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 induces the growth arrest and differentiation of neuroblastoma (NB) cells. However, it has not been completely defined whether N-Myc promotes growth and/or antagonises neuronal differentiation of NB cells or whether the down regulation of N-myc occurs as a consequence of the onset of differentiation. By transfecting an N-myc gene construct into these cells, we found that the constitutive overexpression of N-myc stimulated proliferation in RA containing medium and, although these cells were still responsive to RA, they were no longer able to differentiate. Since N-Myc functions appear to be mediated by heterodimerization with Max, the ectopic overexpression of max in NB cells was also investigated. In contrast to N-Myc, Max strongly induced the differentiation by enhancing the effects of RA. Max-transfected cells rapidly arrested growth and differentiated fully within a few days of RA treatment. These findings suggest that the relative levels of N-Myc compared to Max appears to be crucial in stimulating neuroblastoma growth or differentiation, and may contribute to explain the remarkable clinical behaviour of neuroblastomas.
Peverali
F A
FA
Dipartimento di Genetica e Microbologia A. Buzzati-Traverso, Universita' di Pavia, Italy.
Orioli
D
D
Tonon
L
L
Ciana
P
P
Bunone
G
G
Negri
M
M
Della-Valle
G
G
D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C499330:MAX protein, human; C067850:Myc associated factor X; D014157:Transcription Factors; D014212:Tretinoin