Introduction
The ubiquitin pathway is an ATP-dependent tagging system which regulates a plethora of events in eukaryotic cells by controlling protein stability, localisation, assembly or activity of the target substrate1–3. Together with phosphorylation, the ubiquitin-tagging “ubiquitylation” is the most frequently observed post-translational modification in vivo. Thus, it is no exaggeration to say that at least some key proteins in many seminal pathways and signalling events observed in our body are regulated by ubiquitylation. In this process, ubiquitin, a highly conserved 76-residue protein, is initially linked to a ubiquitin-activating enzyme (E1) in a reaction that uses ATP. The activated ubiquitin is then transferred to a small ubiquitin-conjugating enzyme (E2), forming a thioester-linked E2-ubiquitin intermediate (E2~Ub). E2 acts either alone or in conjunction with an E3 ubiquitin ligase to conjugate ubiquitin, most commonly, onto the ε-amino group of lysine residues in substrate proteins, forming an isopeptide bond1,2,4. These seemingly simple sequential actions of three enzymes (E1-E2-E3) are tightly controlled to achieve accurate and appropriately timed ubiquitylation/proteolysis. More than 3% of genes in eukaryotic genomes are involved in the ubiquitin system, using multiple layers of regulation, to maintain homeostasis throughout the cell and organism.
The anaphase-promoting complex/cyclosome (APC/C) was discovered as an unusually large E3 ubiquitin ligase of cyclin B by biochemical fractionation of Xenopus egg and clam oocyte extracts5,6. Around the same time, genetic screening using yeast mutants defective in cyclin B proteolysis during anaphase and G1 identified genes such as APC6/CDC16 and APC8/CDC237. Purification of APC/C from Xenopus egg extract demonstrated the presence of homologues of budding yeast Apc6/Cdc16 and Apc3/Cdc27, which were required for cyclin destruction and anaphase progression in fungi and mammalian cells8–11. Hence, the idea that the APC/C ubiquitin system5–7, essential cellular machinery, controls not only cyclin destruction but also the initiation of anaphase in all eukaryotes arose and turned out to be true. Shortly thereafter, securin/Cut2/Pds1 was identified as the first non-cyclin APC/C substrate required for sister chromatid separation12,13. This opened up a new chapter of proteolysis-driven cell cycle control in the mid-1990s, and to date a considerable number of APC/C substrates have been identified.
APC/C activity is under tight control to ensure that APC/C substrates are ubiquitylated and degraded at the right time and the right place during the cell cycle14–18. What are the underlying mechanisms? How can we control it if it is mis-regulated? Although we have known for a quarter of a century that the APC/C is an E3 ubiquitin ligase, the enormity (1.2 MDa) and complexity (14 subunits) of the enzyme have hindered the reconstitution of apo-APC/C complex and subsequent detailed analysis until recently19. Now, high-resolution structural studies using reconstituted APC/C and multidisciplinary approaches have advanced our understanding of the APC/C. Here, we give an overview of APC/C regulation to date and highlight emerging themes. Readers interested in aspects of APC/C structural regulation that are beyond the scope of this review are pointed to recent comprehensive review articles20,21.
The APC/C is a multi-subunit cullin-RING E3 ubiquitin ligase
The APC/C belongs to the RING finger family of E3 ubiquitin ligases22–26. Unlike the HECT E3s that form E3~Ub intermediates during ubiquitin transfer, the RING E3s lack active sites and do not participate chemically in ubiquitin transfer. Instead, the RING E3 ubiquitin ligase functions as a scaffold that brings together an E2~Ub and a substrate (Figure 1A), thereby catalysing ubiquitin transfer from the E2 to the substrate. The E3s typically behave as two-substrate enzymes in which the E2~Ub and substrate are the two reactants whose binding affinities both influence the reaction rate. In addition, the APC/C exploits one more component, a co-activator such as Cdc20 and Cdh1, as a substrate recruitment adaptor and APC/C activator (Figure 1B). Thus, APC/C activation can be regulated by multiple mechanisms, including the interactions or spatiotemporal regulations among these four elements together with ubiquitin molecules, all of which can be subject to post-translational modifications such as phosphorylation and inhibitor/pseudo-substrate binding. It is also likely that individual substrate–co-activator binding strength or mode or both regulate the formation of APC/C-E2~Ub and the substrate ubiquitylation. Adding yet another level of complexity, the APC/C (E3) consists of multiple subunits and exploits two E2 enzymes (for example, Ube2C and Ube2S) to achieve programmed ubiquitylation (Figure 1C).
Figure 1. Schematic diagrams of RING E3 ubiquitin ligases.
RING-type E3 ligases serve as scaffolds to bring together the E2~Ub conjugate and the substrate. E3s play a role in stimulating Ub transfer to the substrate from E2~Ub conjugate. E2-binding RING domain is coloured in light blue. (A) Monomeric RING E3 ubiquitin ligases (for example, c-Cbl). (B) A simplified cartoon view of APC/C RING E3 ubiquitin ligase with a co-activator such as Cdc20 and Cdh1. (C) The APC/C is a multi-subunit cullin-RING E3 ubiquitin ligase that uses two E2s. APC/C, anaphase-promoting complex/cyclosome.
Structure and mechanisms of the APC/C
Early cryogenic electron microscopy (cryo-EM) studies of yeast and vertebrate APC/C revealed that APC/C has a triangular or asymmetric heart-shape (V-shape) conformation27–30, which has been refined with the latest high-resolution cryo-EM31–33 (Figure 2A). The APC/C complex consists of 14 mostly highly conserved subunits (Apc1–8, 10–13, 15 and 16) in metazoans (13 subunits in yeast) together with a structurally related interchangeable Cdc20/Fizzy family of co-activators such as Cdc20 and Cdh1, generating an “active” macromolecular machine exceeding 1.2 MDa (Figure 2B). It should be noted that co-activators are not stoichiometric components of the APC/C, but the association of co-activators with the APC/C is essential for the APC/C to function. The most prevalent structural motif is a 34–amino acid tetratricopeptide repeat (TPR), which is present in five subunits (Apc3, Apc5, Apc6, Apc7 and Apc8), highlighting their role in coordinating the higher-order assembly and protein recognition/binding. As an organised structure, the APC/C complex can be divided into three sub-complex structures: the catalytic sub-complex (catalytic module), the substrate recognition sub-complex (TPR lobe) and the scaffolding sub-complex (platform) (Figure 2C). The catalytic module consists of Apc11, the RING domain subunit and Apc2, the cullin subunit. The minimal module of Apc11-Apc2 (heterodimer) can catalyse ubiquitin transfer but with poor substrate specificity24–26. The substrate recognition TPR lobe comprises four TPR subunits (Apc7, Apc3, Apc6 and Apc8), each of which forms a V-shaped homodimer via N-terminal domains, which are packed in a parallel fashion resulting in the formation of a left-handed superhelical structure. Two copies of Apc12/Cdc26/Hcn1, which had been shown to genetically interact with Apc6/Cdc16/Cut934,35, stabilise Apc6A and Apc6B as molecular chaperones. Apc13 and Apc16 also help stabilise TPR subunit interaction and the assembly of the complex. Importantly, the substrate recognition of the TPR lobe is through the WD40 domain of Cdc20/Cdh1 and Apc1036,37, both of which interact with the C-terminal TPR grooves of Apc3 through their C-terminal isoleucine-arginine (IR) tails. Finally, the scaffolding sub-complex of the APC/C comprises the platform subunits Apc4 and Apc5 (heterodimer) and the largest subunit Apc1, which bridges the catalytic module Apc11-Apc2 and the TPR lobe in catalytically favourable conformations (Figure 2C). Since Apc4 and Apc5 had been shown to genetically interact with each other, the dimer formation had been suspected and the detailed interaction has been solved by high-resolution EM studies31,32. Apc1 has a WD40 beta-propeller domain containing several disordered loop domains at the N-terminus, one of which mediates phosphorylation-dependent APC/C control (Figure 3). It also contains a central PC (proteasome-cyclosome) repeat domain, which interacts with Apc10, although the detailed regulation remains elusive. In the overall topology, the surprising beauty of the whole is that vital ubiquitylation elements such as a catalytic E2-binding module (Apc11-Apc2) and substrate-binding module (Cdc20/Cdh1 and Apc10) are all positioned facing a central cavity “catalytic centre” on this enormous multi-subunit complex31,32 (Figure 2).
Figure 2. APC/C structure and overall organisation.
(A) APC/C structure. The image was generated by using the Protein Data Bank file (4UI9). The indicated numbers represent APC/C subunits. (B) Schematic view of the APC/C structure based on (A). Left: APCCdc20; right: APC/CCdh1. Cdc20 activates the APC/C in metaphase and anaphase to degrade substrates such as cyclin B and securin and then Cdh1 takes over to degrade APC/C substrates in late anaphase and G1. (C) The APC/C complex can be divided into three modules: the catalytic module (Apc2-Apc11) that interacts with E2s, the substrate recognition TPR lobe and the scaffolding platform (Apc1-Apc4-Apc5). During the ubiquitylation catalysis, both substrate and E2s are positioned in or near the APC/C central cavity. APC/C, anaphase-promoting complex/cyclosome; TPR, tetratricopeptide repeat.
