Pharmacologic inhibition of the anaphase-promoting complex induces a spindle checkpoint-dependent mitotic arrest in the absence of spindle damage.
Microtubule inhibitors are important cancer drugs that induce mitotic arrest by activating the spindle assembly checkpoint (SAC), which, in turn, inhibits the ubiquitin ligase activity of the anaphase-promoting complex (APC). Here, we report a small molecule, tosyl-L-arginine methyl ester (TAME), which binds to the APC and prevents its activation by Cdc20 and Cdh1. A prodrug of TAME arrests cells in metaphase without perturbing the spindle, but nonetheless the arrest is dependent on the SAC. Metaphase arrest induced by a proteasome inhibitor is also SAC dependent, suggesting that APC-dependent proteolysis is required to inactivate the SAC. We propose that mutual antagonism between the APC and the SAC yields a positive feedback loop that amplifies the ability of TAME to induce mitotic arrest.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Xing
X
Zeng
Frederic
F
Sigoillot
Shantanu
S
Gaur
Sungwoon
S
Choi
Kathleen L
KL
Pfaff
Dong-Chan
DC
Oh
Nathaniel
N
Hathaway
Nevena
N
Dimova
Gregory D
GD
Cuny
Randall W
RW
King
D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008677:Metaphase / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D050505:Mutant Proteins / Q000378:metabolism; D011355:Prodrugs / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011485:Protein Binding / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D008941:Spindle Apparatus / Q000187:drug effects* / Q000473:pathology*; D014106:Tosylarginine Methyl Ester / Q000494:pharmacology*; D043743:Ubiquitin-Protein Ligase Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014981:Xenopus
D004791:Enzyme Inhibitors; D050505:Mutant Proteins; D011355:Prodrugs; D061988:Proteasome Inhibitors; D014106:Tosylarginine Methyl Ester; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D046988:Proteasome Endopeptidase Complex