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Sak/Plk4 and Mitotic Fidelity Oncogene (2005) 24, 306–312 & 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00 www.nature.com/onc Sak/Plk4 and mitotic fidelity Carol J Swallow1,2, Michael A Ko1,2, Najeeb U Siddiqui1,3,4, John W Hudson5 and James W Dennis*,1,3,4 1Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave. R988, Toronto, Ontario, Canada M5G 1X5; 2Department of Surgery, University of Toronto, Ontario, Canada; 3Department of Microbiology and Medical Genetics, University of Toronto, Ontario, Canada; 4Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada; 5Department of Biological Sciences, University of Windsor, Ontario, Canada Sak/Plk4 differs from other polo-like kinases in having (Fernebro et al., 2002). Mutation of classical tumor only a single polo box, which assumes a novel dimer fold suppressor genes follows the Knudsen 2-hit model, that localizes to the nucleolus, centrosomes and the whereby loss of the wild-type allele as a ‘second hit’ cleavage furrow.Sak expression increases gradually in S frequently results in relaxed cellular growth controls through M phase, and Sak is destroyed by APC/C (Knudson, 1971). Inherited cancer syndromes such as dependent proteolysis.Sak-deficient mouse embryos Li-Fraumeni (p53, Chk2) and ataxia telangiectasia arrest at E7.5 and display an increased incidence of (ATM) are examples of autosomal recessive mutations apoptosis and anaphase arrest.Sak þ /À mice are haploin- in checkpoint proteins that normally delay the cell cycle sufficient for tumor suppression, with spontaneous tumors in response to DNA damage and environmental stresses developing primarily in the liver with advanced age. (Malkin et al., 1990; Bell et al., 1999). Partial or During liver regeneration following partial hepatectomy, complete loss of their activities leads to genomic Sak þ /À hepatocytes display a delay in reaching the first M instability, further mutations and cancer (Sherr, 2004). phase, multipolar spindles, disorganized tissue morphol- A weakening of checkpoint controls increases the ogy and loss of acuity for cyclin B1 expression.Similarly, probability of mitotic errors over multiple cell divisions. Sak þ /À MEF cells proliferate slowly, and show a high Thereafter, progression of benign lesions to malignancy incidence of centrosome hyper-amplification.We suggest becomes a form of natural selection for cells bearing that Sak provides feedback to cell cycle regulators, and additional activating mutations in proto-oncogenes and thereby precision to the switch-like transitions of centro- loss of tumor suppressors. Predisposition to CIN also some duplication and exit-from-mitosis.Sak binds to p53, occurs in more subtle forms through partial deficiency in and studies are underway to provide a molecular context genes controlling the cell cycle. Notably, proteins that for the Sak-p53 interaction.Animal models of haploin- affect the sequential expression of cyclins D, E, A, B and sufficiency and more comprehensive models of cell cycle activation of their partners Cdks 6, 4, 2, 1 can alter the regulation should contribute to improvements in cancer timing and fidelity of sequential events, including risk assessment and novel therapies. centrosome duplication, spindle assembly, anaphase Oncogene (2005) 24, 306–312. doi:10.1038/sj.onc.1208275 and cytokinesis (Elledge, 1996). The Cdk family of Ser/Thr kinases determines the sequential order of cell Keywords: mitosis; Sak/Plk4; chromosomal instability; cycle events, but they are also responsive to inputs colorectal cancer; hepatoma from the physical and biochemical environment that can impose delay or arrest (Sherr, 2004). Polo-like kinases (plks) are components of this complex circuitry and impact multiple steps in cell cycle progression, although much remains to be learned concerning Introduction: Chromosomal instability and their interacting partners (Blagden and Glover, 2003; haploinsufficient tumor suppressors Barr et al., 2004). Cyclin-dependent kinase inhibitors (CKI) negatively DNA replication and chromosomal segregation occur regulate Cdks, generally in response to extrinsic condi- with remarkable fidelity at all levels of complexity, from tions, and thereby delay or suppress cell cycle progres- a fertilized egg through to the billions of cells in adult sion. Mice with a single functional allele of the mammals. However, errors do occur and can lead to p21(WAF1/CIP1) or INK4 family members display aneuploidy, chromosome breaks and translocations. early cancer development (Jackson et al., 2003). Chromosomal instability (CIN) is very common in Similarly, mice heterozygous for the CKI p27Kip display malignant tumors, occurring in B80% of colon cancers hypersensitivity to a spectrum of mutagenic agents, producing tumor phenotypes intermediate between that *Correspondence: JW Dennis; of wild type and null mice (Philipp-Staheli et al., 2001). E-mail: [email protected] However, tumors in the heterozygous mice retain the Plk4 and mitotic fidelity CJ Swallow et al 307 wild-type allele and p27Kip protein expression is not a silenced, indicating that reduced dosage is sufficient to Kinase domaincry-pb pb both enhance initiation and progression to malignancy Sak (Philipp-Staheli et al., 2001; Muraoka et al., 2002). 