ArticleGenes & development2007
Bimodal degradation of MLL by SCFSkp2 and APCCdc20 assures cell cycle execution: a critical regulatory circuit lost in leukemogenic MLL fusions.
Article in Genes & development, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.
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Who cites it
79 citing papers in PubMed, 112 citations in OpenAlex.
- KMT2A degradation is observed in decitabine-responsive acute lymphoblastic leukemia cells.Molecular oncology · 2025Article
- Histone lysine methylation modifiers controlled by protein stability.Experimental & molecular medicine · 2024Review
- Identification of ubiquitination-related hub genes in chronic myeloid leukemia cell by bioinformatics analysis.Journal of Cancer · 2024Article
- SKping cell cycle regulation: role of ubiquitin ligase SKP2 in hematological malignancies.Frontiers in oncology · 2024Review
- Unannotated microprotein EMBOW regulates the interactome and chromatin and mitotic functions of WDR5.Cell reports · 2023Article
- DNA Methyltransferase 1 Targeting Using Guadecitabine Inhibits Prostate Cancer Growth by an Apoptosis-Independent Pathway.Cancers · 2023Article
- Telomere Transcription inBiomedicines · 2023Article
- Direct targeted therapy for MLL-fusion-driven high-risk acute leukaemias.Clinical and translational medicine · 2022Article
- CDC20 in and out of mitosis: a prognostic factor and therapeutic target in hematological malignancies.Journal of experimental & clinical cancer research : CR · 2022Review
- The role of reciprocal fusions in MLL-r acute leukemia: studying the chromosomal translocation t(6;11).Oncogene · 2021Article
- Bromodomain proteins: protectors against endogenous DNA damage and facilitators of genome integrity.Experimental & molecular medicine · 2021Review
- The Trithorax group protein ASH1 requires a combination of BAH domain and AT hooks, but not the SET domain, for mitotic chromatin binding and survival.Chromosoma · 2021Article
- SET1/MLL family of proteins: functions beyond histone methylation.Epigenetics · 2021Review
- Bortezomib suppresses self-renewal and leukemogenesis of leukemia stem cell by NF-ĸB-dependent inhibition of CDK6 in MLL-rearranged myeloid leukemia.Journal of cellular and molecular medicine · 2021Article
- EVI1 oncoprotein expression and CtBP1-association oscillate through the cell cycle.Molecular biology reports · 2020Article
- Transforming activities of theHaematologica · 2020Article
- Enhancing Hematopoiesis from Murine Embryonic Stem Cells through MLL1-Induced Activation of a Rac/Rho/Integrin Signaling Axis.Stem cell reports · 2020Article
- MLL1 is essential for retinal neurogenesis and horizontal inner neuron integrity.Scientific reports · 2018Article
- Retinoblastoma Binding Protein 5 Correlates with the Progression in Hepatocellular Carcinoma.BioMed research international · 2018Article
- Novel sub-cellular localizations and intra-molecular interactions may define new functions of Mixed Lineage Leukemia protein.Cell cycle (Georgetown, Tex.) · 2018Article
19 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.