Regulation of APC-Cdc20 by the spindle checkpoint

Current Opinion in Cell Biology

Volumn 14, Issue 6, 2002, Pages 706-714

  Yu, Hongtao ^a  

^a UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANAPHASE PROMOTING COMPLEX; APC PROTEIN; BUB1 RELATED PROTEIN; BUB3 PROTEIN; CELL CYCLE PROTEIN; ISOPROTEIN; LIGASE; PROTEIN; PROTEIN MAD2; UBIQUITIN; UNCLASSIFIED DRUG; ANAPHASE-PROMOTING COMPLEX; CALCIUM BINDING PROTEIN; CARRIER PROTEIN; CDC20 PROTEIN, S CEREVISIAE; FUNGAL PROTEIN; MAD2 PROTEIN, S CEREVISIAE; NUCLEAR PROTEIN; SACCHAROMYCES CEREVISIAE PROTEIN; UBIQUITIN PROTEIN LIGASE;

ANAPHASE; CENTROMERE; CHROMOSOME SEGREGATION; ENZYME ACTIVITY; MEIOSIS; MICROTUBULE; MITOSIS; MITOSIS SPINDLE; NONHUMAN; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN FUNCTION; PROTEIN LOCALIZATION; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; SISTER CHROMATID; ANIMAL; BIOLOGICAL MODEL; CHEMISTRY; MACROMOLECULE; METABOLISM; PHYSIOLOGY;

ANAPHASE; ANIMALS; CALCIUM-BINDING PROTEINS; CARRIER PROTEINS; CELL CYCLE PROTEINS; CHROMOSOME SEGREGATION; FUNGAL PROTEINS; LIGASES; MACROMOLECULAR SUBSTANCES; MEIOSIS; MICROTUBULES; MITOSIS; MITOTIC SPINDLE APPARATUS; MODELS, GENETIC; NUCLEAR PROTEINS; SACCHAROMYCES CEREVISIAE PROTEINS; SIGNAL TRANSDUCTION; UBIQUITIN-PROTEIN LIGASE COMPLEXES;

EID: 0036902234     PISSN: 09550674     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0955-0674(02)00382-4     Document Type: Review

References (64)

1. Nasmyth K., Peters J.M., Uhlmann F. Splitting the chromosome: cutting the ties that bind sister chromatids. Science. 288:2000;1379-1385.
2. Tanaka T.U. Bi-orienting chromosomes on the mitotic spindle. Curr Opin Cell Biol. 14:2002;365-371.
3. Peters J.M. The anaphase-promoting complex. Proteolysis in mitosis and beyond. Mol Cell. 9:2002;931-943.
4. Jallepalli P.V., Lengauer C. Chromosome segregation and cancer: cutting through the mystery. Nat Rev Cancer. 1:2001;109-117.
5. Hunt P., Hassold T. Sex matters in meiosis. Science. 296:2002;2181-2183.
6. Millband D.N., Campbell L., Hardwick K.G. The awesome power of multiple model systems: interpreting the complex nature of spindle checkpoint signaling. Trends Cell Biol. 12:2002;205-209.
7. Gorbsky G.J. The mitotic spindle checkpoint. Curr Biol. 11:2001;R1001-1004.
8. Shah J.V., Cleveland D.W. Waiting for anaphase: Mad2 and the spindle assembly checkpoint. Cell. 103:2000;997-1000.
9. Hoyt M.A. A new view of the spindle checkpoint. J Cell Biol. 154:2001;909-911.
10. Gardner R.D., Burke D.J. The spindle checkpoint: two transitions, two pathways. Trends Cell Biol. 10:2000;154-158.
11. Rieder C.L., Cole R.W., Khodjakov A., Sluder G. The checkpoint delaying anaphase in response to chromosome mono-orientation is mediated by an inhibitory signal produced by unattached kinetochores. J Cell Biol. 130:1995;941-948.
12. Hoffman D.B., Pearson C.G., Yen T.J., Howell B.J., Salmon E.D. Microtubule-dependent changes in assembly of microtubule motor proteins and mitotic spindle checkpoint proteins at PtK1 kinetochores. Mol Biol Cell. 12:2001;1995-2009.
