MYCN AND IFN-GAMMA COOPERATE IN APOPTOSIS OF HUMAN NEUROBLASTOMA-CELLS

Neuroblastomas undergo spontaneous regression at an unusually high rat e. The mechanisms are not clear, but apoptosis may be involved. A larg e proportion of neuroblastomas is characterized by amplification of MY CN, Using human neuroblastoma cells harbouring tetracycline controlled expression of MYCN we have analysed the role of the MycN protein and IFN gamma in cell death decision. Neither conditional expression of MY CN nor treatment with IFN gamma alone was sufficient to trigger cell d eath. However, when acting in concert MycN and IFN gamma efficiently t riggered cell death, which was accompanied by DNA fragmentation and re quired caspase activity, two hallmarks of apoptosis, MycN and IFN gamm a may cooperate along at least two different pathways. First, IFN gamm a increased the CD95 cell surface expression while MycN enhanced the c ellular susceptibility for the CD95 mediated death signal. Second, IFN gamma, treatment induced expression of BAK mRNA while MycN and IFN ga mma in combination increased the amount of Bar protein, another activa tor of apoptosis, without a concomitant increase in BAX mRNA, MycN als o increased cell death in response to TRAIL and TNF alpha, suggesting that enforced MYCN expression in general increases the susceptibility of neuroblastoma cells towards a variety of death stimuli.