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The spindle assembly checkpoint mechanism delays anaphase initiation until all chromosomes are aligned at the metaphase plate. Activation of the anaphase-promoting complex (APC) by binding of CDC20 and CDH1 is required for exit from mitosis, and APC has been implicated as a target for the checkpoint intervention. We show that the human checkpoint protein hMAD2 prevents activation of APC by forming a hMAD2-CDC20-APC complex. When injected into Xenopus embryos, hMAD2 arrests cells at mitosis with an inactive APC. The recombinant hMAD2 protein exists in two-folded states: a tetramer and a monomer. Both the tetramer and the monomer bind to CDC20, but only the tetramer inhibits activation of APC and blocks cell cycle progression. Thus, hMAD2 binding is not sufficient for inhibition, and a change in hMAD2 structure may play a role in transducing the checkpoint signal. There are at least three different forms of mitotic APC that can be detected in vivo: an inactive hMAD2-CDC20-APC ternary complex present at metaphase, a CDC20-APC binary complex active in degrading specific substrates at anaphase, and a CDH1-APC complex active later in mitosis and in G1. We conclude that the checkpoint-mediated cell cycle arrest involves hMAD2 receiving an upstream signal to inhibit activation of APC.
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Amon,
Regulation of B-type cyclin proteolysis by Cdc28-associated kinases in budding yeast.
1997, Pubmed
Amon,
Regulation of B-type cyclin proteolysis by Cdc28-associated kinases in budding yeast.
1997,
Pubmed
Amon,
Closing the cell cycle circle in yeast: G2 cyclin proteolysis initiated at mitosis persists until the activation of G1 cyclins in the next cycle.
1994,
Pubmed
Brandeis,
The proteolysis of mitotic cyclins in mammalian cells persists from the end of mitosis until the onset of S phase.
1996,
Pubmed
Chen,
Association of spindle assembly checkpoint component XMAD2 with unattached kinetochores.
1996,
Pubmed
,
Xenbase
Clute,
Microtubule dependence of chromosome cycles in Xenopus laevis blastomeres under the influence of a DNA synthesis inhibitor, aphidicolin.
1997,
Pubmed
,
Xenbase
Clute,
Regulation of the appearance of division asynchrony and microtubule-dependent chromosome cycles in Xenopus laevis embryos.
1995,
Pubmed
,
Xenbase
Cohen-Fix,
Anaphase initiation in Saccharomyces cerevisiae is controlled by the APC-dependent degradation of the anaphase inhibitor Pds1p.
1996,
Pubmed
,
Xenbase
Dawson,
The Drosophila cell cycle gene fizzy is required for normal degradation of cyclins A and B during mitosis and has homology to the CDC20 gene of Saccharomyces cerevisiae.
1995,
Pubmed
Elledge,
Cell cycle checkpoints: preventing an identity crisis.
1996,
Pubmed
Funabiki,
Cut2 proteolysis required for sister-chromatid seperation in fission yeast.
1996,
Pubmed
Glotzer,
Cyclin is degraded by the ubiquitin pathway.
1991,
Pubmed
,
Xenbase
Hardwick,
Mad1p, a phosphoprotein component of the spindle assembly checkpoint in budding yeast.
1995,
Pubmed
Hardwick,
Activation of the budding yeast spindle assembly checkpoint without mitotic spindle disruption.
1996,
Pubmed
He,
The Schizosaccharomyces pombe spindle checkpoint protein mad2p blocks anaphase and genetically interacts with the anaphase-promoting complex.
1997,
Pubmed
Holloway,
Anaphase is initiated by proteolysis rather than by the inactivation of maturation-promoting factor.
1993,
Pubmed
,
Xenbase
Hoyt,
S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function.
1991,
Pubmed
Hwang,
Budding yeast Cdc20: a target of the spindle checkpoint.
1998,
Pubmed
Irniger,
Genes involved in sister chromatid separation are needed for B-type cyclin proteolysis in budding yeast.