The APC/C employs two E2s and assembles poly-ubiquitin chains
Ubiquitin has seven lysine residues (K6, K11, K27, K29, K33, K48 and K63), so eight structurally distinct types of poly-ubiquitin chain linkage can be formed, together with the N-terminal methionine (M1; a head-to-tail linear linkage). The anaphase-promoting complex (APC/C) can assemble K11-linked and K48-linked ubiquitin chains on substrates38–45. In order to build K11-linked ubiquitin chains, the metazoan APC/C uses two families of E2 enzymes: a “chain-initiating” E2 such as Ube2C/UbcH10 and Ube2D/UbcH5 and an “elongating” E2 such as Ube2S38–40,46,47. The APC/C facilitates these “team tagging” reactions by placing Ube2C and Ube2S at dedicated locations within the APC/C complex31,32. Ube2C binds the RING subunit Apc11 and Apc2 and transfers the first ubiquitin onto substrates (that is, multiple monoubiquitylation), whereas Ube2S binds non-RING subunits Apc2 and Apc4 through its C-terminal LRRL tail and elongates the K11-linked ubiquitin chains onto substrate-attached ubiquitin. RING subunit Apc11 involvement with Ube2C binding is as expected, but Apc2 plays an important role in interacting with both Ube2C and Ube2S through the winged-helix B (WHB) domain and the N-terminal domain of Apc2, respectively32,48,49. It has also been reported that the back surface of Apc11 has an additional role in tracking and presenting the acceptor ubiquitin of the growing ubiquitin chain onto Ube2S, thereby ensuring K11-linked ubiquitin chain formation31,50,51. Yet detailed mechanisms and the control of Ube2C and Ube2S loading and activity are mostly unknown. Interestingly, it has recently been observed that Ube2S does not simply extend a ubiquitin chain but creates mixed or branched K11/K48-linked ubiquitin chains, which act as better degradation signals for the proteasomal receptors than homotypic K11- or K48-linked ubiquitin chains41–43. How proteasomal ubiquitin-receptor proteins by themselves or in combination with UBL-UBA shuttle factors (for example, Rad23 and Dsk2) efficiently recognise branched ubiquitin chain configuration is not known. It is possible that mixed ubiquitin chains are more resistant to de-ubiquitylating enzymes (DUBs). In the past, E2 enzymes were considered just intermediates of the ubiquitin pathway, but more “active” roles have recently been discovered52,53. Not only “team tagging” but also new layers of E2 regulation might emerge in APC/C regulation in the future.
Multifaceted regulation of the APC/C is mediated primarily by co-activators
Cdc20/Fizzy, a co-activator of the APC/C, was originally discovered as fly and yeast mitotic mutants that failed to initiate the onset of anaphase. Cdh1 was subsequently identified as a G1 co-activator54–58. Cdc20 or Cdh1 is around 55 kDa and constitutes less than 5% of the total mass of the APC/C complex (1.2 MDa), but the size does not matter. A co-activator has an absolute requirement for APC/C-dependent ubiquitylation. Initially, the WD40 domain-mediated “substrate capture” role was revealed59–61 and later the “activation role” through the C-box (a conserved motif in the Cdc20/Fizzy family of proteins) at the N-terminal domain was uncovered62,63. From biochemical and EM studies, the activation mechanism is thought to be through conformational changes within the APC/C complex; the C-box and Apc8B interaction shifts the catalytic module (Apc11-Apc2) upward and positions it in a catalytically favourable conformation, allowing E2~Ub loading32,33,63. Here, three key facets of APC/C regulation via co-activators (that is, substrate recognition, phospho-regulation and inhibition) will be discussed briefly.
Co-activator–substrate affinity might determine the rate of ubiquitylation
Substrate recognition, which is a prerequisite for ubiquitylation catalysis, is one of the most important roles performed by co-activators, together with Apc1036,37,59–61,64,65. The APC/C substrates have a destruction motif or degron module sequence to be recognised by the WD40 domain of co-activators. The best-defined destruction motifs are the destruction box (D-box) with a consensus of RxxLxxxxN66 and the KEN-box, named after its consensus sequence, KENxxxN67, although the amino acid residues outside of the core RxxL and KEN are far more variable. The ABBA motif (Fx[ILV][FY]x[DE]) conserved in cyclin A, BubR1, Bub1 and Acm1 is a more recently characterised APC/C degron68–70. Also, there are less characterised degrons such as CRY-box or O-box and presumably as-yet-unidentified cryptic D-box or KEN-box exist. Each degron binds to a designated surface of the WD40 domain; for example, the D-box degron binds to a pocket situated between blades 1 and 7, whereas the KEN-box binds at the centre of the top surface of the wheel-like WD40 repeat domain70–72. Mutations, in the degron module on a substrate or the corresponding channel surface in the WD40 domain, that block substrate–co-activator interaction, render that substrate unavailable for ubiquitylation. The D-box– and the KEN-box–binding pockets/surfaces are evolutionally well conserved despite slight variations between Cdc20 and Cdh1 and those among species. Yet this may be a matchmaker mechanism, generating variable and dynamic affinities, by which degron module sequences on candidate substrates can be scanned and interrogated. As a consequence, if recognised as a genuine substrate, the degron specifically binds the WD40 surface with the correct affinity programmed by its degron sequence, which may determine processive or poor ubiquitylation of the substrate. The strength of interaction is likely to be regulated by environmental cues as it has been reported that the phosphorylation state around the degron region can influence the ubiquitylation of substrates (for example, Cdc6)73. Too strong or too weak interaction is probably not good for ubiquitylation. However, some APC/C inhibitors such as Mes1 or Acm1 seem to use such excessive affinity on purpose to inhibit the APC/C74–76. It should be noted that Cdh1 has a broader substrate specificity than Cdc20. It is likely that traits on the WD40 domain are responsible for such specificity, although the underlying mechanism remains obscure.
Phosphorylation regulates APC/CCdc20 and APC/CCdh1
The APC/C is “cell cycle–regulated”, which was very clearly described in original discovery papers5,6. Cdc20 binds and activates mitotically phosphorylated APC/C77–82. However, because many sites on the APC/C subunits are phosphorylated by cyclin-dependent kinase 1 (Cdk1)83,84, the sites of phosphorylation and their impacts have not been defined. Recently, the expression of recombinant APC/C and extensive site-directed mutagenesis of different subunits has uncovered the mechanism underlying the activation of the APC/C by Cdk1 phosphorylation85,86 and this has been confirmed by high-resolution EM studies87 (Figure 3). The model also supports the theory that Cdk1-dependent APC/C phosphorylation is the trigger for anaphase onset. In addition, the study highlights the importance of disordered loop domains of the APC/C subunits for dynamic regulation. Although Apc3 and Apc1 are clearly key subunits for phospho-regulation, other sites are also phosphorylated in vitro and in vivo. The roles of such phosphorylation remain elusive. Furthermore, how phosphorylation of the APC/C is regulated by phosphatases or how “teamwork” phosphorylation with other mitotic kinases (for example, polo-like kinase) is achieved for APC/C regulation requires elucidation.
Cdk1-dependent phosphorylation of Cdh1 is inhibitory, as shown in the late 1990s88,89, explaining the observation that Cdh1 action is repressed in mitosis and Cdc20 is the predominant co-activator. However, like Cdh1 phosphorylation, Cdk1-dependent phosphorylation of Cdc20 was shown to block an APC/C activation role through the C-box63. In mitosis, protein phosphatases such as PP2A dephosphorylate and activate Cdc2063. Yet the situation is slightly more complicated as in mitosis the APC/C needs to be phosphorylated (Figure 3) whereas Cdc20 needs to be dephosphorylated for the C-box–dependent activation of the APC/C. How can this conundrum be resolved? One mechanism seems to involve PP2A substrate specificity. PP2A complexes have an inherent preference for phosphothreonine over phosphoserine90–93. Notably, the key Cdk1 sites around the C-box of Cdc20 are threonine63 whereas Cdk1-phosphorylation sites in Apc1 loop300 are exclusively serine85–87. Thus, Cdc20 can be more efficiently dephosphorylated than the APC/C, allowing APC/CCdc20 complex formation during the correct window. It is unknown exactly how and which subfamilies of PP2A are involved in Cdc20 and APC/C dephosphorylation and whether other phosphatases such as PP1 are involved and, if so, how they are regulated. It should be noted that key Cdk1 sites of Cdh1 are serine; thus, Cdh1 dephosphorylation and subsequent Cdh1-dependent APC/C activation occur only after Cdk1 inactivation and subsequent activation of Cdk-counteracting phosphatases89,94–97, which initiate mitotic exit. Cdh1 phosphorylation is also involved in its subcellular localisation, contributing to the spatiotemporal regulation of the APC/C98–100.
