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Blood, 15 March 2008, Vol. 111, No. 6, pp. 3145-3154. Prepublished online as a Blood First Edition Paper on December 21, 2007; DOI 10.1182/blood-2007-06-092122. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-06-092122v1 111/6/3145    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Marango, J. Articles by Licht, J. D. PubMed PubMed Citation Articles by Marango, J. Articles by Licht, J. D. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor Jotin Marango1, Manabu Shimoyama1,2, Hitomi Nishio3, Julia A. Meyer4, Dong-Joon Min4, Andres Sirulnik5, Yolanda Martinez-Martinez1, Marta Chesi6, P. Leif Bergsagel6, Ming-Ming Zhou7, Samuel Waxman1, Boris A. Leibovitch1, Martin J. Walsh3, and Jonathan D. Licht1,4 1 Division of Hematology/Oncology and 3 Department of Pediatrics, Mount Sinai School of Medicine, New York, NY; 2 Division of Hematology/Oncology, Kobe University Graduate School of Medicine, Kobe, Japan; 4 Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL; 5 Division of Hematological Malignancy, Dana-Farber Cancer Institute, Boston, MA; 6 Mayo Clinic, Scottsdale, AZ; and 7 Structural Biology Program, Mount Sinai School of Medicine, New York, NY MMSET, identified by its fusion to the IgH locus in t(4;14)-associated multiple myeloma, possesses domains found within chromatin regulators, including the SET domain. MMSET protein is overexpressed and highly associated with chromatin in myeloma cell lines carrying t(4;14). MMSET possesses methyltransferase activity for core histone H3 lysine 4 and histone 4 lysine 20, whereas MMSET made in cells only modified H4. Segments of MMSET fused to the Gal4 DNA binding domain repressed transcription of a chromatin-embedded Gal4 reporter gene. MMSET-mediated repression was associated with increased H4K20 methylation gene and loss of histone acetylation. Consistent with this repressive activity, MMSET could form a complex with HDAC1 and HDAC2, mSin3a, and the histone demethylase LSD1, suggesting that it is a component of corepressor complexes. Furthermore, MMSET coexpression enhances HDAC1- and HDAC2-mediated repression in transcriptional reporter assays. Finally, shRNA-mediated knockdown of MMSET compromised viability of a myeloma cell line, suggesting a biologic role for the protein in malignant cell growth. Collectively, these data suggest that, by acting directly as a modifier of chromatin as well as through binding of other chromatin-modifying enzymes, MMSET influences gene expression and potentially acts as a pathogenic agent in multiple myeloma. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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