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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 (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 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. Social Bookmarking                   What's this? Submitted April 2, 2002 Accepted May 9, 2002 Leukemia proto-oncoprotein MLL is proteolytically processed into two fragments with opposite transcriptional properties Akihiko Yokoyama, Issay Kitabayashi*, Paul M Ayton, Michael L Cleary, and Misao Ohki Chromatin Function in Leukemogenesis Project, National Cancer Center Research Institute, Tokyo, Japan Department of Pathology, Stanford University Medical Center, Stanford, CA, USA Cancer Genomics Division, National Cancer Center Research Institute, Tokyo, Japan * Corresponding author; email: ikitabay{at}gan2.ncc.go.jp. MLL (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 is proteolytically processed into two fragments (MLLN and MLLC) that display opposite transcriptional properties and form an intra-molecular MLL complex in vivo. Proteolytic cleavage occurs at two 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 aa) and C-terminal (3602-3742 aa) 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 post-translational 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. 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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