Randy Y C Poon

The Hong Kong University of Science and Technology, Chiu-lung, Kowloon City, Hong Kong

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Publications (84)493.98 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The ATR-CHK1-WEE1 kinase cascade's functions in the DNA damage checkpoints are well established. Moreover, its roles in the unperturbed cell cycle are also increasingly being recognized. In this connection, a number of small-molecule inhibitors of ATR, CHK1, and WEE1 are being evaluated in clinical trials. Understanding precisely how cells respond to different concentrations of inhibitors is therefore of paramount importance and has broad clinical implications. Here we present evidence that in the absence of DNA damage, pharmacological inactivation of ATR was less effective in inducing mitotic catastrophe than inhibition of WEE1 and CHK1. Small-molecule inhibitors of CHK1 (AZD7762) or WEE1 (MK-1775) induced mitotic catastrophe, as characterized by dephosphorylation of CDK1Tyr15, phosphorylation of histone H3Ser10, and apoptosis. Unexpectedly, partial inhibition of WEE1 and CHK1 had the opposite effect of accelerating the cell cycle without inducing apoptosis, thereby increasing the overall cell proliferation. This was also corroborated by the finding that cell proliferation was enhanced by kinase-inactive versions of WEE1. We demonstrated that these potential limitations of the inhibitors could be overcome by targeting more than one components of the ATR-CHK1-WEE1 simultaneously. These observations reveal insights into the complex responses to pharmacological inactivation of the ATR-CHK1-WEE1 axis.
    Oncotarget 09/2014; · 6.64 Impact Factor
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    ABSTRACT: We report the label-free enumeration of human colorectal-carcinoma cells from blood lymphocytes by using interdigitated ring-array microelectrodes; this enumeration was based on the dielectrophoretic selection of cells. Because of the novel design of the device, a continuous flow of cells is uniformly distributed into parallel streams through 300 rings (~40μm in diameter each) that are integrated into the electrode digits. Using this array, 82% of cancer cells were recovered and 99% of blood lymphocytes were removed. Most of the cancer cells recovered were viable (94%) and could be cultivated for >8 days, during which period they retained their normal cell morphology and proliferation rates. The recovery rate correlated closely with cancer-cell loadings in spiked samples and this relationship was linear over a range of at least 2 orders of magnitude. Importantly, because of the 3D structure of the rings, these results were obtained at a high cell-loading concentration (10(7)cells/mL). The rings could be further optimized for use in accurate label-free identification and measurement of circulating tumor cells in cancer research and disease management.
    Biosensors & bioelectronics. 06/2014; 61C:434-442.
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    Hoi Tang Ma, Sergio Erdal, Shan Huang, Randy Y C Poon
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    ABSTRACT: The mitotic kinesin KIF11 (also called Eg5) plays critical roles in spindle functions. Although a number of small-molecule inhibitors of KIF11 are currently in clinical development, drug-resistance could be developed through compensation by another kinesin called KIF15. Using a newly developed infrared-based cell system, we discovered that the effectiveness of one of the latest generations of KIF11 inhibitor (SB743921) could be enhanced with several inhibitors of Aurora A kinase. Evidence including live-cell imaging and isobologram analysis indicated that targeting KIF11 and Aurora A together promoted monoastral spindle formation and mitotic catastrophe synergistically, supporting a model of parallel pathways of centrosome regulation by Aurora A and KIF11. We also developed a KIF15-dependent SB743921-resistance cell model. Significantly, the drug-resistance could also be overcome with Aurora A inhibitors. These results provide a molecular basis for increasing the effectiveness of Aurora A and KIF11 inhibitors and tackling problems of drug resistance.
    Molecular oncology. 06/2014;
  • Randy Y.C. Poon
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    ABSTRACT: Nasopharyngeal carcinoma (NPC) is a highly invasive cancer with poor prognosis. One of the recurring themes of NPC biology and treatments is DNA damage. Epstein–Barr virus infection, which is generally accepted as a key etiological factor for NPC, triggers DNA damage responses. In normal cells, DNA damage checkpoints are able to prevent cell cycle progression following DNA damage and are critical for maintaining genome stability. Main features of the checkpoints include activation of ATM and ATR by sensors of DNA damage, which activates effector kinases CHK1 and CHK2; they in turn targets the CDC25/WEE1–cyclin B1–CDK1 axis to cause G2 arrest, or the p53–p21CIP1/WAF1 and pRb pathways to cause G1 arrest. Significantly, these checkpoints are typically disrupted in NPC cells. While mutations are relatively rare, mechanisms including promoter modifications, miRNAs, and actions of Epstein–Barr virus-encoded proteins such as EBNA3C and LMP1 have been described. Paradoxically, radiation-mediated DNA damage remains the primary treatment of NPC. How dysregulation of the DNA damage checkpoints contribute to NPC tumorigenesis and responses to treatment remain poorly understood. In this review, the current understanding of the molecular mechanisms of the various DNA damage checkpoints and what is known about them in NPC are discussed.
