May 2004
Volume 45, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2004
The Role of MITF–M during Cell Cycle Progression in Uveal Melanoma
Author Affiliations & Notes
  • A.E. Loercher
    Ophthalmology, Washington University, St Louis, MO
  • E.M. H. Tank
    Ophthalmology, Washington University, St Louis, MO
  • J.W. Harbour
    Ophthalmology, Washington University, St Louis, MO
  • Footnotes
    Commercial Relationships  A.E. Loercher, None; E.M.H. Tank, None; J.W. Harbour, None.
  • Footnotes
    Support  EY13360–03
Investigative Ophthalmology & Visual Science May 2004, Vol.45, 1192. doi:
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      A.E. Loercher, E.M. H. Tank, J.W. Harbour; The Role of MITF–M during Cell Cycle Progression in Uveal Melanoma . Invest. Ophthalmol. Vis. Sci. 2004;45(13):1192.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Abstract: : Purpose: MITF–M is the master melanocyte–specific transcription factor that is required for melanocyte differentiation and maintenance of the melanocytic phenotype. MITF–M is expressed in virtually all melanomas and has been recommended as a histopathologic marker for melanoma. MITF–M regulates not only expression of pigment related genes, but also Bcl–2, which may explain at least in part the extreme resistance to apoptosis in these cells. We wished to determine whether MITF–M may also regulate genes in the Rb pathway in uveal melanomas. Methods and Results: In microarray analysis of primary uveal melanomas, MITF–M was identified as a gene in which expression decreased with the malignant progression of melanoma (i.e., towards a more epithelioid morphology), whereas certain cell cycle related genes, such as cyclin D1 and cyclin D2, increased during tumor progression. In order to determine the effects of MITF–M expression in vitro, MITF–M was transfected into embryonic fibroblasts. Exogenous MITF–M caused the embryonic fibroblasts to assume a melanocytic phenotype that was also associated with a marked reduction in growth rate. The proliferative effects of depleting MITF–M in uveal melanoma cells via RNA interference were also studied and these experiments demonstrated a slight increase in growth rate, although the results were not as dramatic. The promoters of certain cell cycled related genes were examined for canonical MITF–M binding sites, and these sites were identified in 6 of the genes of interest. Reporter assays were performed by transfecting the MITF–M expression vector and promoter constructs for the genes of interest that contained luciferase in order to identify cell cycle related gene promoters that are able to be activated by MITF–M. These experiments showed that MITF transcriptionally activates the p16 promoter. Conclusions: Our findings suggest that MITF–M inhibits cell proliferation by inducing p16, and this may explain why p16 is a target for inactivation in uveal melanoma. Since MITF decreases during tumor progression, this could explain at least in part why more aggressive epithelioid melanomas grow more rapidly. These findings may provide insights for novel therapeutic targets and interventions for uveal melanoma.

Keywords: melanoma • uvea • transcription factors 
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