Figure 3. Phosphorylation-dependent activation of the APC/C for APC/CCdc20.
Interphase APC/C is inactive without the recruitment of Cdc20, which is presented from a front view and a back view of the APC/C. The disordered loop domain of Apc1 (Apc1-loop300), which is located in the N-terminal WD40 domain, blocks Cdc20-NTD access to the APC/C, in particular the C-box–binding sites on Apc8B. Yellow dotted circle highlights the C-box–binding site. In mitosis, Cdk1-cyclinB-Cks phosphorylates the disordered loop domain of Apc3 (Apc3loop), which allows Cks-bound Cdk1-cyclin B loading to Apc3loop. Cdk1-cyclinB-Cks then stimulates phosphorylation of Apc1-loop300 as an intramolecular phosphorylation relay. Upon phosphorylation, inhibitory domain Apc1-loop300 is dislocated from the C-box–binding site, allowing Cdc20 association, the C-box-dependent activation and subsequent ubiquitylation catalysis (“cartoon view of the APC/C”). The isoleucine-arginine (IR) tail of Cdc20 binds to Apc3 and the C-box interacts with Apc8B for activation of the APC/C. Both IR tail binding and C-box binding ensure stable binding of co-activator (Cdc20) to the APC/C. The WD40 domain of co-activator is responsible for substrate degron recognition. The RING subunit Apc11 is coloured in light blue. APC/C, anaphase-promoting complex/cyclosome.
APC/C activity can be inhibited at multiple levels
Inhibitors are often very useful to explore the underlying mechanisms or processes of how a regulatory system works as critical processes are often targeted (Figure 4). Classic APC/C inhibition may involve overproduction of the D-box (high dose of the D-box) fragments, which can overwhelm the substrate recognition of Cdc20 (Figure 4A) and arrest cells at metaphase (by inhibiting APC/C)101–103. This finding suggested that proteins other than cyclin must be degraded to initiate anaphase, leading to the discovery of Cut2/securin12,13. Through the degron–WD40 interactions, Mes1 in Schizosaccharomyces pombe acts as a pseudo-substrate inhibitor for Fzr1/Mfr1 but works as a competitive substrate for Slp1/Cdc20, by which Mes1 controls the activity of the APC/C required for the meiosis I/II transition76,104,105. Similarly, the degron motifs of Acm1 in Saccharomyces cerevisiae are recognised in different ways by the WD40 domain of Cdh1 and Cdc2070,74,75,106,107, so that Acm1 becomes an inhibitor of Cdh1 but not Cdc20.
Figure 4. APC/C inhibitors target the APC/C at multiple levels.
(A) Overexpression or high dose of the destruction box (D-box) fragment (+op-D-box) competes with substrates to bind to the D-box–binding pocket on the WD40 domain (competitive inhibition). A small-molecule Apcin binds the D-box–binding pocket on the side face of the WD40 domain (+Apcin). (B) A small-molecule tosyl-l-arginine methyl ester (TAME), which resembles the isoleucine-arginine (IR) tail of Cdc20 and Cdh1, binds APC3 to interfere with the IR tail–binding site (+TAME). EM study suggests that TAME might compete with Cdc20 to bind at the IR tail and the C-box–binding sites. (C) Emi1 inhibits the APC/C at multiple levels (+Emi1). The D-box (weak) binds the WD40 domain of Cdc20/Cdh1, a zinc-binding region (ZBR) interferes with Ubc2C-dependent APC/C activity and the C-terminal LRRL tail interferes with Ube2S binding to the APC/C. The LRRL tail sequence of Emi1 is identical to the LRRL motif of Ube2S. In vivo target of Emi1 is Cdh1. (D) The main effector of the spindle assembly checkpoint (SAC) is the mitotic checkpoint complex (MCC), which inhibits the APC/C at multiple levels. In vivo target of MCC is Cdc20. MCC binds both the D-box–binding pocket and the KEN-box–binding surface of the WD40 domain and blocks WD40-mediated substrate binding. MCC also blocks Ube2C-dependent APC/C activity at the closed MCC configuration; however, Ube2S-dependent APC/C activity is not inhibited by MCC. Schematic diagrams are based on the cartoon view of the APC/C in Figure 3 (bottom left). APC/C, anaphase-promoting complex/cyclosome.
Through a chemical genetic screen in Xenopus egg extracts, tosyl-L-arginine methyl ester (TAME), a small-molecule APC/C inhibitor, has been isolated108. TAME structurally resembles the IR tail of co-activators and thus blocks Cdc20/Cdh1 loading onto the APC/C via the IR tail109 (Figure 4B). As the C-box–binding site on Apc8 is structurally equivalent to the IR tail–binding site on Apc332, TAME potentially affects the C-box function as well as the IR tail87. TAME is more specific to Cdc20 than Cdh1. This seems to be due in part to the fact that Cdh1 has more contact with the APC/C, achieving higher affinity, but the detailed mechanism remains elusive. Another inhibitor molecule, known as Apcin, which was isolated from the same chemical screenings, binds to the D-box–binding site of the WD40 domain of Cdc20 (Figure 4A)110. This finding has created a great opportunity for synergistic inhibition using both TAME and Apcin, which has proven to be more effective than either alone110.
Early mitotic inhibitor (Emi)1 is a metazoan APC/C inhibitor111 which is a vertebrate homologue of Rca1 (regulator of cyclin A). In Drosophila, Rca1 inhibits APC/CCdh1 and stabilises cyclin A in S phase112,113. Emi1 has been shown to inhibit both APC/CCdc20 and APC/CCdh1 activity in vitro111,114 but its main purpose is thought to be inhibition of APC/CCdh1 during S and G2115,116. Emi1 has a C-terminal inhibitory domain composed of structural components such as the D-box, Linker, ZBR and RL tail (Emi1DLZT)117,118. The Emi1 C-terminal domain was previously proposed to be a pseudo-substrate inhibitor119, but cryo-EM and quantitative biochemical analysis have revealed a more sophisticated inhibition mechanism; Emi1 apparently uses every structural property within the Emi1DLZT domain and blocks APC/C ubiquitylation processes, including Ube2S-dependent ubiquitin chain elongation32,117,118 (Figure 4C). It should be noted that Emi1 destruction is regulated by another E3 ubiquitin ligase, SCFβTRCP, through the degron on its N-terminal domain upon phosphorylation120–122. Also, Emi1 activity is negatively regulated by Cdk1 phosphorylation123. Because of the high potency of Emi1, it is controlled by multiple layers of regulation, including transcriptional and translational changes124,125. Emi2 (also called Erp1), a maternal paralogue of Emi1, inhibits the APC/C in a similar manner to Emi1, so that vertebrate eggs awaiting fertilisation are arrested at metaphase of meiosis II126,127.
Finally, the spindle assembly checkpoint (SAC) monitors unattached or tensionless kinetochores and delays the onset of anaphase until all the kinetochores are attached to form a proper bipolar spindle structure128–130. The mitotic checkpoint complex (MCC) consisting of Mad2, BubR1, Bub3 and Cdc20 is a potent APC/C inhibitor (Figure 4D). MCC was recently shown to inhibit a second Cdc20APC/C that has already bound and activated the APC/C, highlighting that MCC can indeed act as a direct APC/C inhibitor, rather than sequestering Cdc20131. High-resolution cryo-EM studies of APC/C-MCC complex reveal that BubR1 binding mislocates Cdc20APC/C and blocks substrate recognition48,49. The MCC docks into the APC/C central cavity and also interferes with Ube2C recruitment, inhibiting most of the substrate ubiquitylation. Intriguingly, a subset of substrates such as Nek2A or cyclin A, which can bind the APC/C independently of the WD40 of co-activators, can be degraded even when SAC is active132–134. It might be that Nek2A binds to a TPR subunit that MCC does not interfere with (for example, Apc6B or Apc7) by which Nek2A is ubiquitylated and degraded as long as the proper interaction between the C-box and Apc8B is ensured. Once all kinetochores become stably attached to the spindle, the SAC has to be silenced to allow anaphase onset. p31comet is an SAC antagonist135 and is involved in SAC silencing in multiple ways, such as blocking Mad2 activation by binding to C-Mad2136,137 and assisting MCC disassembly together with the AAA+ ATPase TRIP13138–143. Cdc20 auto-ubiquitylation is also involved in MCC disassembly144–149. Yet it appears that several pathways regulate SAC activation as well as SAC silencing in vivo150–155, so further work is necessary to elucidate the detailed mechanisms. Regulation of the SAC pathway has been reviewed by others20,21,156–158.
