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Regulation of Cell Cycle Checkpoints by Polo-Like Kinases

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Regulation of Cell Cycle Checkpoints by Polo-Like Kinases Oncogene (2005) 24, 277–286 & 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00 www.nature.com/onc Regulation of cell cycle checkpoints by polo-like kinases Suqing Xie1, Bin Xie2, Marietta Y Lee2 and Wei Dai*,1 1Molecular Carcinogenesis Division, Department of Medicine & Brander Cancer Research Institute, New York Medical College, Valhalla, NY 10595, USA; 2Department of Biochemistry, Molecular Carcinogenesis Division, New York Medical College, Valhalla, NY 10595, USA Protein kinases play a pivotal role in execution of cell abnormal cell division and/or transformation. To date, division. Polo and Polo-like kinases have emerged as several families of protein kinases such as cyclin- major regulators for various cell cycle checkpoints. Early dependent kinases (Cdks), polo-like kinases (Plks), and genetic studies have demonstrated that CDC5,a budding Aurora family of kinases have been characterized, which yeast counterpart of vertebrate Plks,is essential for are important to cell cycle regulation. Extensive research successful mitotic progression. Mammalian Plks localize in the past decade or so has demonstrated that Polo and primarily to the centrosome during interphase and the Plks are involved in regulation of various cell cycle mitotic apparatus during mitosis. Many key cell cycle checkpoints that ensure the timing and order of cell regulators such as p53,Cdc25C,cyclin B,components of cycle events such as DNA repair, bipolar spindle the anaphase-promoting complex,and mitotic motor formation, chromosome segregation, and mitotic exit proteins are directly targeted by Plks. Although the exact (Nigg, 1998; Dai et al., 2002; Barr et al., 2004). mechanism of action of these protein kinases in vivo In this review, we summarize the properties of Polo remains to be elucidated,Plks are important mediators for and Plks in various cell cycle checkpoint controls. We various cell cycle checkpoints that monitor centrosome also present new lines of evidence supporting the role of duplication,DNA replication,formation of bipolar mammalian Plks in regulating both an intra-S-phase mitotic spindle,segregation of chromosomes,and mitotic checkpoint and a spindle checkpoint. exit,thus protecting cells against genetic instability during cell division. Oncogene (2005) 24, 277–286. doi:10.1038/sj.onc.1208218 Plks’ role in intra-S-phase checkpoint Keywords: polo; polo-like kinases; cell cycle; check- point; cell division Checkpoint activation pathway During the S phase, the genome is most susceptible to damage caused by environmental stresses and/or inter- nal perturbations. Thus, it is natural that cells have Introduction evolved sophisticated mechanisms to monitor DNA damage and initiate repair processes if the damage is not The progression of the cell cycle is tightly regulated in extensive. Extensive research in the past decade has order to maintain genetic integrity and to ensure that shown that the signaling pathways that underlie the genetic information is correctly passed on to daughter cellular response to DNA damage (or genotoxic stress) cells. Surveillance mechanisms, known as checkpoints, consist of sensors, signal transducers, and effectors have thus been discovered, that monitor the integrity of (Zhou and Elledge, 2000). Although the identities of the the cell cycle progression (Elledge, 1996). By definition, damage sensors remain unclear, the molecular entities cell cycle checkpoints inhibit cell cycle progression until responsible for transducing the damage signals to the specific cellular processes under surveillance are specific effectors are relatively well characterized. completed with high fidelity. In eukaryotes, both DNA ATM (ataxia telangiectasia mutated) and its homolog replication and chromosome segregation are highly ATR (ATM-related) function early in the signaling regulated and are monitored at several steps in the cell pathways and are central tothe DNA damage response cycle. A loss of checkpoint function can result in (Sancar et al., 2004). Downstream mediators/transdu- infidelity of DNA replication or of chromosome cers of ATM and ATR include the protein kinases segregation, and thereby predispose cells to genetic Chk1, Chk2, and likely Plk3 (Xie et al., 2001b; Sancar instability. et al., 2004). The effectors of the checkpoint include p53 Reversible phosphorylation is a fundamental mole- and Cdc25 (Sancar et al., 2004). cular mechanism that is critical for regulating cell Both CDC5 in the budding yeast and mammalian division. Deregulated phosphorylation of the compo- Plks are known to participate in the DNA damage nents important to cell cycle control frequently leads to response. An early study shows that the electrophoretic mobility of Cdc5 in denaturing gels is affected when the *Correspondence: W Dai; E-mail: [email protected] cells are exposed to DNA damage agents, and this Plks and cell cycle checkpoints SXieet al 278 modification of Cdc5 is dependent on Mec1, Rad53 (a 2001a, b). Plk3 interacts with and phosphorylates p53, yeast