2. Academic Validation
  3. Paradoxical mitotic exit induced by a small molecule inhibitor of APC/CCdc20

Paradoxical mitotic exit induced by a small molecule inhibitor of APC/CCdc20

  • Nat Chem Biol. 2020 May;16(5):546-555. doi: 10.1038/s41589-020-0495-z.
Katherine V Richeson 1,  Tatyana Bodrug 2,  Katharine L Sackton 1,  Masaya Yamaguchi 3,  Joao A Paulo 1,  Steven P Gygi 1,  Brenda A Schulman 3 4,  Nicholas G Brown 5,  Randall W King 6
Affiliations

Affiliations

  • 1 Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • 2 Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • 3 Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 4 Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany.
  • 5 Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • 6 Department of Cell Biology, Harvard Medical School, Boston, MA, USA. randy_king@hms.harvard.edu.
PMID: 32152539 DOI: 10.1038/s41589-020-0495-z
Abstract

The anaphase-promoting complex/cyclosome (APC/C) is a ubiquitin ligase that initiates anaphase and mitotic exit. APC/C is activated by Cdc20 and inhibited by the mitotic checkpoint complex (MCC), which delays mitotic exit when the spindle assembly checkpoint (SAC) is activated. We previously identified apcin as a small molecule ligand of Cdc20 that inhibits APC/CCdc20 and prolongs mitosis. Here we find that apcin paradoxically shortens mitosis when SAC activity is high. These opposing effects of apcin arise from targeting of a common binding site in Cdc20 required for both substrate ubiquitination and MCC-dependent APC/C inhibition. Furthermore, we found that apcin cooperates with p31comet to relieve MCC-dependent inhibition of APC/C. Apcin therefore causes either net APC/C inhibition, prolonging mitosis when SAC activity is low, or net APC/C activation, shortening mitosis when SAC activity is high, demonstrating that a small molecule can produce opposing biological effects depending on regulatory context.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-110287
    99.71%, APC/C 抑制剂
    APC
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