QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Research Data Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Carreira, S. Articles by Goding, C. R. Search for Related Content PubMed PubMed Citation Articles by Carreira, S. Articles by Goding, C. R. Social Bookmarking                   What's this?

Mitf regulation of Dia1 controls melanoma proliferation and invasiveness

¹ Signalling and Development Laboratory, Marie Curie Research Institute, Oxted, Surrey, RH8 0TL, United Kingdom; ² Developmental Genetics of Melanocytes, UMR146 Centre national de la recherche scientifique (CNRS), Institut Curie, 91405 Orsay Cedex, France; ³ Instituto FIRC di Oncologia Molecolare-Fondazione Italiana per la Ricerca sul Cancro Institute of Molecular Oncology, 20139 Milano, Italy; ⁴ Department of Dermatology, University Hospital of Zürich, 8091 Zürich, Switzerland, ⁵ Melanoma Unit, European Institute of Oncology, 20141 Milano, Italy

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 p27^Kip1-degradation such that reduced Mitf levels lead to a p27^Kip1-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.

[Keywords: Dia1; melanoma; Mitf; actin; p27]

Received August 17, 2006; revised version accepted October 30, 2006.

E-MAIL c.goding{at}mcri.ac.uk; FAX 44-1882-714375.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.406406

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				C. Chiaverini, L. Beuret, E. Flori, R. Busca, P. Abbe, K. Bille, P. Bahadoran, J.-P. Ortonne, C. Bertolotto, and R. Ballotti Microphthalmia-associated Transcription Factor Regulates RAB27A Gene Expression and Controls Melanosome Transport J. Biol. Chem., May 2, 2008; 283(18): 12635 - 12642. [Abstract] [Full Text] [PDF]

				F. Felicetti, M. C. Errico, L. Bottero, P. Segnalini, A. Stoppacciaro, M. Biffoni, N. Felli, G. Mattia, M. Petrini, M. P. Colombo, et al. The Promyelocytic Leukemia Zinc Finger-MicroRNA-221/-222 Pathway Controls Melanoma Progression through Multiple Oncogenic Mechanisms Cancer Res., April 15, 2008; 68(8): 2745 - 2754. [Abstract] [Full Text] [PDF]

				K. S. Hoek, O. M. Eichhoff, N. C. Schlegel, U. Dobbeling, N. Kobert, L. Schaerer, S. Hemmi, and R. Dummer In vivo Switching of Human Melanoma Cells between Proliferative and Invasive States Cancer Res., February 1, 2008; 68(3): 650 - 656. [Abstract] [Full Text] [PDF]

				V. Delmas, F. Beermann, S. Martinozzi, S. Carreira, J. Ackermann, M. Kumasaka, L. Denat, J. Goodall, F. Luciani, A. Viros, et al. beta-Catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development Genes & Dev., November 15, 2007; 21(22): 2923 - 2935. [Abstract] [Full Text] [PDF]

				L. Beuret, E. Flori, C. Denoyelle, K. Bille, R. Busca, M. Picardo, C. Bertolotto, and R. Ballotti Up-regulation of MET Expression by {alpha}-Melanocyte-stimulating Hormone and MITF Allows Hepatocyte Growth Factor to Protect Melanocytes and Melanoma Cells from Apoptosis J. Biol. Chem., May 11, 2007; 282(19): 14140 - 14147. [Abstract] [Full Text] [PDF]