13. Li X., Nicklas R.B. Mitotic forces control a cell-cycle checkpoint. Nature. 373:1995;630-632.
14. Nicklas R.B. How cells get the right chromosomes. Science. 275:1997;632-637.
15. Nicklas R.B., Waters J.C., Salmon E.D., Walter S.C. Checkpoint signals in grasshopper meiosis are sensitive to microtubule attachment, but tension is still essential. J Cell Sci. 114:2001;4173-4183.
16. Skoufias D.A., Andreassen P.R., Lacroix F.B., Wilson L., Margolis R.L. Mammalian mad2 and bub1/bubR1 recognize distinct spindle-attachment and kinetochore-tension checkpoints. Proc Natl Acad Sci USA. 98:2001;4492-4497. The authors find that low concentrations of vinblastine arrest HeLa cells in mitosis, with all kinetochores attached to microtubules but not under tension. These kinetochores recruit Bub1 and BubR1, but not Mad2. Higher concentrations of vinblastine destroy the mitotic spindle and the kinetochores are not attached by microtubules. Under these conditions, Mad2 is recruited to the kinetochores. Zhou et al. (2002) [19•] describe similar findings in HeLa cells arrested in mitosis with noscapine. This drug does not affect microtubule polymerisation, but alters the dynamics of microtubule assembly and causes loss of tension at the kinetochores. They show that Mad2 and Bub1/BubR1 behave differently in response to loss of microtubule attachment or tension at the kinetochores. These results suggest that specific subsets of checkpoint proteins may be activated by different spindle defects.
17. Kapoor T.M., Mayer T.U., Coughlin M.L., Mitchison T.J. Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, Eg5. J Cell Biol. 150:2000;975-988.
18. Taylor S.S., Hussein D., Wang Y., Elderkin S., Morrow C.J. Kinetochore localisation and phosphorylation of the mitotic checkpoint components Bub1 and BubR1 are differentially regulated by spindle events in human cells. J Cell Sci. 114:2001;4385-4395.
19. Zhou J., Panda D., Landen J.W., Wilson L., Joshi H.C. Minor alteration of microtubule dynamics causes loss of tension across kinetochore pairs and activates the spindle checkpoint. J Biol Chem. 277:2002;17200-17208. See annotation Skoufias et al. (2001) [16•].
20. Shonn M.A., McCarroll R., Murray A.W. Requirement of the spindle checkpoint for proper chromosome segregation in budding yeast meiosis. Science. 289:2000;300-303.
21. Stern B.M., Murray A.W. Lack of tension at kinetochores activates the spindle checkpoint in budding yeast. Curr Biol. 11:2001;1462-1467. Budding yeast cells with the CDC6 gene deleted do not replicate their DNA, but are able to duplicate spindle pole bodies and enter mitosis. The unreplicated chromosomes in these cells appear to attach to the mitotic spindle normally. Obviously, without the opposing sister chromatids, the kinetochores in these cells lack tension. The authors then used the degradation kinetics of Pds1 (a known APC-Cdc20 substrate) to monitor the status of the spindle checkpoint. They show that the degradation of Pds1 is delayed in CDC6-null cells, and this delay in the kinetics of Pds1 degradation requires the function of Mad2. Thus, tension-lacking kinetochores activate the spindle checkpoint in yeast.
22. Tanaka T.U., Rachidi N., Janke C., Pereira G., Galova M., Schiebel E., Stark M.J., Nasmyth K. Evidence that the Ipl1-Sli15 (Aurora kinase-INCENP) complex promotes chromosome bi-orientation by altering kinetochore-spindle pole connections. Cell. 108:2002;317-329. Before DNA replication, the kinetochores of yeast chromosomes are attached to the microtubules from the lone spindle pole in G1. As the spindle poles duplicate, the old spindle pole moves to the daughter cell while the newly duplicated one remains in the mother. In the CDC6-null yeast cells, the unreplicated chromosomes are initially all attached to the old spindle pole. As these cells enter mitosis, the unreplicated chromosomes detach from the old spindle pole and re-attach to the new one with equal frequency, resulting in more or less equal chromosome segregation into mother and daughter cells. However, inactivation of Ipl1 in yeast cells depleted of Cdc6 causes all the unreplicated chromosomes to segregate to the daughter cell, suggesting that the kinetochores of ipl1/cdc6 double mutant cells fail to detach from the old spindle pole. Therefore, Ipl1 is required for establishing chromosome bi-orientation by promoting the turnover of the microtubule connections between the kinetochores and the spindle poles.