Future perspectives
Recent progress on the resolution of cryo-EM is amazing, entailing near atomic resolution now and inevitable atomic resolution in the future. The MultiBac-based reconstitution pipeline of the whole APC/C complex allows construction of any mutation(s) in any subunit(s) at will, which provides an unprecedented opportunity to interrogate detailed dynamic regulation in physiological conditions such as Xenopus egg extracts together with the latest structural technologies, in combination with cell biological, genetic, biochemical, bioinformatics or mathematical modelling approaches. By combining genome editing and RNA interference, mammalian cell biology approaches will also provide unprecedented details of APC/C regulation. Yet we still face a number of outstanding questions. Why is the APC/C so large and why are so many subunits required for APC/C activity? Has evolution contributed to the enormous size and the complexity of the subunits? Are there any as-yet-unidentified subunit or sub-complex functions besides ubiquitylation? Is the APC/C complex disassembled partly or even fully and how is it regulated? We know that cellular subunit expression levels vary depending on subunit, so it may be that some subunits behave as a core regulating the assembly. Another key issue is the influence of subcellular localisation on APC/C function in vivo. Local concentration of not only the APC/C but also co-activators, E2s, substrates and inhibitors would all affect APC/C activity. Furthermore, our knowledge of ubiquitin dynamics regulating and maintaining the relationship between the APC/C and the action of DUBs is still very limited, although very recently Cezanne/OTUD7B was shown to be a cell cycle–regulated DUB antagonising APC/C activity159. Moreover, increasing evidence suggests that dysregulation of Cdc20 or Cdh1 is involved in disease conditions and progression as in cancer. Deeper knowledge of the APC/C ubiquitin system and the mechanisms of distinct co-activator working will ultimately contribute to not only a better understanding of the cell cycle but also the possible development of therapies or tools to control or monitor dysregulated APC/C.
Closing remarks
The discovery of MPF as a complex of cyclin B and Cdk1/Cdc2 in the late 1980s heralded the first wave of understanding of the cell cycle in modern times. Many scientists following their own interests and curiosity had conducted studies in a number of model organisms such as frog, starfish, clam, sea urchin, yeast (budding and fission), fly and human cell culture systems160–173. Collaborative and comparative analysis of all this research unveiled the MPF story. In September 1988, at a key moment in the beginning of cell cycle research, the first CNRS Cell Cycle meeting in Roscoff (France) was organised, highlighting the efficacy of collaboration and a multidisciplinary approach to solve important questions in science. With continued passion and curiosity, hard work and luck, much can be achieved, not only to further our understanding of the cell cycle but to pave the way for exciting new advances in the field of medicine.
Grant information
Our research is supported by the Wellcome Trust, the Biotechnology and Biological Sciences Research Council, the Medical Research Council, and Cancer Research UK.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Faculty Opinions recommendedReferences
- 1.
Hershko A, Ciechanover A:
The ubiquitin system.
Annu Rev Biochem.
1998; 67: 425–79. PubMed Abstract
| Publisher Full Text
- 2.
Pickart CM, Eddins MJ:
Ubiquitin: structures, functions, mechanisms.
Biochim Biophys Acta.
2004; 1695(1–3): 55–72. PubMed Abstract
| Publisher Full Text
- 3.
Komander D, Rape M:
The ubiquitin code.
Annu Rev Biochem.
2012; 81: 203–29. PubMed Abstract
| Publisher Full Text
- 4.
Hershko A, Ciechanover A:
Mechanisms of intracellular protein breakdown.
Annu Rev Biochem.
1982; 51: 335–64. PubMed Abstract
| Publisher Full Text
- 5.
King RW, Peters JM, Tugendreich S, et al.:
A 20S complex containing CDC27 and CDC16 catalyzes the mitosis-specific conjugation of ubiquitin to cyclin B.
Cell.
1995; 81(2): 279–88. PubMed Abstract
| Publisher Full Text
- 6.
Sudakin V, Ganoth D, Dahan A, et al.:
The cyclosome, a large complex containing cyclin-selective ubiquitin ligase activity, targets cyclins for destruction at the end of mitosis.
Mol Biol Cell.
1995; 6(2): 185–97. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 7.
Irniger S, Piatti S, Michaelis C, et al.:
Genes involved in sister chromatid separation are needed for B-type cyclin proteolysis in budding yeast.
Cell.
1995; 81(2): 269–78. PubMed Abstract
| Publisher Full Text
- 8.
Hirano T, Hiraoka Y, Yanagida M:
A temperature-sensitive mutation of the Schizosaccharomyces pombe gene nuc2+ that encodes a nuclear scaffold-like protein blocks spindle elongation in mitotic anaphase.
J Cell Biol.
1988; 106(4): 1171–83. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 9.
Tugendreich S, Tomkiel J, Earnshaw W, et al.:
CDC27Hs colocalizes with CDC16Hs to the centrosome and mitotic spindle and is essential for the metaphase to anaphase transition.
Cell.
1995; 81(2): 261–8. PubMed Abstract
| Publisher Full Text
- 10.
Lamb JR, Michaud WA, Sikorski RS, et al.:
Cdc16p, Cdc23p and Cdc27p form a complex essential for mitosis.
EMBO J.
1994; 13(18): 4321–8. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 11.
O'Donnell KL, Osmani AH, Osmani SA, et al.:
bimA encodes a member of the tetratricopeptide repeat family of proteins and is required for the completion of mitosis in Aspergillus nidulans.
J Cell Sci.
1991; 99(Pt 4): 711–9. PubMed Abstract
- 12.
Funabiki H, Yamano H, Kumada K, et al.:
Cut2 proteolysis required for sister-chromatid seperation in fission yeast.
Nature.
1996; 381(6581): 438–41. PubMed Abstract
| Publisher Full Text
- 13.
Cohen-Fix O, Peters JM, Kirschner MW, et al.:
Anaphase initiation in Saccharomyces cerevisiae is controlled by the APC-dependent degradation of the anaphase inhibitor Pds1p.
Genes Dev.
1996; 10(24): 3081–93. PubMed Abstract
| Publisher Full Text
- 14.
Sullivan M, Morgan DO:
Finishing mitosis, one step at a time.
Nat Rev Mol Cell Biol.
2007; 8(11): 894–903. PubMed Abstract
| Publisher Full Text
- 15.
Peters JM:
The anaphase promoting complex/cyclosome: a machine designed to destroy.
Nat Rev Mol Cell Biol.
2006; 7(9): 644–56. PubMed Abstract
| Publisher Full Text
- 16.
Pines J:
Cubism and the cell cycle: the many faces of the APC/C.
Nat Rev Mol Cell Biol.
2011; 12(7): 427–38. PubMed Abstract
| Publisher Full Text
- 17.
Barford D:
Structure, function and mechanism of the anaphase promoting complex (APC/C).
Q Rev Biophys.
2011; 44(2): 153–90. PubMed Abstract
| Publisher Full Text
- 18.
Primorac I, Musacchio A:
Panta rhei: the APC/C at steady state.
J Cell Biol.
2013; 201(2): 177–89. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 19.
Schreiber A, Stengel F, Zhang Z, et al.:
Structural basis for the subunit assembly of the anaphase-promoting complex.
Nature.
2011; 470(7333): 227–32. PubMed Abstract
| Publisher Full Text
- 20.
Alfieri C, Zhang S, Barford D:
Visualizing the complex functions and mechanisms of the anaphase promoting complex/cyclosome (APC/C).
Open Biol.
2017; 7(11): pii: 170204. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 21.
Watson ER, Brown NG, Peters JM, et al.:
Posing the APC/C E3 Ubiquitin Ligase to Orchestrate Cell Division.
Trends Cell Biol.
2019; 29(2): 117–34. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 22.
Zachariae W, Shevchenko A, Andrews PD, et al.:
Mass spectrometric analysis of the anaphase-promoting complex from yeast: identification of a subunit related to cullins.
Science.
1998; 279(5354): 1216–9. PubMed Abstract
| Publisher Full Text
- 23.
Yu H, Peters JM, King RW, et al.:
Identification of a cullin homology region in a subunit of the anaphase-promoting complex.
Science.
1998; 279(5354): 1219–22. PubMed Abstract
| Publisher Full Text
- 24.
Gmachl M, Gieffers C, Podtelejnikov AV, et al.:
The RING-H2 finger protein APC11 and the E2 enzyme UBC4 are sufficient to ubiquitinate substrates of the anaphase-promoting complex.
Proc Natl Acad Sci U S A.
2000; 97(16): 8973–8. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 25.
Leverson JD, Joazeiro CA, Page AM, et al.:
The APC11 RING-H2 finger mediates E2-dependent ubiquitination.
Mol Biol Cell.
2000; 11(7): 2315–25. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 26.
Tang Z, Li B, Bharadwaj R, et al.:
APC2 Cullin protein and APC11 RING protein comprise the minimal ubiquitin ligase module of the anaphase-promoting complex.
