Induction of neuronal differentiation by p73 in a neuroblastoma cell line

The p53-related p73 and p63 genes encode proteins that share considerable s tructural and functional homology with p53, Despite similarities, their del etion in mice has different outcomes, implying that the three genes may pla y distinct roles in vivo. Here we show that endogenous p73 levels increase in neuroblastoma cells induced to differentiate by retinoic acid and that e xogenously expressed p73, but not p53, is sufficient to induce both morphol ogical (neurite outgrowth) and biochemical (expression of neurofilaments an d neural cell adhesion molecule (N-CAM); down-regulation of N-MYC and up-re gulation of pRB) markers of neuronal differentiation. This activity is shar ed, to different extents, by all p73 isoforms, whereas the transcriptionall y inactive mutants of p73 isoforms are ineffective. Conversely, blockage of endogenous p73 isoforms with a dominant negative p73 results in the abroga tion of retinoid-induced N-CAM promoter-driven transcription. Our results i ndicate that the p73 isoforms activate a pathway that is not shared by p53 and that is required for neuroblastoma cell differentiation in vitro.