23. Stern B.M. Mitosis: Aurora gives chromosomes a healthy stretch. Curr Biol. 12:2002;R316-318.
24. Biggins S., Murray A.W. The budding yeast protein kinase Ipl1/Aurora allows the absence of tension to activate the spindle checkpoint. Genes Dev. 15:2001;3118-3129. Despite the importance of Ipl1 in establishing chromosome bi-orientation, ipl1 mutant cells do not activate the spindle checkpoint, suggesting that the defects in ipl1 mutant cells are not sufficient to activate the checkpoint or Ipl1 itself is a part of the tension-sensing mechanism of the checkpoint. The authors show that Ipl1 is not required for the mitotic arrest induced by nocodazole. However, it is required for the mitotic arrest caused by Mps1 overexpression. Furthermore, yeast mutants lacking Cdc6 or Scc1/Mcd1 (cohesin) functions activate the checkpoint, due to lack of tension at chromosomes, and delay the degradation of the anaphase inhibitor Pds1 in a checkpoint-dependent manner. Ipl1 is required for the checkpoint-mediated stabilisation of Pds1 in CDC6 or MCD1 mutants. The Ipl1 protein also localises to the vicinity of kinetochores. The authors argue that Ipl1 is involved in the spindle checkpoint. Specifically, Ipl1 might monitor tension at the kinetochores and act upstream of Mps1.
25. Murata-Hori M., Tatsuka M., Wang Y.L. Probing the dynamics and functions of Aurora B kinase in living cells during mitosis and cytokinesis. Mol Biol Cell. 13:2002;1099-1108.
26. Kallio M.J., McCleland M.L., Stukenberg P.T., Gorbsky G.J. Inhibition of Aurora B kinase blocks chromosome segregation, overrides the spindle checkpoint, and perturbs microtubule dynamics in mitosis. Curr Biol. 12:2002;900-905. Injection of antibodies against Xenopus Aurora B into Xenopus tissue-culture cells causes defects in chromosome movement to the metaphase plate, and mitotic exit in the absence of anaphase and cytokinesis. It also causes alteration of the microtubule network in the mitotic spindle, and a failure of the injected cells to arrest in mitosis in the presence spindle-damaging drugs. These observations are consistent with the vertebrate Aurora B protein playing a role in establishing chromosome bi-orientation and in the spindle checkpoint. However, unlike in budding yeast, Aurora B appears to be essential for the checkpoint-mediated mitotic arrest induced by severe spindle defects.
27. Murata-Hori M., Wang Y. The kinase activity of Aurora B Is required for kinetochore-microtubule interactions during mitosis. Curr Biol. 12:2002;894-899.
28. Abrieu A., Kahana J.A., Wood K.W., Cleveland D.W. CENP-E as an essential component of the mitotic checkpoint ##in vitro. Cell. 102:2000;817-826.
29. Li R., Murray A.W. Feedback control of mitosis in budding yeast. Cell. 66:1991;519-531.
30. Hoyt M.A., Totis L., Roberts B.T. S. cerevisiae## genes required for cell cycle arrest in response to loss of microtubule function. Cell. 66:1991;507-517.
31. Dobles M., Liberal V., Scott M.L., Benezra R., Sorger P.K. Chromosome missegregation and apoptosis in mice lacking the mitotic checkpoint protein Mad2. Cell. 101:2000;635-645.
32. Kalitsis P., Earle E., Fowler K.J., Choo K.H. Bub3 gene disruption in mice reveals essential mitotic spindle checkpoint function during early embryogenesis. Genes Dev. 14:2000;2277-2282.