Mol Biol Cell.
2001; 12(12): 3839–51. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 27.
Gieffers C, Dube P, Harris JR, et al.:
Three-dimensional structure of the anaphase-promoting complex.
Mol Cell.
2001; 7(4): 907–13. PubMed Abstract
| Publisher Full Text
- 28.
Dube P, Herzog F, Gieffers C, et al.:
Localization of the coactivator Cdh1 and the cullin subunit Apc2 in a cryo-electron microscopy model of vertebrate APC/C.
Mol Cell.
2005; 20(6): 867–79. PubMed Abstract
| Publisher Full Text
- 29.
Ohi MD, Feoktistova A, Ren L, et al.:
Structural organization of the anaphase-promoting complex bound to the mitotic activator Slp1.
Mol Cell.
2007; 28(5): 871–85. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 30.
Passmore LA, Booth CR, Vénien-Bryan C, et al.:
Structural analysis of the anaphase-promoting complex reveals multiple active sites and insights into polyubiquitylation.
Mol Cell.
2005; 20(6): 855–66. PubMed Abstract
| Publisher Full Text
- 31.
Brown NG, VanderLinden R, Watson ER, et al.:
Dual RING E3 Architectures Regulate Multiubiquitination and Ubiquitin Chain Elongation by APC/C.
Cell.
2016; 165(6): 1440–53. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 32.
Chang L, Zhang Z, Yang J, et al.:
Atomic structure of the APC/C and its mechanism of protein ubiquitination.
Nature.
2015; 522(7557): 450–4. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 33.
Chang LF, Zhang Z, Yang J, et al.:
Molecular architecture and mechanism of the anaphase-promoting complex.
Nature.
2014; 513(7518): 388–93. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 34.
Yamada H, Kumada K, Yanagida M:
Distinct subunit functions and cell cycle regulated phosphorylation of 20S APC/cyclosome required for anaphase in fission yeast.
J Cell Sci.
1997; 110(Pt 15): 1793–804. PubMed Abstract
- 35.
Yoon HJ, Feoktistova A, Chen JS, et al.:
Role of Hcn1 and its phosphorylation in fission yeast anaphase-promoting complex/cyclosome function.
J Biol Chem.
2006; 281(43): 32284–93. PubMed Abstract
| Publisher Full Text
- 36.
da Fonseca PCA, Kong EH, Zhang Z, et al.:
Structures of APC/CCdh1 with substrates identify Cdh1 and Apc10 as the D-box co-receptor.
Nature.
2011; 470(7333): 274–8. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 37.
Buschhorn BA, Petzold G, Galova M, et al.:
Substrate binding on the APC/C occurs between the coactivator Cdh1 and the processivity factor Doc1.
Nat Struct Mol Biol.
2011; 18(1): 6–13. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 38.
Wu T, Merbl Y, Huo Y, et al.:
UBE2S drives elongation of K11-linked ubiquitin chains by the anaphase-promoting complex.
Proc Natl Acad Sci U S A.
2010; 107(4): 1355–60. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 39.
Matsumoto ML, Wickliffe KE, Dong KC, et al.:
K11-linked polyubiquitination in cell cycle control revealed by a K11 linkage-specific antibody.
Mol Cell.
2010; 39(3): 477–84. PubMed Abstract
| Publisher Full Text
| Faculty Opinions Recommendation
- 40.
Williamson A, Wickliffe KE, Mellone BG, et al.:
Identification of a physiological E2 module for the human anaphase-promoting complex.
Proc Natl Acad Sci U S A.
2009; 106(43): 18213–8. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 41.
Meyer HJ, Rape M:
Enhanced protein degradation by branched ubiquitin chains.
Cell.
2014; 157(4): 910–21. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 42.
Rana ASJB, Ge Y, Strieter ER:
Ubiquitin Chain Enrichment Middle-Down Mass Spectrometry (UbiChEM-MS) Reveals Cell-Cycle Dependent Formation of Lys11/Lys48 Branched Ubiquitin Chains.
J Proteome Res.
2017; 16(9): 3363–9. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 43.
Yau RG, Doerner K, Castellanos ER, et al.:
Assembly and Function of Heterotypic Ubiquitin Chains in Cell-Cycle and Protein Quality Control.
Cell.
2017; 171(4): 918–933.e20. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 44.
Rodrigo-Brenni MC, Morgan DO:
Sequential E2s drive polyubiquitin chain assembly on APC targets.
Cell.
2007; 130(1): 127–39. PubMed Abstract
| Publisher Full Text
| Faculty Opinions Recommendation
- 45.
Meza Gutierrez F, Simsek D, Mizrak A, et al.:
Genetic analysis reveals functions of atypical polyubiquitin chains.
eLife.
2018; 7: pii: e42955. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 46.
Yu H, King RW, Peters JM, et al.:
Identification of a novel ubiquitin-conjugating enzyme involved in mitotic cyclin degradation.
Curr Biol.
1996; 6(4): 455–66. PubMed Abstract
| Publisher Full Text
- 47.
Garnett MJ, Mansfeld J, Godwin C, et al.:
UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit.
Nat Cell Biol.
2009; 11(11): 1363–9. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 48.
Yamaguchi M, VanderLinden R, Weissmann F, et al.:
Cryo-EM of Mitotic Checkpoint Complex-Bound APC/C Reveals Reciprocal and Conformational Regulation of Ubiquitin Ligation.
Mol Cell.
2016; 63(4): 593–607. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 49.
Alfieri C, Chang L, Zhang Z, et al.:
Molecular basis of APC/C regulation by the spindle assembly checkpoint.
Nature.
2016; 536(7617): 431–6. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 50.
Brown NG, Watson ER, Weissmann F, et al.:
Mechanism of polyubiquitination by human anaphase-promoting complex: RING repurposing for ubiquitin chain assembly.
Mol Cell.
2014; 56(2): 246–60. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 51.
Kelly A, Wickliffe KE, Song L, et al.:
Ubiquitin chain elongation requires E3-dependent tracking of the emerging conjugate.
Mol Cell.
2014; 56(2): 232–45. PubMed Abstract
| Publisher Full Text
| Faculty Opinions Recommendation
- 52.
Alpi AF, Chaugule V, Walden H:
Mechanism and disease association of E2-conjugating enzymes: lessons from UBE2T and UBE2L3.
Biochem J.
2016; 473(20): 3401–19. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 53.
Stewart MD, Ritterhoff T, Klevit RE, et al.:
E2 enzymes: More than just middle men.
Cell Res.
2016; 26(4): 423–40. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 54.
Kim SH, Lin DP, Matsumoto S, et al.:
Fission yeast Slp1: an effector of the Mad2-dependent spindle checkpoint.
Science.
1998; 279(5353): 1045–7. PubMed Abstract
| Publisher Full Text
- 55.
Sigrist SJ, Lehner CF:
Drosophila fizzy-related down-regulates mitotic cyclins and is required for cell proliferation arrest and entry into endocycles.
Cell.
1997; 90(4): 671–81. PubMed Abstract
| Publisher Full Text
- 56.
Visintin R, Prinz S, Amon A:
CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis.
Science.
1997; 278(5337): 460–3. PubMed Abstract
| Publisher Full Text
- 57.
Schwab M, Lutum AS, Seufert W:
Yeast Hct1 is a regulator of Clb2 cyclin proteolysis.
Cell.
1997; 90(4): 683–93. PubMed Abstract
| Publisher Full Text
- 58.
Dawson IA, Roth S, Artavanis-Tsakonas S:
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.
J Cell Biol.
1995; 129(3): 725–37. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 59.
Schwab M, Neutzner M, Möcker D, et al.:
Yeast Hct1 recognizes the mitotic cyclin Clb2 and other substrates of the ubiquitin ligase APC.
EMBO J.
2001; 20(18): 5165–75. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 60.
Hilioti Z, Chung YS, Mochizuki Y, et al.:
The anaphase inhibitor Pds1 binds to the APC/C-associated protein Cdc20 in a destruction box-dependent manner.
Curr Biol.
2001; 11(17): 1347–52. PubMed Abstract
| Publisher Full Text
| Faculty Opinions Recommendation
- 61.
Burton JL, Solomon MJ:
D box and KEN box motifs in budding yeast Hsl1p are required for APC-mediated degradation and direct binding to Cdc20p and Cdh1p.
Genes Dev.
2001; 15(18): 2381–95. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 62.
Kimata Y, Baxter JE, Fry AM, et al.:
A role for the Fizzy/Cdc20 family of proteins in activation of the APC/C distinct from substrate recruitment.
Mol Cell.
2008; 32(4): 576–83. PubMed Abstract
| Publisher Full Text
- 63.
Labit H, Fujimitsu K, Bayin NS, et al.:
Dephosphorylation of Cdc20 is required for its C-box-dependent activation of the APC/C.
EMBO J.
