation on Ser-63/73 and, consequentl y, AP-1 activation, by blocking the induction of the JNK signaling cas cade. Consistently, nuclear receptors also antagonize other INK-activa ted transcription factors such as Elk-l and ATF-2. Interference with t he INK signaling pathway represents a novel mechanism by which nuclear hormone receptors antagonize AP-1. This mechanism is based on the blo ckade of the AP-1 activation step, which is a requisite to interact wi th CBP. In addition to acting directly on gene transcription, regulati on of the INK cascade activity constitutes an alternative mode whereby steroids and retinoids may control cell fate and conduct their pharma cological actions as immunosupressive, anti-inflammatory, and antineop lastic agents.