Lineage-specific Signaling in Melanocytes
c-Kit STIMULATION RECRUITS p300/CBP TO MICROPHTHALMIA*
- E. Roydon Price‡§,
- Han-Fei Dingद,
- Tina Badalian‡,
- Shoumo Bhattacharya‖,
- Cliff Takemoto‡,
- Tso-Pang Yao‖,
- Timothy J. Hemesath‡** and
- David E. Fisher‡‡
- From the ‡Pediatric Hematology/Oncology and‖Neoplastic Disease Mechanisms, Dana Farber Cancer Research Institute and Harvard Medical School, Boston, Massachusetts 02115
Abstract
During melanocyte development, the cytokine Steel factor activates its receptor c-Kit, initiating a signal transduction cascade, which is vital for lineage determination via unknown downstream nuclear targets. c-Kit has recently been found to trigger mitogen-activated protein kinase-mediated phosphorylation of Microphthalmia (Mi), a lineage-restricted transcription factor, which, like Steel factor and c-Kit, is essential for melanocyte development. This cascade results in increased Mi-dependent transcriptional reporter activity. Here we examine the mechanism by which Mi is activated by this pathway. Phosphorylation does not significantly alter Mi’s nuclear localization, DNA binding, or dimerization. However, the transcriptional coactivator p300/CBP selectively associates with mitogen-activated protein kinase-phosphorylated Mi, even under conditions in which non-MAPK phospho-Mi is more abundant. Moreover, p300/CBP coactivates Mi transcriptional activity in a manner dependent upon this phosphorylation. Mi thus joins CREB as a transcription factor whose signal-responsive phosphorylation regulates coactivator recruitment, in this case modulating lineage development in melanocytes.
Footnotes
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↵* This work was supported by grants from the National Institutes of Health, the Pew Foundation, and the James S. McDonnell Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵§ These authors contributed equally to this work.
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↵¶ Novartis Fellow.
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↵** Medical Foundation Fellow.
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↵‡ Nirenberg Fellow at Dana-Farber Cancer Institute. To whom correspondence should be addressed. Tel.: 617-632-4916; Fax: 617-632-2085; E-mail: david_fisher{at}dfci.harvard.edu.
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↵1 The abbreviations used are: Mi, Microphthalmia; MAPK, mitogen-activated protein kinase; BHK, baby hamster kidney; HAT, histone acetyltransferase; CREB, cAMP-responsive element-binding protein; CBP, CREB-binding protein.
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- Received March 10, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