2012; 31(15): 3351–62. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 64.
Yamano H, Gannon J, Mahbubani H, et al.:
Cell cycle-regulated recognition of the destruction box of cyclin B by the APC/C in Xenopus egg extracts.
Mol Cell.
2004; 13(1): 137–47. PubMed Abstract
| Publisher Full Text
| Faculty Opinions Recommendation
- 65.
Kraft C, Vodermaier HC, Maurer-Stroh S, et al.:
The WD40 propeller domain of Cdh1 functions as a destruction box receptor for APC/C substrates.
Mol Cell.
2005; 18(5): 543–53. PubMed Abstract
| Publisher Full Text
- 66.
Glotzer M, Murray AW, Kirschner MW:
Cyclin is degraded by the ubiquitin pathway.
Nature.
1991; 349(6305): 132–8. PubMed Abstract
| Publisher Full Text
- 67.
Pfleger CM, Kirschner MW:
The KEN box: an APC recognition signal distinct from the D box targeted by Cdh1.
Genes Dev.
2000; 14(6): 655–65. PubMed Abstract
| Free Full Text
- 68.
Di Fiore B, Davey NE, Hagting A, et al.:
The ABBA motif binds APC/C activators and is shared by APC/C substrates and regulators.
Dev Cell.
2015; 32(3): 358–72. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 69.
Lu D, Hsiao JY, Davey NE, et al.:
Multiple mechanisms determine the order of APC/C substrate degradation in mitosis.
J Cell Biol.
2014; 207(1): 23–39. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 70.
He J, Chao WC, Zhang Z, et al.:
Insights into degron recognition by APC/C coactivators from the structure of an Acm1-Cdh1 complex.
Mol Cell.
2013; 50(5): 649–60. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 71.
Tian W, Li B, Warrington R, et al.:
Structural analysis of human Cdc20 supports multisite degron recognition by APC/C.
Proc Natl Acad Sci U S A.
2012; 109(45): 18419–24. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 72.
Chao WC, Kulkarni K, Zhang Z, et al.:
Structure of the mitotic checkpoint complex.
Nature.
2012; 484(7393): 208–13. PubMed Abstract
| Publisher Full Text
| Faculty Opinions Recommendation
- 73.
Mailand N, Diffley JF:
CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis.
Cell.
2005; 122(6): 915–26. PubMed Abstract
| Publisher Full Text
| Faculty Opinions Recommendation
- 74.
Enquist-Newman M, Sullivan M, Morgan DO:
Modulation of the mitotic regulatory network by APC-dependent destruction of the Cdh1 inhibitor Acm1.
Mol Cell.
2008; 30(4): 437–46. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 75.
Burton JL, Xiong Y, Solomon MJ:
Mechanisms of pseudosubstrate inhibition of the anaphase promoting complex by Acm1.
EMBO J.
2011; 30(9): 1818–29. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 76.
Kimata Y, Trickey M, Izawa D, et al.:
A mutual inhibition between APC/C and its substrate Mes1 required for meiotic progression in fission yeast.
Dev Cell.
2008; 14(3): 446–54. PubMed Abstract
| Publisher Full Text
- 77.
Rudner AD, Murray AW:
Phosphorylation by Cdc28 activates the Cdc20-dependent activity of the anaphase-promoting complex.
J Cell Biol.
2000; 149(7): 1377–90. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 78.
Shteinberg M, Protopopov Y, Listovsky T, et al.:
Phosphorylation of the cyclosome is required for its stimulation by Fizzy/cdc20.
Biochem Biophys Res Commun.
1999; 260(1): 193–8. PubMed Abstract
| Publisher Full Text
- 79.
Kramer ER, Scheuringer N, Podtelejnikov AV, et al.:
Mitotic regulation of the APC activator proteins CDC20 and CDH1.
Mol Biol Cell.
2000; 11(5): 1555–69. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 80.
Fang G, Yu H, Kirschner MW:
Direct binding of CDC20 protein family members activates the anaphase-promoting complex in mitosis and G1.
Mol Cell.
1998; 2(2): 163–71. PubMed Abstract
| Publisher Full Text
- 81.
Yudkovsky Y, Shteinberg M, Listovsky T, et al.:
Phosphorylation of Cdc20/fizzy negatively regulates the mammalian cyclosome/APC in the mitotic checkpoint.
Biochem Biophys Res Commun.
2000; 271(2): 299–304. PubMed Abstract
| Publisher Full Text
- 82.
Patra D, Dunphy WG:
Xe-p9, a Xenopus Suc1/Cks protein, is essential for the Cdc2-dependent phosphorylation of the anaphase- promoting complex at mitosis.
Genes Dev.
1998; 12(16): 2549–59. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 83.
Steen JA, Steen H, Georgi A, et al.:
Different phosphorylation states of the anaphase promoting complex in response to antimitotic drugs: a quantitative proteomic analysis.
Proc Natl Acad Sci U S A.
2008; 105(16): 6069–74. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 84.
Kraft C, Herzog F, Gieffers C, et al.:
Mitotic regulation of the human anaphase-promoting complex by phosphorylation.
EMBO J.
2003; 22(24): 6598–609. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 85.
Fujimitsu K, Grimaldi M, Yamano H:
Cyclin-dependent kinase 1-dependent activation of APC/C ubiquitin ligase.
Science.
2016; 352(6289): 1121–4. PubMed Abstract
| Publisher Full Text
| Faculty Opinions Recommendation
- 86.
Qiao R, Weissmann F, Yamaguchi M, et al.:
Mechanism of APC/CCDC20 activation by mitotic phosphorylation.
Proc Natl Acad Sci U S A.
2016; 113(19): E2570–8. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 87.
Zhang S, Chang L, Alfieri C, et al.:
Molecular mechanism of APC/C activation by mitotic phosphorylation.
Nature.
2016; 533(7602): 260–4. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 88.
Zachariae W, Schwab M, Nasmyth K, et al.:
Control of cyclin ubiquitination by CDK-regulated binding of Hct1 to the anaphase promoting complex.
Science.
1998; 282(5394): 1721–4. PubMed Abstract
| Publisher Full Text
- 89.
Visintin R, Craig K, Hwang ES, et al.:
The phosphatase Cdc14 triggers mitotic exit by reversal of Cdk-dependent phosphorylation.
Mol Cell.
1998; 2(6): 709–18. PubMed Abstract
| Publisher Full Text
- 90.
Hein JB, Hertz EPT, Garvanska DH, et al.:
Distinct kinetics of serine and threonine dephosphorylation are essential for mitosis.
Nat Cell Biol.
2017; 19(12): 1433–40. PubMed Abstract
| Publisher Full Text
| Faculty Opinions Recommendation
- 91.
Cundell MJ, Hutter LH, Nunes Bastos R, et al.:
A PP2A-B55 recognition signal controls substrate dephosphorylation kinetics during mitotic exit.
J Cell Biol.
2016; 214(5): 539–54. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 92.
Pinna LA, Donella A, Clari G, et al.:
Preferential dephosphorylation of protein bound phosphorylthreonine and phosphorylserine residues by cytosol and mitochondrial "casein phosphatases".
Biochem Biophys Res Commun.
1976; 70(4): 1308–15. PubMed Abstract
| Publisher Full Text
- 93.
Deana AD, Marchiori F, Meggio F, et al.:
Dephosphorylation of synthetic phosphopeptides by protein phosphatase-T, a phosphothreonyl protein phosphatase.
J Biol Chem.
1982; 257(15): 8565–8. PubMed Abstract
- 94.
Mochida S, Ikeo S, Gannon J, et al.:
Regulated activity of PP2A-B55 delta is crucial for controlling entry into and exit from mitosis in Xenopus egg extracts.
EMBO J.
2009; 28(18): 2777–85. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 95.
Jaspersen SL, Charles JF, Morgan DO:
Inhibitory phosphorylation of the APC regulator Hct1 is controlled by the kinase Cdc28 and the phosphatase Cdc14.
Curr Biol.
1999; 9(5): 227–36. PubMed Abstract
| Publisher Full Text
- 96.
Wu JQ, Guo JY, Tang W, et al.:
PP1-mediated dephosphorylation of phosphoproteins at mitotic exit is controlled by inhibitor-1 and PP1 phosphorylation.
Nat Cell Biol.
2009; 11(5): 644–51. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 97.
Schmitz MH, Held M, Janssens V, et al.:
Live-cell imaging RNAi screen identifies PP2A-B55alpha and importin-beta1 as key mitotic exit regulators in human cells.
Nat Cell Biol.
2010; 12(9): 886–93. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 98.
Jaquenoud M, van Drogen F, Peter M:
Cell cycle-dependent nuclear export of Cdh1p may contribute to the inactivation of APC/CCdh1.
EMBO J.
2002; 21(23): 6515–26. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 99.
