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Cyclin B1: Conductor of Mitotic Symphony Orchestra Huijuan Yu1, Xuebiao Yao1

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Cyclin B1: Conductor of Mitotic Symphony Orchestra Huijuan Yu1, Xuebiao Yao1 npg 218 Cell Research (2008) 18:218-220. npg © 2008 IBCB, SIBS, CAS All rights reserved 1001-0602/08 $ 30.00 RESEARCH HIGHLIGHT www.nature.com/cr Cyclin B1: conductor of mitotic symphony orchestra Huijuan Yu1, Xuebiao Yao1 1Laboratory of Cellular Dynamics, Hefei National Laboratory for Physical Science at Microscale; and the University of Science and Technology of China, Hefei, Anhui 230027, China. [email protected] Cell Research (2008) 18:218-220. doi: 10.1038/cr.2008.20; published online 4 February 2008 The inheritance of human genome kinetochore [e.g., 4] [7], and then at condensed chromatin, through mitosis is precisely regulated Mitosis is orchestrated by signal- spindle microtubules, and centrosomes by a series of tightly orchestrated events ing cascades that coordinate mitotic during prometaphase, corresponding such as chromosome condensation, processes and ensure accurate chromo- to localizations of known CDK1 sub- bi-orientated spindle formation, chro- some segregation. The key switch for strates, including nuclear lamins and the mosome congression, segregation and the onset of mitosis is the archetypal chromatin-associated protein RCC1. In cytokinesis. Chromosome movements cyclin-dependent kinase Cdk1. Besides contrast, cyclin B2 remains associated during mitosis are governed by the in- the master mitotic kinase Cdk1, three with the disassembled Golgi during teraction of spindle microtubules with a other protein serine/threonine kinase mitosis. Domain mapping studies have specialized chromosome domain located families are also involved, including the suggested that the N-terminal domain is within the centromere. This specialized Polo kinases, Aurora kinases, and the important in dictating the distinct func- region, called the kinetochore, is the NEK (NIMA-related kinases) [e.g., 5]. tions of B-type cyclins. Replacement site for spindle microtubule-centromere Recent studies have demonstrated that of the cyclin B1 N-terminal domain association. In addition to serving as a NEK2A interacts with SAC proteins at with that of cyclin B2 is sufficient to physical link between chromosomes and the kinetochore and plays a vital role in mislocalize the chimeric protein to the spindle microtubules, the kinetochore SAC signaling and centromeric cohe- Golgi [8]. This chimeric protein retains exhibits an active role in chromosomal sion regulation [6]. the ability to induce Golgi disassem- segregation through microtubule motors In mitosis, A- and B-type cyclins bly, but it loses the ability to induce and spindle assembly checkpoint (SAC) bind and activate CDK1 to phosphory- chromosome condensation, nuclear sensors located at or near it [e.g., 1]. late proteins that mediate the dramatic lamina solubilization, and mitotic aster Several lines of evidence have impli- changes in nuclear and cytoskeletal assembly demonstrating that subcellular cated the kinetochore in generation of architecture required for chromosome localization of different B-type cyclins a diffusible SAC signal that can block segregation [e.g., 5]. Even though all is a critical determinant of their ability cell cycle progression into anaphase CDKs phosphorylate a consensus motif to properly promote the events of mito- until all kinetochores have successfully consisting of S/TPxK/R, different cy- sis. The SAC determines the anaphase attached to spindle microtubules. Aber- clin-CDK complexes phosphorylate dis- onset by inhibiting the activity of ana- rant attachment of one or more chromo- tinct substrates, raising the question of phase-promoting complex/cyclosome somes to the spindle is correlated with how substrate specificity is achieved by (APC/C; e.g., reference 4) — an enzyme a corresponding delay in the onset of different cyclin-CDK complexes. At mi- that adds chains of the small protein anaphase. Genetic screen in budding totic entry, cyclin B1-CDK1 promotes ubiquitin to specific substrate proteins, yeast for mutants that fail to arrest the chromosome condensation, nuclear thereby targeting them for destruction. cell cycle in mitosis after disassembly of lamina resolution and mitotic spindle These ubiquitinating cascades are in- microtubules, has identified three MAD assembly while cyclin B2-CDK1 can hibited when unattached kinetochores (mitotic arrest deficiency) and three only induce Golgi disassembly. It has keep the SAC active. The kinetochores BUB (budding uninhibited by benomyl) been proposed that the spatiotemporal promote the association of Cdc20 with genes [2, 3]. Vertebrate homologues dynamics of cyclin B1 and cyclin B2 Mad2 when Cdc20 is phosphorylated by of MAD1, MAD2, BUB3, BUB1, and determines the plasticity of cyclin-CDK cyclin B-CDK1, which prevents Cdc20 BUBR1 are spindle checkpoint com- on substrate selection. Indeed, cyclin B1 from activating the APC/C and hence ponents transiently associated with the accumulates in the nucleus at prophase regulates SAC [9]. Cyclin B-CDK1 Cell Research | Vol 18 No 2 | February 2008 npg 219 also regulates the kinetochore localiza- prometaphase