Prevention of anti-IgM-induced apoptosis accompanying G(1) arrest in B lymphoma cells overexpressing dominant-negative mutant form of c-jun N-terminal kinase 1

A family of mitogen-activated protein (MAP) kinases comprising the extracel lular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38 MAP kinases are involved in proliferation and apoptosis, However, ther e are some arguments concerning the role of these kinases in Ag-induced B c ell apoptosis, Two of the B lymphoma cell lines (CH31 and WEHI-231) suscept ible to anti-IgM-induced apoptosis were used as a model. To address these i ssues, we examined the kinetics of anti-IgM-induced activation of MAP kinas es and established cell lines overexpressing a dominant-negative (dn) mutan t form of JNK1 (dnJNK1), Anti-IgM induced a sustained JNK1 activation with a peak at 8 h, with a marginal activation of ERK1/ERK2 in CH31 cells, The s ustained JNK1 activation was not a secondary event through a caspase activa tion, The peak point of the JNK1 activation was just before the onset of a decline in mitochondrial membrane potential, which preceded anti-IgM-induce d cell death. Following anti-IgM stimulation, dnJNK1 prevented a decline in mitochondrial membrane potential at 24 h, with a prolonged inhibition up t o 72 h in WEHI-231, although it did so only partially during a later time p eriod in CH31, The dnJNK1 cells also demonstrated diminished procaspase-3 a ctivation and a decreased rate of apoptosis upon anti-IgM stimulation, with a concomitant increased arrest in G(1) phase, which could be explained by enhanced levels of cyclin-dependent kinase inhibitor p27(Kip1) protein, Thu s, anti-IgM-induced JNK activation might be implicated in cell cycle progre ssion as well as in apoptosis regulation, probably involving p27(Kip1) prot ein.