Höckner S, Neumann-Arnold L, Seufert W:
Dual control by Cdk1 phosphorylation of the budding yeast APC/C ubiquitin ligase activator Cdh1.
Mol Biol Cell.
2016; 27(14): 2198–212. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 100.
Zhou Y, Ching YP, Chun ACS, et al.:
Nuclear localization of the cell cycle regulator CDH1 and its regulation by phosphorylation.
J Biol Chem.
2003; 278(14): 12530–6. PubMed Abstract
| Publisher Full Text
- 101.
Yamano H, Gannon J, Hunt T:
The role of proteolysis in cell cycle progression in Schizosaccharomyces pombe.
EMBO J.
1996; 15(19): 5268–79. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 102.
Yamano H, Tsurumi C, Gannon J, et al.:
The role of the destruction box and its neighbouring lysine residues in cyclin B for anaphase ubiquitin-dependent proteolysis in fission yeast: defining the D-box receptor.
EMBO J.
1998; 17(19): 5670–8. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 103.
Holloway SL, Glotzer M, King RW, et al.:
Anaphase is initiated by proteolysis rather than by the inactivation of maturation-promoting factor.
Cell.
1993; 73(7): 1393–402. PubMed Abstract
| Publisher Full Text
- 104.
Izawa D, Goto M, Yamashita A, et al.:
Fission yeast Mes1p ensures the onset of meiosis II by blocking degradation of cyclin Cdc13p.
Nature.
2005; 434(7032): 529–33. PubMed Abstract
| Publisher Full Text
| Faculty Opinions Recommendation
- 105.
Kimata Y, Kitamura K, Fenner N, et al.:
Mes1 controls the meiosis I to meiosis II transition by distinctly regulating the anaphase-promoting complex/cyclosome coactivators Fzr1/Mfr1 and Slp1 in fission yeast.
Mol Biol Cell.
2011; 22(9): 1486–94. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 106.
Hall MC, Jeong DE, Henderson JT, et al.:
Cdc28 and Cdc14 control stability of the anaphase-promoting complex inhibitor Acm1.
J Biol Chem.
2008; 283(16): 10396–407. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 107.
Ostapenko D, Burton JL, Wang R, et al.:
Pseudosubstrate inhibition of the anaphase-promoting complex by Acm1: regulation by proteolysis and Cdc28 phosphorylation.
Mol Cell Biol.
2008; 28(15): 4653–64. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 108.
Verma R, Peters NR, D'Onofrio M, et al.:
Ubistatins inhibit proteasome-dependent degradation by binding the ubiquitin chain.
Science.
2004; 306(5693): 117–20. PubMed Abstract
| Publisher Full Text
| Faculty Opinions Recommendation
- 109.
Zeng X, Sigoillot F, Gaur S, et al.:
Pharmacologic inhibition of the anaphase-promoting complex induces a spindle checkpoint-dependent mitotic arrest in the absence of spindle damage.
Cancer Cell.
2010; 18(4): 382–95. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 110.
Sackton KL, Dimova N, Zeng X, et al.:
Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C.
Nature.
2014; 514(7524): 646–9. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 111.
Reimann JD, Freed E, Hsu JY, et al.:
Emi1 is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex.
Cell.
2001; 105(5): 645–55. PubMed Abstract
| Publisher Full Text
| Faculty Opinions Recommendation
- 112.
Dong X, Zavitz KH, Thomas BJ, et al.:
Control of G1 in the developing Drosophila eye: rca1 regulates Cyclin A.
Genes Dev.
1997; 11(1): 94–105. PubMed Abstract
| Publisher Full Text
- 113.
Grosskortenhaus R, Sprenger F:
Rca1 inhibits APC-Cdh1Fzr and is required to prevent cyclin degradation in G2.
Dev Cell.
2002; 2(1): 29–40. PubMed Abstract
| Publisher Full Text
| Faculty Opinions Recommendation
- 114.
Reimann JD, Gardner BE, Margottin-Goguet F, et al.:
Emi1 regulates the anaphase-promoting complex by a different mechanism than Mad2 proteins.
Genes Dev.
2001; 15(24): 3278–85. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 115.
Di Fiore B, Pines J:
Emi1 is needed to couple DNA replication with mitosis but does not regulate activation of the mitotic APC/C.
J Cell Biol.
2007; 177(3): 425–37. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 116.
Machida YJ, Dutta A:
The APC/C inhibitor, Emi1, is essential for prevention of rereplication.
Genes Dev.
2007; 21(2): 184–94. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 117.
Wang W, Kirschner MW:
Emi1 preferentially inhibits ubiquitin chain elongation by the anaphase-promoting complex.
Nat Cell Biol.
2013; 15(7): 797–806. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 118.
Frye JJ, Brown NG, Petzold G, et al.:
Electron microscopy structure of human APC/CCDH1-EMI1 reveals multimodal mechanism of E3 ligase shutdown.
Nat Struct Mol Biol.
2013; 20(7): 827–35. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 119.
Miller JJ, Summers MK, Hansen DV, et al.:
Emi1 stably binds and inhibits the anaphase-promoting complex/cyclosome as a pseudosubstrate inhibitor.
Genes Dev.
2006; 20(17): 2410–20. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 120.
Guardavaccaro D, Kudo Y, Boulaire J, et al.:
Control of meiotic and mitotic progression by the F box protein beta-Trcp1 in vivo.
Dev Cell.
2003; 4(6): 799–812. PubMed Abstract
| Publisher Full Text
- 121.
Margottin-Goguet F, Hsu JY, Loktev A, et al.:
Prophase destruction of Emi1 by the SCFbetaTrCP/Slimb ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase.
Dev Cell.
2003; 4(6): 813–26. PubMed Abstract
| Publisher Full Text
- 122.
Moshe Y, Boulaire J, Pagano M, et al.:
Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome.
Proc Natl Acad Sci U S A.
2004; 101(21): 7937–42. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 123.
Moshe Y, Bar-On O, Ganoth D, et al.:
Regulation of the action of early mitotic inhibitor 1 on the anaphase-promoting complex/cyclosome by cyclin-dependent kinases.
J Biol Chem.
2011; 286(19): 16647–57. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 124.
Tanenbaum ME, Stern-Ginossar N, Weissman JS, et al.:
Regulation of mRNA translation during mitosis.
eLife.
2015; 4: e07957. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 125.
Belloc E, Méndez R:
A deadenylation negative feedback mechanism governs meiotic metaphase arrest.
Nature.
2008; 452(7190): 1017–21. PubMed Abstract
| Publisher Full Text
| Faculty Opinions Recommendation
- 126.
Schmidt A, Duncan PI, Rauh NR, et al.:
Xenopus polo-like kinase Plx1 regulates XErp1, a novel inhibitor of APC/C activity.
Genes Dev.
2005; 19(4): 502–13. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 127.
Rauh NR, Schmidt A, Bormann J, et al.:
Calcium triggers exit from meiosis II by targeting the APC/C inhibitor XErp1 for degradation.
Nature.
2005; 437(7601): 1048–52. PubMed Abstract
| Publisher Full Text
| Faculty Opinions Recommendation
- 128.
Lara-Gonzalez P, Westhorpe FG, Taylor SS:
The spindle assembly checkpoint.
Curr Biol.
2012; 22(22): R966–80. PubMed Abstract
| Publisher Full Text
- 129.
Musacchio A, Salmon ED:
The spindle-assembly checkpoint in space and time.
Nat Rev Mol Cell Biol.
2007; 8(5): 379–93. PubMed Abstract
| Publisher Full Text
- 130.
Foley EA, Kapoor TM:
Microtubule attachment and spindle assembly checkpoint signalling at the kinetochore.
Nat Rev Mol Cell Biol.
2013; 14(1): 25–37. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 131.
Izawa D, Pines J:
The mitotic checkpoint complex binds a second CDC20 to inhibit active APC/C.
Nature.
2015; 517(7536): 631–4. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 132.
Hayes MJ, Kimata Y, Wattam SL, et al.:
Early mitotic degradation of Nek2A depends on Cdc20-independent interaction with the APC/C.
Nat Cell Biol.
2006; 8(6): 607–14. PubMed Abstract
| Publisher Full Text
- 133.
Hames RS, Wattam SL, Yamano H, et al.:
APC/C-mediated destruction of the centrosomal kinase Nek2A occurs in early mitosis and depends upon a cyclin A-type D-box.
EMBO J.
2001; 20(24): 7117–27. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 134.
Geley S, Kramer E, Gieffers C, et al.:
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.
2001; 153(1): 137–48. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 135.
Habu T, Kim SH, Weinstein J, et al.:
Identification of a MAD2-binding protein, CMT2, and its role in mitosis.
EMBO J.
2002; 21(23): 6419–28. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 136.
Mapelli M, Filipp FV, Rancati G, et al.:
Determinants of conformational dimerization of Mad2 and its inhibition by p31comet.
EMBO J.
2006; 25(6): 1273–84. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 137.