depends on both Hec1 Cdc20 in SAC signaling. In sum, the tion of Plk1 through phosphorylation and Mad2 as either depletion abolishes findings of cyclin B1-CDK1 dynamics of the kinetochore proteins Bub1 and kinetochore localization of cyclin B1. in the mitotic apparatus provide a new INCENP [e.g., reference 4]. Interest- Since it has never been shown that Mad2 direction in delineating the SAC signal- ingly, CDK1 had been shown to localize is essential for localization of other ing cascade. to kinetochores during mitosis, but the checkpoint proteins, it would be of great relevant cyclin partner had remained significance to delineate the underlying References uncharacterized. mechanisms accounting for the depen- In this issue of Cell Research, Zhang dencies of cyclin B1 on Mad2. Given 1 Yao X, Abrieu A, Zheng Y, Sullivan and his colleagues, in an effort to the fact that non-degradable cyclin B1 KF, Cleveland DW. CENP-E forms a link between attachment of spindle delineate the function of cyclin B1 in exhibits normal turnover dynamics at microtubules to kinetochores and the mitosis, carried out a thorough analysis the kinetochore, these new data argue mitotic checkpoint. Nat Cell Biol 2000; of cyclin B1 distribution in mamma- that Cdc20 or APC/C-association alone 2:484-491. lian cells [10]. They demonstrated that is sufficient to recruit cyclin B1 to ki- 2 Li R, Murray AW. Feedback control of cyclin B1 is preferentially localized to netochores. mitosis in budding yeast. Cell 1990; unattached kinetochores and involved The findings of cyclin B1 enriched 66:519-531. in chromosome alignment in mitosis. at unattached kinetochores of mamma- 3 Hoyt MA, Totis L, Roberts BTS. S. In addition, they provided evidence that lian cells are consistent with the early cerevisiae genes required for cell cycle arrest in response to loss of microtubule the CDK1 population at kinetochores hypothesis of a positive role of CDK1 function. Cell 1990; 66:507-517. is in fact active and that the abundance in SAC activity. One potential function 4 Musacchio A, Salmon ED. The spindle- of the complex varies during mitotic of kinetochore-associated cyclin B1- assembly checkpoint in space and time. progression. An interesting parallel CDK1 could be to promote inhibition Nat Rev Mol Cell Biol 2007; 8:379- was recently reported by King’s group of Cdc20 by Mad2. Cdc20 contains two 393. in which they characterized the precise putative Cdk1 phosphorylation sites, 5 Nigg EA. Mitotic kinases as regulators localization of cyclin B1 using spin- and Cdc20 phosphorylation is required of cell division and its checkpoints. Nat Rev Mol Cell Biol 2001; 2:21-32. ning disk confocal microscopy and for Mad2 binding, as nonphosphorylat- 6 Fang L, Fang G. Centromere cohesion: revealed the structural determinants for able versions of Cdc20 are resistant to regulating the guardian. Cell Res 2007; spatial distribution of cyclin B1 to the Mad2 binding and inhibition [9, 12]. 17:664-665. mitotic apparatus during mitosis [11]. Cdc20 localizes to kinetochores from 7 Pines J, Hunter T. The differential They concluded that separable and prophase through anaphase, but its as- localization of human cyclins A and B distinct mechanisms target cyclin B1 sociation is highly dynamic. It is likely is due to a cytoplasmic retention signal to kinetochores, chromatin, and centro- that localization of cyclin B1-CDK1 to in cyclin B. EMBO J 1994; 13:3772- 3781. somes during mitosis. King’s group also unattached kinetochores could enable 8 Draviam VM, Orrechia S, Lowe M, revealed that CDK1 can target the cyclin the local phosphorylation of Cdc20, Pardi R, Pines J. The localization of B1-CDK1 complex to kinetochores. promoting its binding to the active human cyclins B1 and B2 determines This mechanism is demonstrated by conformation of Mad2 generated at the CDK1 substrate specificity and neither the localization of cyclin B1 mutants kinetochore. In addition, other kineto- enzyme requires MEK to disassemble lacking the N-terminal domain that chore proteins are known substrates of the Golgi apparatus. J Cell Biol 2001; binds to CDK1. Zhang’s group further the cyclin B1-CDK1 complex, includ- 152:945-958. examined the molecular mechanism ing INCENP, Bub1, and APC/C sub- 9 D’Angiolella V, Mari C, Nocera D, Rametti L, Grieco D. The spindle check- underlying cyclin B1 localization to units. Therefore, recruitment of cyclin point requires cyclin-dependent kinase the kinetochore and demonstrated B1-CDK1 to unattached kinetochores activity. Genes Dev 2003; 17:2520- the function of the dynein/dynactin could affect the activity of other SAC 2525. complex in regulating the dynamics of components or regulate other signaling 10 Chen Q, Zhang X, Jiang Q et al. Cy- cyclin B1 on kinetochores. In addition, events essential for anaphase onset. clin B1 is localized to unattached ki- Zhang’s group revealed that cyclin B1 is Given the recent identification of the netochores and contributes to efficient translocated from kinetochores toward deubiquitinating enzyme USP44 at the microtubule attachment and proper chromosome alignment during mitosis. spindle poles along microtubules when kinetochore by Elledge and Kirschiner Cell Res 2008; 18:268-280.
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