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MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A

Cell cycle exit is required for proper differentiation in most cells and is critical for normal development, tissue homeostasis, and tumor suppression. However, the mechanisms that link cell cycle exit with differentiation remain poorly understood. Here, we show that the master melanocyte differenti...

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Detalles Bibliográficos
Autores principales: Loercher, Amy E., Tank, Elizabeth M.H., Delston, Rachel B., Harbour, J. William
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2005
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2171666/
https://www.ncbi.nlm.nih.gov/pubmed/15623583
http://dx.doi.org/10.1083/jcb.200410115
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author Loercher, Amy E.
Tank, Elizabeth M.H.
Delston, Rachel B.
Harbour, J. William
author_facet Loercher, Amy E.
Tank, Elizabeth M.H.
Delston, Rachel B.
Harbour, J. William
author_sort Loercher, Amy E.
collection PubMed
description Cell cycle exit is required for proper differentiation in most cells and is critical for normal development, tissue homeostasis, and tumor suppression. However, the mechanisms that link cell cycle exit with differentiation remain poorly understood. Here, we show that the master melanocyte differentiation factor, microphthalmia transcription factor (MITF), regulates cell cycle exit by activating the cell cycle inhibitor INK4A, a tumor suppressor that frequently is mutated in melanomas. MITF binds the INK4A promoter, activates p16(Ink4a) mRNA and protein expression, and induces retinoblastoma protein hypophosphorylation, thereby triggering cell cycle arrest. This activation of INK4A was required for efficient melanocyte differentiation. Interestingly, MITF was also required for maintaining INK4A expression in mature melanocytes, creating a selective pressure to escape growth inhibition by inactivating INK4A. These findings demonstrate that INK4A can be regulated by a differentiation factor, establish a mechanistic link between melanocyte differentiation and cell cycle exit, and potentially explain the tissue-specific tendency for INK4A mutations to occur in melanoma.
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spelling pubmed-21716662008-03-05 MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A Loercher, Amy E. Tank, Elizabeth M.H. Delston, Rachel B. Harbour, J. William J Cell Biol Research Articles Cell cycle exit is required for proper differentiation in most cells and is critical for normal development, tissue homeostasis, and tumor suppression. However, the mechanisms that link cell cycle exit with differentiation remain poorly understood. Here, we show that the master melanocyte differentiation factor, microphthalmia transcription factor (MITF), regulates cell cycle exit by activating the cell cycle inhibitor INK4A, a tumor suppressor that frequently is mutated in melanomas. MITF binds the INK4A promoter, activates p16(Ink4a) mRNA and protein expression, and induces retinoblastoma protein hypophosphorylation, thereby triggering cell cycle arrest. This activation of INK4A was required for efficient melanocyte differentiation. Interestingly, MITF was also required for maintaining INK4A expression in mature melanocytes, creating a selective pressure to escape growth inhibition by inactivating INK4A. These findings demonstrate that INK4A can be regulated by a differentiation factor, establish a mechanistic link between melanocyte differentiation and cell cycle exit, and potentially explain the tissue-specific tendency for INK4A mutations to occur in melanoma. The Rockefeller University Press 2005-01-03 /pmc/articles/PMC2171666/ /pubmed/15623583 http://dx.doi.org/10.1083/jcb.200410115 Text en Copyright © 2005, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Loercher, Amy E.
Tank, Elizabeth M.H.
Delston, Rachel B.
Harbour, J. William
MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A
title MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A
title_full MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A
title_fullStr MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A
title_full_unstemmed MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A
title_short MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A
title_sort mitf links differentiation with cell cycle arrest in melanocytes by transcriptional activation of ink4a
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2171666/
https://www.ncbi.nlm.nih.gov/pubmed/15623583
http://dx.doi.org/10.1083/jcb.200410115
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