Yang M, Li B, Tomchick DR, et al.:
p31comet blocks Mad2 activation through structural mimicry.
Cell.
2007; 131(4): 744–55. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 138.
Eytan E, Wang K, Miniowitz-Shemtov S, et al.:
Disassembly of mitotic checkpoint complexes by the joint action of the AAA-ATPase TRIP13 and p31comet.
Proc Natl Acad Sci U S A.
2014; 111(33): 12019–24. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 139.
Wang K, Sturt-Gillespie B, Hittle JC, et al.:
Thyroid hormone receptor interacting protein 13 (TRIP13) AAA-ATPase is a novel mitotic checkpoint-silencing protein.
J Biol Chem.
2014; 289(34): 23928–37. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 140.
Ye Q, Kim DH, Dereli I, et al.:
The AAA+ ATPase TRIP13 remodels HORMA domains through N-terminal engagement and unfolding.
EMBO J.
2017; 36(16): 2419–34. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 141.
Westhorpe FG, Tighe A, Lara-Gonzalez P, et al.:
p31comet-mediated extraction of Mad2 from the MCC promotes efficient mitotic exit.
J Cell Sci.
2011; 124(Pt 22): 3905–16. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 142.
Alfieri C, Chang L, Barford D:
Mechanism for remodelling of the cell cycle checkpoint protein MAD2 by the ATPase TRIP13.
Nature.
2018; 559(7713): 274–8. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 143.
Teichner A, Eytan E, Sitry-Shevah D, et al.:
p31comet Promotes disassembly of the mitotic checkpoint complex in an ATP-dependent process.
Proc Natl Acad Sci U S A.
2011; 108(8): 3187–92. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 144.
Reddy SK, Rape M, Margansky WA, et al.:
Ubiquitination by the anaphase-promoting complex drives spindle checkpoint inactivation.
Nature.
2007; 446(7138): 921–5. PubMed Abstract
| Publisher Full Text
| Faculty Opinions Recommendation
- 145.
Eytan E, Sitry-Shevah D, Teichner A, et al.:
Roles of different pools of the mitotic checkpoint complex and the mechanisms of their disassembly.
Proc Natl Acad Sci U S A.
2013; 110(26): 10568–73. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 146.
Jia L, Li B, Warrington RT, et al.:
Defining pathways of spindle checkpoint silencing: functional redundancy between Cdc20 ubiquitination and p31comet.
Mol Biol Cell.
2011; 22(22): 4227–35. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 147.
Uzunova K, Dye BT, Schutz H, et al.:
APC15 mediates CDC20 autoubiquitylation by APC/CMCC and disassembly of the mitotic checkpoint complex.
Nat Struct Mol Biol.
2012; 19(11): 1116–23. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 148.
Mansfeld J, Collin P, Collins MO, et al.:
APC15 drives the turnover of MCC-CDC20 to make the spindle assembly checkpoint responsive to kinetochore attachment.
Nat Cell Biol.
2011; 13(10): 1234–43. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 149.
Foster SA, Morgan DO:
The APC/C subunit Mnd2/Apc15 promotes Cdc20 autoubiquitination and spindle assembly checkpoint inactivation.
Mol Cell.
2012; 47(6): 921–32. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 150.
Ma HT, Poon RYC:
TRIP13 Functions in the Establishment of the Spindle Assembly Checkpoint by Replenishing O-MAD2.
Cell Rep.
2018; 22(6): 1439–50. PubMed Abstract
| Publisher Full Text
| Faculty Opinions Recommendation
- 151.
Ma HT, Poon RYC:
TRIP13 Regulates Both the Activation and Inactivation of the Spindle-Assembly Checkpoint.
Cell Rep.
2016; 14(5): 1086–99. PubMed Abstract
| Publisher Full Text
| Faculty Opinions Recommendation
- 152.
Yost S, de Wolf B, Hanks S, et al.:
Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation.
Nat Genet.
2017; 49(7): 1148–51. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 153.
Choi E, Zhang X, Xing C, et al.:
Mitotic Checkpoint Regulators Control Insulin Signaling and Metabolic Homeostasis.
Cell.
2016; 166(3): 567–81. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 154.
Marks DH, Thomas R, Chin Y, et al.:
Mad2 Overexpression Uncovers a Critical Role for TRIP13 in Mitotic Exit.
Cell Rep.
2017; 19(9): 1832–45. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 155.
Nelson CR, Hwang T, Chen PH, et al.:
TRIP13PCH-2 promotes Mad2 localization to unattached kinetochores in the spindle checkpoint response.
J Cell Biol.
2015; 211(3): 503–16. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 156.
Musacchio A:
The Molecular Biology of Spindle Assembly Checkpoint Signaling Dynamics.
Curr Biol.
2015; 25(20): R1002–18. PubMed Abstract
| Publisher Full Text
- 157.
Jia L, Kim S, Yu H:
Tracking spindle checkpoint signals from kinetochores to APC/C.
Trends Biochem Sci.
2013; 38(6): 302–11. PubMed Abstract
| Publisher Full Text
- 158.
London N, Biggins S:
Signalling dynamics in the spindle checkpoint response.
Nat Rev Mol Cell Biol.
2014; 15(11): 736–47. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 159.
Bonacci T, Suzuki A, Grant GD, et al.:
Cezanne/OTUD7B is a cell cycle-regulated deubiquitinase that antagonizes the degradation of APC/C substrates.
EMBO J.
2018; 37(16): pii: e98701. PubMed Abstract
| Publisher Full Text
| Free Full Text
| Faculty Opinions Recommendation
- 160.
Dunphy WG, Brizuela L, Beach D, et al.:
The Xenopus cdc2 protein is a component of MPF, a cytoplasmic regulator of mitosis.
Cell.
1988; 54(3): 423–31. PubMed Abstract
| Publisher Full Text
- 161.
Draetta G, Luca F, Westendorf J, et al.:
Cdc2 protein kinase is complexed with both cyclin A and B: evidence for proteolytic inactivation of MPF.
Cell.
1989; 56(5): 829–38. PubMed Abstract
| Publisher Full Text
- 162.
Lohka MJ, Hayes MK, Maller JL:
Purification of maturation-promoting factor, an intracellular regulator of early mitotic events.
Proc Natl Acad Sci U S A.
1988; 85(9): 3009–13. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 163.
Gautier J, Minshull J, Lohka M, et al.:
Cyclin is a component of maturation-promoting factor from Xenopus.
Cell.
1990; 60(3): 487–94. PubMed Abstract
| Publisher Full Text
- 164.
Gautier J, Norbury C, Lohka M, et al.:
Purified maturation-promoting factor contains the product of a Xenopus homolog of the fission yeast cell cycle control gene cdc2+.
Cell.
1988; 54(3): 433–9. PubMed Abstract
| Publisher Full Text
- 165.
Labbe JC, Lee MG, Nurse P, et al.:
Activation at M-phase of a protein kinase encoded by a starfish homologue of the cell cycle control gene cdc2+.
Nature.
1988; 335(6187): 251–4. PubMed Abstract
| Publisher Full Text
- 166.
Draetta G, Beach D:
Activation of cdc2 protein kinase during mitosis in human cells: cell cycle-dependent phosphorylation and subunit rearrangement.
Cell.
1988; 54(1): 17–26. PubMed Abstract
| Publisher Full Text
- 167.
Arion D, Meijer L, Brizuela L, et al.:
cdc2 is a component of the M phase-specific histone H1 kinase: evidence for identity with MPF.
Cell.
1988; 55(2): 371–8. PubMed Abstract
| Publisher Full Text
- 168.
Lee MG, Nurse P:
Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2.
Nature.
1987; 327(6117): 31–5. PubMed Abstract
| Publisher Full Text
- 169.
Murray AW, Kirschner MW:
Cyclin synthesis drives the early embryonic cell cycle.
Nature.
1989; 339(6222): 275–80. PubMed Abstract
| Publisher Full Text
- 170.
Wittenberg C, Reed SI:
Control of the yeast cell cycle is associated with assembly/disassembly of the Cdc28 protein kinase complex.
Cell.
1988; 54(7): 1061–72. PubMed Abstract
| Publisher Full Text
- 171.
Meijer L, Arion D, Golsteyn R, et al.:
Cyclin is a component of the sea urchin egg M-phase specific histone H1 kinase.
EMBO J.
1989; 8(8): 2275–82. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 172.
Murray AW, Solomon MJ, Kirschner MW:
The role of cyclin synthesis and degradation in the control of maturation promoting factor activity.
Nature.
1989; 339(6222): 280–6. PubMed Abstract
| Publisher Full Text
- 173.
Minshull J, Blow JJ, Hunt T:
Translation of cyclin mRNA is necessary for extracts of activated xenopus eggs to enter mitosis.
Cell.
1989; 56(6): 947–56. PubMed Abstract
| Publisher Full Text
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