Mitogen-activated protein kinase phosphorylates and targets inducible cAMPearly repressor to ubiquitin-mediated destruction

Inducible cAMP early repressor (ICER) is an important mediator of cAMP anti proliferative activity that acts as a putative tumor suppressor gene produc t. In this study, we examined the regulation of ICER protein by phosphoryla tion and ubiquitination in human choriocarcinoma JEG-3 and mouse pituitary AtT20 cells. We found that cAMP stabilized ICER protein by inhibiting the m itogen-activated protein kinase (MAPK) cascade. Activation of the MAPK path way increased ICER phosphorylation. ICER phosphorylation was abrogated by i nhibition of the MAPK pathway either by cAMP or directly by the MAPK inhibi tor PD098059. The MAPKs extracellular signal-regulated kinases 1 and 2 phys ically interact with ICER and mediated the phosphorylation of ICER on a cri tical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was su bstituted by alanine had a half-life 4-5 h longer than its wild-type counte rpart. This alteration in stability was due to the inability of the Ser-41- mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin- proteasome pathway. These results present a novel cell signaling crosstalk mechanism at the cell nucleus between the MAPK and cAMP pathways, whereby M APK targets a repressor of the cAMP-dependent gene expression for ubiquitin ation and proteasomal degradation.