12 265 596 836 847 911 Compound mutant mice heterozygous for CKIs or aa lacking other negative regulators of G1/S progression, for example p21Cip1 þ /À plus p18INK4cÀ/À or Rb þ /À, display further acceleration and increased penetrance of tumor ATP T-loop PEST1 PEST2 PEST3 binding development (Tsai et al., 2002; Bai et al., 2003; Jackson Thr170 272-300 808-832 840-878 et al., 2003). Haploinsufficiency for cancer suppression Lys41 has been observed for the spindle assembly checkpoint n k protein Mad2, with elderly heterozygote mice showing io b t c a pb c S k ∆ D e one k an increased incidence of cancer, as seems typical for 0 M f l T a s a 7 1 W Moc S k 1 4 n a a n these spindle assembly checkpoint insufficiencies T K r i S t e k k s T IP: Flag (Michel et al., 2001). The majority of human cancers a a o a W S S N C show no obvious inheritance pattern, but it appears Probe: Flag rather that mildly hypomorphic alleles of genes that encode mitotic regulators may act in combination to IP: p53 increase the probability of chromosomal pathologies and 12345 Probe: Flag cancer. Furthermore, the aging process involves cumula- 123 tive oxidative damage to gene promoters (Lu et al., 2004), Figure 1 (a) Structural features of Sak. Sak has a Ser/Thr kinase and a selective reduction in expression of mitotic domain at the amino-terminus, a single polo-box domain (pb) at regulators and centrosome proteins including cyclins A, the carboxy-terminus, and three PEST destruction motifs. The B, F and Plk1 (Ly et al., 2000). In combination, conserved ATP-binding domain with the required Lys41 residue and the T-loop activation domain with the required Thr170 are incremental losses in multiple mitotic regulators may indicated. The cryptic polo-box (cry-pb) interacts with the Sak dampen the switch-like behavior of cyclin/cdk activation kinase domain and with Tec kinase . Both pb and cry-pb are self- and destruction, thereby increasing the likelihood of association domains, suggesting that Sak may form a homodimer. mitotic errors and cancers over time. Sak/Plk4 is required (b) Sak kinase activity. In vitro phosphorylation of casein by for mitotic fidelity, and mice with a single Sak gene FLAG-Sak constructs immunoprecipitated from NIH 3T3 cells. Lane 1, Wild-type FLAG-Sak; lane 2, FLAG-SakT170D (activat- display an increased incidence of cancer with advancing ing); lane 3, FLAG-SakK41M (inactivating); lane 4, no transfec- age (Ko et al., submitted). Herein we review the current tion; lane 5, casein only. (c) Sak associates with p53. Proteins information on Sak kinase structure, function and role in immunoprecipitated from NIH-3T3 cells transfected with 3X- cell cycle control and carcinogenesis. FLAG-Sak constructs using anti-FLAG (upper panel) or anti-p53 (lower panel) antibodies, probed with anti-FLAG. Lane 1, Wild- type FLAG-Sak; lane 2, mock transfection; lane 3, FLAG-Sak pb deleted (SakDpb) Sak gene structure The Sak gene is found on mouse chromosome 3 and additional complexities of coordinating cell division, human chromosome 4q28, a region that frequently polarity and checkpoints in animals. Curiously, plk undergoes rearrangement or loss in human cancers, and homologs are absent in Arabidopsis (Initiative, 2000), at a particularly high rate in hepatocellular carcinomas suggesting a possible connection with basic structural (E70%) (Hammond et al., 1999). The kinase domain of differences, such as the absence of centrosomes and the murine Sak is followed by 660 amino acids containing a presence of a preprophase band that can contribute to single 64 amino-acid polo box (pb) domain at the spindle and phragmoplast orientation in plants, while COOH end (Figure 1a). The Sak-pb is equally related by yeast and animal cells require additional inputs from phylogenetic comparison to the pb1 and pb2 domains of spindle poles, the membrane cortex and other extrinsic other plks. The Sak-pb domain (Sak839–925) and the sources. Mammalian Plk1 and Plk3 functions overlap upstream region designated the ‘cryptic polo box’ and are conserved, as expression of either Plk1 or Plk3 (cry-pb) (Sak596–836) are both self-association domains in ts cdc5-1 mutant yeast cells rescues the mitotic defects (Leung et al., 2002). As might be expected, Sak kinase (Ouyang et al., 1997; Lee et al., 1998). These and other activity is markedly increased by a SakT170D muta- observations suggest that the mitotic functions of Cdc5 tion in the T loop, while SakK41M, an inactiva- may be distributed among the various mammalian plks, ting mutation in the ATP-binding domain, eliminates thereby affording additional levels of cell cycle control activity (Figure 1b). during development. However, Sak expression in ts The kinase domain of Sak is most closely related to cdc5-1 cells did not rescue the growth defect, suggesting that of plks, but Sak appears to have diverged from a a nonredundant role for Sak kinase.
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