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Bimodal degradation of MLL by SCF^Skp2 and APC^Cdc20 assures cell cycle execution: a critical regulatory circuit lost in leukemogenic MLL fusions

¹ Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA; ² Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63110, USA; ³ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA; ⁴ Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, USA

Human chromosome 11q23 translocations disrupting MLL result in poor prognostic leukemias. It fuses the common MLL N-terminal 1400 amino acids in-frame with >60 different partners without shared characteristics. In addition to the well-characterized activity of MLL in maintaining Hox gene expression, our recent studies established an MLL–E2F axis in orchestrating core cell cycle gene expression including Cyclins. Here, we demonstrate a biphasic expression of MLL conferred by defined windows of degradation mediated by specialized cell cycle E3 ligases. Specifically, SCF^Skp2 and APC^Cdc20 mark MLL for degradation at S phase and late M phase, respectively. Abolished peak expression of MLL incurs corresponding defects in G1/S transition and M-phase progression. Conversely, overexpression of MLL blocks S-phase progression. Remarkably, MLL degradation initiates at its N-terminal 1400 amino acids, and tested prevalent MLL fusions are resistant to degradation. Thus, impaired degradation of MLL fusions likely constitutes the universal mechanism underlying all MLL leukemias. Our data conclude an essential post-translational regulation of MLL by the cell cycle ubiquitin/proteasome system (UPS) assures the temporal necessity of MLL in coordinating cell cycle progression.

[Keywords: MLL; Taspase1; Skp2; Cdc20; cell cycle; leukemia]

Received May 22, 2007; revised version accepted August 3, 2007.

E-MAIL jhsieh{at}im.wustl.edu; FAX (314) 362-1589.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1574507

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