Mitf cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression
Résumé
The controls that enable melanoblasts and melanoma cells to proliferate are likely to be related, but so far no key regulator of cell cycle progression specific to the melanocyte lineage has been identified. The microphthalmia-associated transcription factor Mitf has a crucial but poorly defined role in melanoblast and melanocyte survival and in differentiation. Here we show that Mitf can act as a novel anti-proliferative transcription factor able to induce a G1 cell-cycle arrest that is dependent on Mitf-mediated activation of the p21(Cip1) (CDKN1A) cyclin-dependent kinase inhibitor gene. Moreover, cooperation between Mitf and the retinoblastoma protein Rb1 potentiates the ability of Mitf to activate transcription. The results indicate that Mitf-mediated activation of p21Cip1 expression and consequent hypophosphorylation of Rb1 will contribute to cell cycle exit and activation of the differentiation programme. The mutation of genes associated with melanoma, such as INK4a or BRAF that would affect either Mitf cooperation with Rb1 or Mitf stability respectively, would impair Mitf-mediated cell cycle control.
Mots clés
Animals
Base Sequence
Cell Cycle
Cell Cycle Proteins
Cell Line
Tumor
Cells
Cultured
Chromatin Immunoprecipitation
Cyclin-Dependent Kinase Inhibitor p21
DNA-Binding Proteins
Humans
Melanocytes
Melanoma
Mice
Microphthalmia-Associated Transcription Factor
NIH 3T3 Cells
Phosphorylation
Protein Binding
Retinoblastoma Protein
Transcription Factors
Transcriptional Activation