1995,
Pubmed
Jin,
Human T cell leukemia virus type 1 oncoprotein Tax targets the human mitotic checkpoint protein MAD1.
1998,
Pubmed
Jörgensen,
A subunit of the anaphase-promoting complex is a centromere-associated protein in mammalian cells.
1998,
Pubmed
,
Xenbase
Kim,
Fission yeast Slp1: an effector of the Mad2-dependent spindle checkpoint.
1998,
Pubmed
King,
A 20S complex containing CDC27 and CDC16 catalyzes the mitosis-specific conjugation of ubiquitin to cyclin B.
1995,
Pubmed
,
Xenbase
King,
Mutagenic analysis of the destruction signal of mitotic cyclins and structural characterization of ubiquitinated intermediates.
1996,
Pubmed
,
Xenbase
Lahav-Baratz,
Reversible phosphorylation controls the activity of cyclosome-associated cyclin-ubiquitin ligase.
1995,
Pubmed
Li,
Feedback control of mitosis in budding yeast.
1991,
Pubmed
Li,
MAD2 associates with the cyclosome/anaphase-promoting complex and inhibits its activity.
1997,
Pubmed
,
Xenbase
Li,
Identification of a human mitotic checkpoint gene: hsMAD2.
1996,
Pubmed
Matsumoto,
A fission yeast homolog of CDC20/p55CDC/Fizzy is required for recovery from DNA damage and genetically interacts with p34cdc2.
1997,
Pubmed
Minshull,
A MAP kinase-dependent spindle assembly checkpoint in Xenopus egg extracts.
1994,
Pubmed
,
Xenbase
Murray,
The genetics of cell cycle checkpoints.
1995,
Pubmed
Murray,
Cell cycle checkpoints.
1994,
Pubmed
Nicklas,
How cells get the right chromosomes.
1997,
Pubmed
Parker,
Radiolabeling of proteins.
1990,
Pubmed
Peters,
Identification of BIME as a subunit of the anaphase-promoting complex.
1996,
Pubmed
,
Xenbase
Rudner,
The spindle assembly checkpoint.
1996,
Pubmed
Schwab,
Yeast Hct1 is a regulator of Clb2 cyclin proteolysis.
1997,
Pubmed
Sigrist,
Drosophila fizzy-related down-regulates mitotic cyclins and is required for cell proliferation arrest and entry into endocycles.
1997,
Pubmed
,
Xenbase
Sudakin,
The cyclosome, a large complex containing cyclin-selective ubiquitin ligase activity, targets cyclins for destruction at the end of mitosis.
1995,
Pubmed
Taylor,
Kinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage.
1997,
Pubmed
Tugendreich,
CDC27Hs colocalizes with CDC16Hs to the centrosome and mitotic spindle and is essential for the metaphase to anaphase transition.
1995,
Pubmed
Visintin,
CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis.
1997,
Pubmed
Wang,
Cdc55p, the B-type regulatory subunit of protein phosphatase 2A, has multiple functions in mitosis and is required for the kinetochore/spindle checkpoint in Saccharomyces cerevisiae.
1997,
Pubmed
Weinstein,
Cell cycle-regulated expression, phosphorylation, and degradation of p55Cdc. A mammalian homolog of CDC20/Fizzy/slp1.
1997,
Pubmed
Weinstein,
A novel mammalian protein, p55CDC, present in dividing cells is associated with protein kinase activity and has homology to the Saccharomyces cerevisiae cell division cycle proteins Cdc20 and Cdc4.
1994,
Pubmed
Yamaguchi,
A WD repeat protein controls the cell cycle and differentiation by negatively regulating Cdc2/B-type cyclin complexes.
1997,
Pubmed
Yamamoto,
Pds1p, an inhibitor of anaphase in budding yeast, plays a critical role in the APC and checkpoint pathway(s).
1996,
Pubmed
Yamamoto,
Pds1p is required for faithful execution of anaphase in the yeast, Saccharomyces cerevisiae.
1996,
Pubmed
