Protein kinases and protein phosphatases regulate cellular transformation, apoptosis and differentiation

Using normal human oral keratinocytes (NHOKs) and other oral cancer cells, we studied the MAPKs, in particular JNK pathway. We found that TPA could induce JNK activity only in NHOKs and not in any other oral cancer cells. The inability of TPA to induce JNK activity in oral cancer cells was not due to a signaling defect because TPA still induced NF-kappaB binding activity in these oral cancer cells. A protein tyrosine phosphatase inhibitor, sodium orthovanadate, restored the ability of TPA response in oral cancer cells. The combination of sodium orthovanadate and TPA synergistically activated JNK activity in oral cancer cells. These results suggested that a TPA-inducible, sodium orthovanadate-sensitive phosphatase was involved in the TPA induction of the JNK pathway.;UV-C has long been known to be a strong inducer of JNK activity. Studying UV-C-induced JNK activity in NHOKs and oral cancer cells, we found that UV-C induced JNK activity and reached its peak at 1 or 2 hours in both NHOKs and oral cancer cells. Cells started to undergoing apoptosis within 4 hours of UV-C treatment, the time of which JNK started to decline. By 24 hours, almost all the cells had undergone apoptosis and the JNK activity had declined to basal levels. There was no direct correlation between JNK or ERK activity with the degree of UV-induced apoptosis in oral keratinocytes.;In these studies, we also showed the binding of RB and cyclophilin A (CyPA). When p19 EC cells were treated with retinoic acid (RA), there was enhanced RB: CyPA complex formation along with neuronal differentiation of p19 EC cells. In p19 EC cells stably transfected with antisense CyPA, the expression of endogenous CyPA was blocked and there was no neuronal differentiation. This suggested that RB: CyPA complex has functional role in p19 EC cell differentiation.