Mitf regulation of Dia1 controls melanoma proliferation and invasiveness

Suzanne Carreira, Jane Goodall, Laurence Denat, Mercedes Rodriguez, Paolo Nuciforo, Keith S. Hoek, Alessandro Testori, Lionel Larue, Colin R. Goding

Research output: Contribution to journalArticle

Abstract

It is widely held that cells with metastatic properties such as invasiveness and expression of matrix metalloproteinases arise through the stepwise accumulation of genetic lesions arising from genetic instability and "clonal evolution." By contrast, we show here that in melanomas invasiveness can be regulated epigenetically by the microphthalmia-associated transcription factor, Mitf, via regulation of the DIAPH1 gene encoding the diaphanous-related formin Dia1 that promotes actin polymerization and coordinates the actin cytoskeleton and microtubule networks at the cell periphery. Low Mitf levels lead to down-regulation of Dia1, reorganization of the actin cytoskeleton, and increased ROCK-dependent invasiveness, whereas increased Mitf expression leads to decreased invasiveness. Significantly the regulation of Dia1 by Mitf also controls p27Kip1-degradation such that reduced Mitf levels lead to a p27Kip1-dependent G1 arrest. Thus Mitf, via regulation of Dia1, can both inhibit invasiveness and promote proliferation. The results imply variations in the repertoire of environmental cues that determine Mitf activity will dictate the differentiation, proliferative, and invasive/migratory potential of melanoma cells through a dynamic epigenetic mechanism.

Original languageEnglish
Pages (from-to)3426-3439
Number of pages14
JournalGenes and Development
Volume20
Issue number24
DOIs
Publication statusPublished - Dec 15 2006

Keywords

  • Actin
  • Dia1
  • Melanoma
  • Mitf
  • p27

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    Carreira, S., Goodall, J., Denat, L., Rodriguez, M., Nuciforo, P., Hoek, K. S., Testori, A., Larue, L., & Goding, C. R. (2006). Mitf regulation of Dia1 controls melanoma proliferation and invasiveness. Genes and Development, 20(24), 3426-3439. https://doi.org/10.1101/gad.406406