Chk1 homolog), and Rad9 (Cheng et al., 1998). In targeting serine-20 of p53 in vitro (Xie et al., 2001b). In addition, a functionally defective Cdc5 mutant protein response to DNA damage, the kinase activity of Plk3 is suppresses a Rad53 checkpoint defect, whereas over- rapidly increased in an ATM-dependent manner (Xie expression of Cdc5 overrides checkpoint-induced cell et al., 2001a, b). Peptide mapping, as well as in vitro cycle arrest (Sanchez et al., 1999), suggesting that Cdc5 phosphorylation followed by immunoblot analysis with acts downstream of Rad53. Several recent studies show antibodies specific for phosphorylated forms of p53, also that Plk1 activity is inhibited upon DNA damage (Smits indicates that Plk3 phosphorylates p53 on physiologi- et al., 2000; van Vugt et al., 2001; Ando et al., 2004). The cally relevant sites. Immunoprecipitation and ‘pull- DNA damage-induced inhibition of Plk1 appears to be down’ assays reveal that Plk3 physically interacts with mediated by blocking its activation because expression p53 and that the extent of this interaction is increased in of activation mutants of Plk1 can override the G2/M response to DNA damage (Xie et al., 2001b). The role of arrest induced by DNA damage (Smits et al., 2000). Plk3 in regulation of serine-20 phosphorylation of p53 in Subsequent studies by this group reveal that DNA vivo is further supported by our recent RNAi study. damage-induced inhibition of Plk1 is at least in part Downregulation of endogenous Plk3 through transfec- dependent on ATM or ATR because caffeine treatment tion of small-interfering RNA (siRNA) to Plk3, but not blocks the inhibition of Plk1 after IR- or UV-induced to luciferease, significantly compromises phosphoryla- DNA damage (van Vugt et al., 2001). The activity of tion of p53 on serine-20 before and after oxidative stress p53 is greatly enhanced upon DNA damage checkpoint (Figure 1). Plk3 alsophysically interacts with Chk2 activation. (Bahassi et al., 2002; Xie et al., 2002), and there exists a A recent study shows that Plk1 binds p53 and inhibits functional connection as well between these two the transactivating activity of this tumor suppressor enzymes during DNA damage checkpoint activation. protein; the kinase activity of Plk1 is required for Plk3 phosphorylates Chk2 on a residue different from inhibition of p53 activity; besides, Plk1 also negatively threonine-68, and it may contribute to the full activation affects the proapoptotic function of p53 in human lung of Chk2 although ATM is necessary for phosphoryla- tumor cell lines (Ando et al., 2004). Again, ATM is tion and activation of Chk2 in vivo (Bahassi et al., 2002). capable of attenuating Plk1-mediated suppression of Together, these combined studies suggest that Plk3 p53 activity (Ando et al., 2004). Given the potential role functionally links DNA damage to the induction of cell of Plk1 in promoting cell proliferation and tumorigen- cycle arrest or apoptosis. esis (Dai and Cogswell, 2003), these observations are consistent with the negative role of Plk1 in DNA damage-induced cell cycle arrest. On the other hand, DNA damage repair there are alsoreportssuggesting that Plk1 may play a A possible role for Plks in DNA synthesis or repair is positive role in DNA damage checkpoint activation. implied from several early studies. Expression of both Chk2 co-immunoprecipitates with Plk1, overexpression mammalian Plk2 and Plk3 is rapidly induced by mitogen of which enhances phosphorylation of Chk2 at T68 treatment (Simmons et al., 1992; Li et al., 1996). (Tsvetkov et al., 2003), a site primarily targeted by Induction of Plk3 mRNA by mitogens is protein ATM, and its phosphorylation is correlated with its synthesis-independent, suggesting that it is an immedi- activation (Ahn et al., 2000); in addition, Plk1 phos- ate-early gene product (Li et al., 1996). Furthermore, phorylates recombinant Chk2 in vitro at the same site and colocalizes with Chk2 to a certain mitotic apparatus (Tsvetkov et al., 2003). In a separate study, Drosophila Polo has also been implicated to be a substrate of Chk2 as well (Xu and Du, 2003). Other mammalian Plks are alsoinvolved in the DNA damage checkpoint activation pathway. Expression of Plk2 mRNA is rapidly induced in human thyroid cells upon X-ray irradiation; a radiation-responsive element has been identified as p53RE, a p53-binding homology element, in the basal promoter region of this gene (Shimizu-Yoshida et al., 2001). Consistent with that observation, a separate study shows that Plk2 expres- sion is partly mediated by p53 (Burns et al., 2003). A recent study by Swallow et al shows that Plk4 interacts with p53 and that this interaction is mediated by the Figure 1 Silencing of Plk3 results in significantly reduced p53 polo box (this review issue). Several lines of evidence phosphorylation on serine-20. GM00637 cells, which constitutively indicate that Plk3 is an important mediator in the DNA express high levels of p53, were transfected with siRNA duplexes to damage checkpoint response pathway. Plk3 kinase Plk3 (Plk3-siRNA) or to luciferase GL3 (Luc-siRNA) (SMART- activity is activated upon oxidative stress and DNA pool, Dharmacon) for 72 h.
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