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J. Biol. Chem., Vol. 280, Issue 1, 146-155, January 7, 2005

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Sumoylation of MITF and Its Related Family Members TFE3 and TFEB^*

Arlo J. Miller, Carmit Levy¶, Ian J. Davis, Ehud Razin¶, and David E. Fisher, A Jan and Charles Nirenberg Fellow at the Dana Farber Cancer Institute||

From the Dana-Farber Cancer Institute and Children's Hospital, Department of Pediatric Hematology/Oncology, Melanoma Program in Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 and ^¶Department of Biochemistry, Hebrew University Hadassah Medical School, Jerusalem 91120, Israel

MITF and its related family members TFE3 and TFEB heterodimerize with each other, recognize the same DNA sequences, and are subject to many of the same post-translational modifications. We show that lysine residues within conserved small ubiquitin-like modifier (SUMO) consensus sites in these family members are subject to SUMO modification. Mutation of these sites significantly affects the transcriptional activity of MITF but does not alter dimerization, DNA binding, stability, or nuclear localization. Mutagenesis reducing the number of MITF binding sites in the promoter of TRPM1 from three to one eliminated the difference in transcriptional activity between the MITF mutants. Among other MITF target gene promoter constructs, differences in transcriptional activity between wild type and non-sumoylatable MITF were only seen in promoters with multiple MITF binding sites. These data support a synergy control model in which the functional consequences of MITF sumoylation depend on promoter context. Sumoylation, thus, provides a possible mechanism for altering the effects of MITF by affecting the target genes that it activates.

Received for publication, October 15, 2004

^* This work was funded in part by National Institutes of Health Grants AR45662 and AR43369 (to D. E. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a National Institutes of Health Medical Scientist Training Program grant.

^|| To whom correspondence should be addressed. E-mail: David_Fisher{at}dfci.harvard.edu.

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