33. Luo X., Tang Z., Rizo J., Yu H. The Mad2 spindle checkpoint protein undergoes similar major conformational changes upon binding to either Mad1 or Cdc20. Mol Cell. 9:2002;59-71. Mad1 and Cdc20, two otherwise unrelated proteins, contain similar short peptide motifs that bind to Mad2. Binding of Mad1 and Cdc20 to Mad2 is mutually exclusive. Overexpression of Mad1 antagonises the checkpoint function of Mad2. Upon binding to a peptide that mimics the Mad2-binding motifs of Mad1 and Cdc20, Mad2 undergoes a major conformational change with extensive reshuffling of secondary structural elements. They also provide evidence that Mad2 undergoes similar structural rearrangements when bound to the native Mad1 and Cdc20 peptides. Despite the apparent antagonism between Mad1- and Cdc20-binding to Mad2, Mad1 might convert Mad2 to a form more suitable for Cdc20-binding under the right circumstances.
34. Fang G., Yu H., Kirschner M.W. The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation. Genes Dev. 12:1998;1871-1883.
35. Hardwick K.G., Johnston R.C., Smith D.L., Murray A.W. MAD3 encodes a novel component of the spindle checkpoint which interacts with Bub3p, Cdc20p, and Mad2p. J Cell Biol. 148:2000;871-882.
36. Fraschini R., Beretta A., Sironi L., Musacchio A., Lucchini G., Piatti S. Bub3 interaction with Mad2, Mad3 and Cdc20 is mediated by WD40 repeats and does not require intact kinetochores. EMBO J. 20:2001;6648-6659.
37. Millband D.N., Hardwick K.G. Fission yeast Mad3p is required for Mad2p to inhibit the anaphase-promoting complex and localizes to kinetochores in a Bub1p-, Bub3p-, and Mph1p-dependent manner. Mol Cell Biol. 22:2002;2728-2742. Combining biochemistry and genetics elegantly in fission yeast, this work confirms and extends the authors' previous findings in budding yeast. They show that Mad3, Bub3, Mad2 and Slp1(Cdc20) form a complex in fission yeast. The kinetochore localisation of Mad3 depends on Bub1, Bub3 and Mph1, but not Mad1 and Mad2.
38. Tang Z., Bharadwaj R., Li B., Yu H. Mad2-independent inhibition of ##APC##Cdc20 by the mitotic checkpoint protein BubR1. Dev Cell. 1:2001;227-237. BubR1Bub3Cdc20 and Mad2-Cdc20 interactions are enhanced upon checkpoint activation. In the absence of Mad2, a purified recombinant BubR1-Bub3 complex inhibits APC-Cdc20 in vitro. Furthermore, BubR1 inhibits APC-Cdc20 much more efficiently than Mad2. The kinase domain of BubR1 is dispensable for its APC inhibitory activity. These data, along with data from Sudakin et al. (2001) [39••] and Fang (2002) [40•], suggest that BubR1 and Mad2 inhibit APC-Cdc20 collaboratively.
39. Sudakin V., Chan G.K., Yen T.J. Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2. J Cell Biol. 154:2001;925-936. A mitotic checkpoint complex (MCC) containing BubR1, Bub3, Mad2, and Cdc20 was purified from HeLa cells. MCC binds to the APC directly and inhibits it much more efficiently than Mad2 alone. Active MCC is also isolated from interphase cells, suggesting that unattached kinetochores are not absolutely required for the assembly of MCC. Interestingly, MCC only inhibits the activity of mitotic APC. Mitotic chromosomes also suppress APC activity, although the mechanism of inhibition is not established.
40. Fang G. Checkpoint Protein BubR1 Acts Synergistically with Mad2 to Inhibit Anaphase-promoting Complex. Mol Biol Cell. 13:2002;755-766. See annotations Tang et al. (2001) [38••] and Sudakin et al. (2001) [39••].
41. Chen R.H., Shevchenko A., Mann M., Murray A.W. Spindle checkpoint protein Xmad1 recruits Xmad2 to unattached kinetochores. J Cell Biol. 143:1998;283-295.
