Regulation Of AP-1 And ATM Activity By Jlip, A Plasma Membrane-associated Protein

Transcription factor activator protein-1 (AP-1) regulates many aspects of cell physiology* including cell proliferation, apoptosis and differentiation, in response to environmental changes such as stress, radiation, or growth factor signals thereby acting like an environmental biosensor. Its activity is likely to be tightly and dynamically regulated. c-Jun, encoded by proto-oncogene c-jun, is the core component of AP-1. At present, the regulation of c-Jun can occur at two main levels: transcriptional control and post-translational regulation. The latter includes phosphorylation, dephosphorylation, acetylation, ubiquitination and modulation by interacting proteins. In this report we identified Jlip (Jun leucine zipper interacting protein) as a novel AP-1 repressor. Jlip is a predominant plasma membrane-localized protein, in which the N-terminal PH domain is required for the plasma membrane localization. In response to cycloheximide treatment, Jlip is cleaved by caspase-3 and consequently, translocated to the cytoplasm and the nucleus. Cleaved C-terminal fragments of Jlip strongly repress AP-1 activity, whereas the full-length Jlip not. In addition, expression of Jlip sensitizes the cells to apoptotic signals and cleavage of Jlip accelerates cycloheximide-induced apoptosis. Expression of Jlip inhibits the cell proliferation. Furthermore, Jlip prevents cycloheximide-induced p53 degradation in an ATM-dependent manner. These findings argue for an in vivo inhibitory role of Jlip on AP-1 activity and establish the functional link between Jlip and ATM. Jlip mediated a novel pathway linking the apoptotic signals to the nuclear AP-1 biosensor.