ROLE OF P53 IN THE REGULATION OF IRRADIATION-INDUCED APOPTOSIS IN NEUROBLASTOMA-CELLS

Wild-type p53 plays a crucial role in the control of apoptosis followi ng ionizing radiation (IR); conversely, mutant p53 is associated with lit resistance. Although wild-type p53 is expressed in virtually all n euroblastoma tumors, treatment failures secondary to inadequate local control with radiotherapy are a problem in patients with advanced stag e disease. This apparent paradox is the focus of our interest, The She p-1 neuroblastoma cell line is highly resistant to IR. This cell line contains a wild-type p53 gene and is an ideal model for studying the m echanism of IR resistance in this disease. Following high-dose IR, cel l fractionation demonstrated that p53 is induced and targeted to the n ucleus, The induced p53 is functional as p53-responsive genes (Waf-1 a nd MDM-2) are appropriately induced following IR, intriguingly, overex pression of p53 could reverse the inherent IR resistance of Shep-1 cel ls, Multiple cell lines expressing variable levels of exogenous temper ature-sensitive p53 were generated, Pulse induction of p53 alone did n ot affect Shep-1 cell viability, while induction of p53, followed by I R, resulted in cell death and DNA fragmentation proportional to the do se of IR and the level of p53 expression. These findings demonstrate t hat p53 overexpression renders Shep-1 cells IR-sensitive and suggest t hat large quantities of exogenous p53 can overcome the factors inhibit ing p53-mediated, IR-induced apoptosis, (C) 1998 Academic Press.