42. Abrieu A., Magnaghi-Jaulin L., Kahana J.A., Peter M., Castro A., Vigneron S., Lorca T., Cleveland D.W., Labbe J.C. Mps1 is a kinetochore-associated kinase essential for the vertebrate mitotic checkpoint. Cell. 106:2001;83-93. This is the first demonstration that the vertebrate homologue of yeast Mps1 is required for the spindle checkpoint. The Xenopus Mps1 localises to kinetochores. The kinase activity of Mps1 is essential for its checkpoint function. Mps1 is also required for the kinetochore localisation of CENP-E, Mad1 and Mad2.
43. Stucke V.M., Sillje H.H., Arnaud L., Nigg E.A. Human Mps1 kinase is required for the spindle assembly checkpoint but not for centrosome duplication. EMBO J. 21:2002;1723-1732. The mammalian homologue of Mps1 is required for the spindle checkpoint. Antibody injection and RNA-interference-mediated depletion of Mps1 from mammalian cells cause cells to escape from the mitotic arrest induced by spindle-damaging drugs.
44. Chan G.K., Jablonski S.A., Starr D.A., Goldberg M.L., Yen T.J. Human Zw10 and ROD are mitotic checkpoint proteins that bind to kinetochores. Nat Cell Biol. 2:2000;944-947.
45. Sharp-Baker H., Chen R.H. Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity. J Cell Biol. 153:2001;1239-1250. This is one of several elegant studies on the spindle checkpoint in Xenopus from Chen and co-workers. Xenopus CSF extracts supplemented with sperm nuclei and nocodazole establish an active spindle checkpoint. Immunodepletion of Bub1 from these extracts abolish the kinetochore localisation of Mad1, Mad2, Bub3 and CENP-E. Unlike Mps1, the kinase activity of Bub1 is not required for its function in recruiting or keeping other checkpoint proteins at the kinetochores.
46. Kallio M., Weinstein J., Daum J.R., Burke D.J., Gorbsky G.J. Mammalian p55CDC mediates association of the spindle checkpoint protein Mad2 with the cyclosome/anaphase-promoting complex, and is involved in regulating anaphase onset and late mitotic events. J Cell Biol. 141:1998;1393-1406.
47. Howell B.J., Hoffman D.B., Fang G., Murray A.W., Salmon E.D. Visualization of Mad2 dynamics at kinetochores, along spindle fibers, and at spindle poles in living cells. J Cell Biol. 150:2000;1233-1250.
48. Chung E., Chen R.H. Spindle checkpoint requires Mad1-bound and Mad1-free Mad2. Mol Biol Cell. 13:2002;1501-1511.
49. Brady D.M., Hardwick K.G. Complex formation between Mad1p, Bub1p and Bub3p is crucial for spindle checkpoint function. Curr Biol. 10:2000;675-678.
50. Wu H., Lan Z., Li W., Wu S., Weinstein J., Sakamoto K.M., Dai W. p55CDC/hCDC20 is associated with BUBR1 and may be a downstream target of the spindle checkpoint kinase. Oncogene. 19:2000;4557-4562.
51. Zhang Y., Lees E. Identification of an overlapping binding domain on Cdc20 for Mad2 and anaphase-promoting complex: model for spindle checkpoint regulation. Mol Cell Biol. 21:2001;5190-5199.
52. Luo X., Fang G., Coldiron M., Lin Y., Yu H., Kirschner M.W., Wagner G. Structure of the Mad2 spindle assembly checkpoint protein and its interaction with Cdc20. Nat Struct Biol. 7:2000;224-229.
53. Sironi L., Mapelli M., Knapp S., Antoni A.D., Jeang K.T., Musacchio A. Crystal structure of the tetrameric Mad1-Mad2 core complex: implications of a'safety belt' binding mechanism for the spindle checkpoint. EMBO J. 21:2002;2496-2506. The authors determine the crystal structure of Mad2 in complex with a 100-residue Mad2-binding domain of Mad1. Compared with the apo-Mad2 structure [52], Mad2 undergoes a dramatic conformational change upon binding to Mad1. The Mad1 portion of the complex forms a dimer, with the Mad2-binding region adopting an extended conformation and threading through the Mad2 protein. As revealed by the structure, the dissociation of Mad2 from this complex requires partial unfolding of Mad2.
