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Prepublished online as a Blood First Edition Paper on June 28, 2002; DOI 10.1182/blood-2002-04-1015. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-04-1015v1 100/10/3710    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Yokoyama, A. Articles by Ohki, M. Search for Related Content PubMed PubMed Citation Articles by Yokoyama, A. Articles by Ohki, M. Related Collections Neoplasia Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 November 2002, Vol. 100, No. 10, pp. 3710-3718 NEOPLASIA Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties Akihiko Yokoyama, Issay Kitabayashi, Paul M. Ayton, Michael L. Cleary, and Misao Ohki From the Chromatin Function in Leukemogenesis Project and Cancer Genomics Division, National Cancer Center Research Institute, Tokyo, Japan; and the Department of Pathology, Stanford University School of Medicine, Stanford, CA. MLL (mixed lineage leukemia; also ALL-1 or HRX) is a proto-oncogene that is mutated in a variety of acute leukemias. Its product is normally required for the maintenance of Hox gene expression during embryogenesis and hematopoiesis through molecular mechanisms that remain poorly defined. Here we demonstrate that MLL (mixed lineage leukemia) is proteolytically processed into 2 fragments (MLLN and MLLC) that display opposite transcriptional properties and form an intramolecular MLL complex in vivo. Proteolytic cleavage occurs at 2 amino acids (D2666 and D2718) within a consensus processing sequence (QXD/GZDD, where X is a hydrophobic amino acid and Z is an alanine or a valine) that is conserved in TRX, the Drosophila homolog of MLL, and in the MLL-related protein MLL2, suggesting that processing is important for MLL function. Processed MLLN and MLLC associate with each other via N-terminal (1253-2254 amino acids) and C-terminal (3602-3742 amino acids) intramolecular interaction domains. MLL processing occurs rapidly within a few hours after translation and is followed by the phosphorylation of MLLC. MLLN displays transcriptional repression activity, whereas MLLC has strong transcriptional activation properties. Leukemia-associated MLL fusion proteins lack the MLL processing sites, do not undergo cleavage, and are unable to interact with MLLC. These observations suggest that posttranslational modifications of MLL may participate in regulating its activity as a transcription factor and that this aspect of its function is perturbed by leukemogenic fusions. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. K. Slany The molecular biology of mixed lineage leukemia Haematologica, July 1, 2009; 94(7): 984 - 993. [Abstract] [Full Text] [PDF] M. Tariq, U. Nussbaumer, Y. Chen, C. Beisel, and R. Paro Trithorax requires Hsp90 for maintenance of active chromatin at sites of gene expression PNAS, January 27, 2009; 106(4): 1157 - 1162. [Abstract] [Full Text] [PDF] B. W. Robinson, N.-K. V. Cheung, C. P. Kolaris, S. C. Jhanwar, J. K. Choi, N. Osheroff, and C. A. 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