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

Amy E. Loercher, Elizabeth M H Tank, Rachel B. Delston, J. William Harbour

Research output: Contribution to journalArticle

185 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)35-40
Number of pages6
JournalJournal of Cell Biology
Volume168
Issue number1
DOIs
StatePublished - Jan 3 2005
Externally publishedYes

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Microphthalmia-Associated Transcription Factor
Melanocytes
Cell Cycle Checkpoints
Transcriptional Activation
Cell Cycle
Melanoma
Retinoblastoma Protein
Neoplasms
Homeostasis
Messenger RNA
Mutation
Growth
Proteins

ASJC Scopus subject areas

  • Cell Biology

Cite this

MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A. / Loercher, Amy E.; Tank, Elizabeth M H; Delston, Rachel B.; William Harbour, J.

In: Journal of Cell Biology, Vol. 168, No. 1, 03.01.2005, p. 35-40.

Research output: Contribution to journalArticle

Loercher, Amy E. ; Tank, Elizabeth M H ; Delston, Rachel B. ; William Harbour, J. / MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A. In: Journal of Cell Biology. 2005 ; Vol. 168, No. 1. pp. 35-40.
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