54. Reimann J.D., Freed E., Hsu J.Y., Kramer E.R., Peters J.M., Jackson P.K. Emi1 is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex. Cell. 105:2001;645-655.
55. Yudkovsky Y., Shteinberg M., Listovsky T., Brandeis M., Hershko A. Phosphorylation of Cdc20/fizzy negatively regulates the mammalian cyclosome/APC in the mitotic checkpoint. Biochem Biophys Res Commun. 271:2000;299-304.
56. Geley S., Kramer E., Gieffers C., Gannon J., Peters J.M., Hunt T. Anaphase-promoting complex/cyclosome-dependent proteolysis of human cyclin A starts at the beginning of mitosis and is not subject to the spindle assembly checkpoint. J Cell Biol. 153:2001;137-148. This paper shows that cyclin A is degraded by APC-Cdc20 at pro-metaphase, before chromosome segregation. Surprisingly, cyclin A degradation is not inhibited by the spindle checkpoint. This remains one of many mysteries of regulated protein degradation involving the APC.
57. Tang Z., Li B., Bharadwaj R., Zhu H., Ozkan E., Hakala K., Deisenhofer J., Yu H. APC2 Cullin protein and APC11 RING protein comprise the minimal ubiquitin ligase module of the anaphase-promoting complex. Mol Biol Cell. 12:2001;3839-3851.
58. Vodermaier H.C. Cell cycle: waiters serving the destruction machinery. Curr Biol. 11:2001;R834-837.
59. Hilioti Z., Chung Y.S., Mochizuki Y., Hardy C.F., Cohen-Fix O. The anaphase inhibitor Pds1 binds to the APC/C-associated protein Cdc20 in a destruction box-dependent manner. Curr Biol. 11:2001;1347-1352. This paper demonstrates the direct binding between yeast Cdc20 and the APC substrate, Pds1, which has long been suspected from indirect observations. This suggests that the role of Cdc20 in the APC is to recruit substrate. The Cdc20-Pds1 interaction is not blocked by the spindle checkpoint.
60. Pfleger C.M., Lee E., Kirschner M.W. Substrate recognition by the Cdc20 and Cdh1 components of the anaphase-promoting complex. Genes Dev. 15:2001;2396-2407. The authors show that Cdc20 and Cdh1 bind to several APC substrates directly, establishing a role for Cdc20 and Cdh1 in substrate recruitment in APC-mediated ubiquitination reactions.
61. Pfleger C.M., Salic A., Lee E., Kirschner M.W. Inhibition of Cdh1-APC by the MAD2-related protein MAD2L2: a novel mechanism for regulating Cdh1. Genes Dev. 15:2001;1759-1764. This paper describes a novel mechanism for the inhibition of the APC. Mad2 does not block the ability of Cdc20 to recruit substrates. Instead, it appears to prevent the substrate release of APC.
62. Howell B.J., McEwen B.F., Canman J.C., Hoffman D.B., Farrar E.M., Rieder C.L., Salmon E.D. Cytoplasmic dynein/dynactin drives kinetochore protein transport to the spindle poles and has a role in mitotic spindle checkpoint inactivation. J Cell Biol. 155:2001;1159-1172. In addition to passive diffusion, dynein/dynactin-mediated transport along the microtubules is involved in the removal of checkpoint proteins such as Mad2 from the kinetochores. This mechanism might be important for turning off the checkpoint.
63. Rieder C.L., Khodjakov A., Paliulis L.V., Fortier T.M., Cole R.W., Sluder G. Mitosis in vertebrate somatic cells with two spindles: implications for the metaphase/anaphase transition checkpoint and cleavage. Proc Natl Acad Sci USA. 94:1997;5107-5112.
64. Chen R.H. BubR1 is essential for kinetochore localization of other spindle checkpoint proteins and its phosphorylation requires Mad1. J Cell Biol. 158:2002;487-496.