N18-RE-105 CELLS - DIFFERENTIATION AND ACTIVATION OF P53 IN RESPONSE TO GLUTAMATE AND ADRIAMYCIN IS BLOCKED BY SV40 LARGE T-ANTIGEN TSA58

Process extension was induced in cells of the N18-RE-105 neuroblastoma -retinal hybrid line by toxic agents, including glutamate and the p53- inducing anticancer agents adriamycin and etoposide. Both adriamycin a nd glutamate activated p53 as measured by a plasmid transfection assay . It was therefore hypothesized that SV40 large T antigen, which binds p53, would interfere with cellular differentiation. To test this hypo thesis, the temperature-sensitive form of SV40 large T was transduced into N18-RE-105 cells by retroviral infection. SV40 large T-infected c ells became de-differentiated, grew in tightly-packed colonies, lost e xpression of neurofilament, and lost the ability to differentiate in r esponse to glutamate and adriamycin. The de-differentiating effect of SV40 large T antigen may be due to binding and inactivation of cellula r proteins, such as p53, p107, p130, p300, and retinoblastoma protein, which are important in cellular growth and differentiation. It is sug gested that p53 may play a role in cellular differentiation, perhaps u nder unusual circumstances involving stress or cytotoxicity.