RETINOIC ACID-INDUCED GROWTH ARREST AND DIFFERENTIATION OF NEUROBLASTOMA-CELLS ARE COUNTERACTED BY N-MYC AND ENHANCED BY MAX OVEREXPRESSIONS

N-myc expression is negatively regulated by retinoic acid (RA) which i nduces the growth arrest and differentiation of neuroblastoma (NB) cel ls. However, it has not been completely defined whether N-Myc promotes growth and/or antagonises neuronal differentiation of NE cells or whe ther the down regulation of N-myc occurs as a consequence of the onset of differentiation. By transfecting an N-myc gene construct into thes e cells, we found that the constitutive overexpression of N-myc stimul ated proliferation in RA containing medium and, although these cells w ere still responsive to RA, they were no longer able to differentiate. Since N-Myc functions appear to be mediated by heterodimerization wit h Max, the ectopic overexpression of max in NE cells was also investig ated, In contrast to N-Myc, Max strongly induced the differentiation b y enhancing the effects of RA. Max-transfected cells rapidly arrested growth and differentiated fully within a few days of RA treatment. The se findings suggest that the relative levels of N-Myc compared to Max appears to be crucial in stimulating neuroblastoma growth or different iation, and may contribute to explain the remarkable clinical behaviou r of neuroblastomas.