Letter | Published:

Mitf cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression

Abstract

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 differentiation1. 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 p21Cip1 (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.

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Acknowledgements

We thank M. Serrano for the WT and p21-null MEFs; S. Mittnacht for the Rb1 expression vectors and the C33a cells; B. Vogelstein for the p21Cip1 promoter; K. Helin for the HA.ER-expression vector; D. Stillman for yeast reporter strain DY1641; C. Wellbrock, R. Marais, R. Ballotti and C. Bertolotto for communication of unpublished results; and H. Arnheiter for discussions. This work was supported by Marie Curie Cancer Care, the Association for International Cancer Research and a European Union Marie Curie fellowship to M.-D.G.

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Correspondence to Colin R. Goding.

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Further reading

Figure 1: Mitf is a negative-regulator of cell cycle progression.
Figure 2: Mitf regulates p21Cip1 expression.
Figure 3: Mitf does not cause a cell cycle arrest in p21Cip1-deficient cells.
Figure 4: Mitf cooperates with Rb1.

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