Induction of neuronal differentiation by p73 in a neuroblastoma cell line.
The p53-related p73 and p63 genes encode proteins that share considerable structural and functional homology with p53. Despite similarities, their deletion in mice has different outcomes, implying that the three genes may play distinct roles in vivo. Here we show that endogenous p73 levels increase in neuroblastoma cells induced to differentiate by retinoic acid and that exogenously expressed p73, but not p53, is sufficient to induce both morphological (neurite outgrowth) and biochemical (expression of neurofilaments and neural cell adhesion molecule (N-CAM); down-regulation of N-MYC and up-regulation of pRB) markers of neuronal differentiation. This activity is shared, to different extents, by all p73 isoforms, whereas the transcriptionally inactive mutants of p73 isoforms are ineffective. Conversely, blockage of endogenous p73 isoforms with a dominant negative p73 results in the abrogation of retinoid-induced N-CAM promoter-driven transcription. Our results indicate that the p73 isoforms activate a pathway that is not shared by p53 and that is required for neuroblastoma cell differentiation in vitro.
De Laurenzi
V
V
Biochemistry Laboratory, IDI-IRCCS, c/o Department of Experimental Medicine, Tor Vergata University, Via Tor Vergata 135, 00133, Italy.
Raschellá
G
G
Barcaroli
D
D
Annicchiarico-Petruzzelli
M
M
Ranalli
M
M
Catani
M V
MV
Tanno
B
B
Costanzo
A
A
Levrero
M
M
Melino
G
G
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002454:Cell Differentiation / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D016161:Genes, Retinoblastoma; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D006801:Humans; D008156:Luciferases / Q000235:genetics; D051379:Mice; D019006:Neural Cell Adhesion Molecules / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D019006:Neural Cell Adhesion Molecules; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D014212:Tretinoin; D008156:Luciferases