Bimodal degradation of MLL by SCFSkp2 and APCCdc20 assures cell cycle execution: a critical regulatory circuit lost in leukemogenic MLL fusions.
Human chromosome 11q23 translocations disrupting MLL result in poor prognostic leukemias. It fuses the common MLL N-terminal approximately 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 approximately 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.
Liu
Han
H
Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Cheng
Emily H-Y
EH
Hsieh
James J-D
JJ
D000595:Amino Acid Sequence; D064199:Cdc20 Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; C497422:KMT2A protein, human; D015514:Oncogene Proteins, Fusion; D044786:S-Phase Kinase-Associated Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; C577488:CDC20 protein, human; D011495:Histone-Lysine N-Methyltransferase; D044767:Ubiquitin-Protein Ligases