    Oral Oncology 01/2014; · 2.70 Impact Factor
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    ABSTRACT: Many mitotic kinases are both critical for maintaining genome stability and are important targets for anticancer therapies. We provide evidence that SIK3 (salt-inducible kinase 3), an AMP-activated protein kinase-related kinase, is important for mitosis to occur properly in mammalian cells. Downregulation of SIK3 resulted in an extension of mitosis in both mouse and human cells but did not affect the DNA damage checkpoint. Time-lapse microscopy and other approaches indicated that mitotic exit but not mitotic entry was delayed. Although repression of SIK3 alone simply delayed mitotic exit, it was able to sensitize cells to various antimitotic chemicals. Both mitotic arrest and cell death caused by spindle poisons were enhanced after SIK3 depletion. Likewise, the antimitotic effects due to pharmacological inhibition of mitotic kinases including Aurora A, Aurora B, and polo-like kinase 1 were enhanced in the absence of SIK3. Finally, in addition to promoting the sensitivity of a small-molecule inhibitor of the mitotic kinesin Eg5, SIK3 depletion was able to overcome cells that developed drug resistance. These results establish the importance of SIK3 as a mitotic regulator and underscore the potential of SIK3 as a druggable antimitotic target.
    Cell Death & Disease 01/2014; 5:e1177. · 6.04 Impact Factor
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    Wing Yu Man, Joyce P Y Mak, Randy Y C Poon
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    ABSTRACT: Dovitinib (TKI258; formerly CHIR-258) is an orally bioavailable inhibitor of multiple receptor tyrosine kinases. Interestingly, Dovitinib triggered a G2 /M arrest in cancer cell lines from diverse origins including HeLa, nasopharyngeal carcinoma, and hepatocellular carcinoma. Single-cell analysis revealed that Dovitinib promoted a delay in mitotic exit in a subset of cells, causing the cells to undergo mitotic slippage. Higher concentrations of Dovitinib induced a G2 arrest similar to the G2 DNA damage checkpoint. In support of this, DNA damage was triggered by Dovitinib as revealed by γ-H2AX and comet assays. The mitotic kinase CDK1 was found to be inactivated by phosphorylation in the presence of Dovitinib. Furthermore, the G2 arrest could be overcome by abrogation of the G2 DNA damage checkpoint using small molecule inhibitors of CHK1 and WEE1. Finally, Dovitinib-mediated G2 cell cycle arrest and subsequent cell death could be promoted after DNA damage repair was disrupted by inhibitors of poly(ADP-ribose) polymerases. These results are consistent with the recent finding that Dovitinib can also target topoisomerases. Collectively, these results suggest additional directions for use of Dovitinib, in particular with agents that target the DNA damage checkpoint.
    Journal of Cellular and Molecular Medicine 11/2013; · 4.75 Impact Factor
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    ABSTRACT: Nasopharyngeal carcinoma (NPC) is a rare but highly invasive cancer. As options of agents for effective combination chemoradiotherapy of advanced NPC are limited, novel therapeutic approaches are desperately needed. The ubiquitin ligase CHFR is known to target poly(ADP-ribose) polymerase 1 (PARP1) for degradation and is epigenetically inactivated in NPC. We present evidence that PARP1 protein is indeed overexpressed in NPC cells in comparison to immortalized normal nasopharyngeal epithelial cells. Tissue microarray analysis also indicated that PARP1 protein is significantly elevated in primary NPC tissues, with strong correlation with all stages of NPC development. We found that the PARP inhibitor AZD2281 (Olaparib) increased DNA damage, cell cycle arrest, and apoptosis in NPC cells challenged with ionizing radiation or temozolomide. Isobologram analysis confirmed that the cytotoxicity triggered by AZD2281 and DNA damaging agents was synergistic. Finally, AZD2281 also enhanced the tumor-inhibitory effects of ionizing radiation in animal xenograft models. These observations implicate that PARP1 overexpression is an early event in NPC development and provide a molecular basis of using PARP inhibitors to potentiate treatment of NPC with radiotherapy and chemotherapy.
    Molecular Cancer Therapeutics 08/2013; · 5.60 Impact Factor
  • M Marxer, H T Ma, W Y Man, R Y C Poon
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    ABSTRACT: A number of small-molecule inhibitors of Aurora kinases have been developed and are undergoing clinical trials for anti-cancer therapies. Different Aurora kinases, however, behave as very different targets: while inhibition of Aurora A (AURKA) induces a delay in mitotic exit, inhibition of Aurora B (AURKB) triggers mitotic slippage. Furthermore, while it is evident that p53 is regulated by Aurora kinase-dependent phosphorylation, how p53 may in turn regulate Aurora kinases remains mysterious. To address these issues, isogenic p53-containing and -negative cells were exposed to classic inhibitors that target both AURKA and AURKB (Alisertib and ZM447439), as well as to new generation of inhibitors that target AURKA (MK-5108), AURKB (Barasertib) individually. The fate of individual cells was then tracked with time-lapse microscopy. Remarkably, loss of p53, either by gene disruption or small interfering RNA-mediated depletion, sensitized cells to inhibition of both AURKA and AURKB, promoting mitotic arrest and slippage respectively. As the p53-dependent post-mitotic checkpoint is also important for preventing genome reduplication after mitotic slippage, these studies indicate that the loss of p53 in cancer cells represents a major opportunity for anti-cancer drugs targeting the Aurora kinases.Oncogene advance online publication, 19 August 2013; doi:10.1038/onc.2013.325.
    Oncogene 08/2013; · 8.56 Impact Factor
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    Xianxian Han, Randy Y C Poon
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    ABSTRACT: Sister chromatid separation depends on the activity of separase, which in turn requires the proteolysis of its inhibitor securin. It has also been speculated that securin also supports the activation of separase. In this study, we found that PTTG1 was the major securin isoform expressed in most normal and cancer cell lines. Remarkably, a highly homologous isoform called PTTG2 was unable to interact or stabilize with separase. Using chimeras between PTTG1 and PTTG2 and other approaches, we pinpointed a single amino acid that accounted for the loss of securin function in PTTG2. Mutation of the homologous position in PTTG1 (H(134)) switched PTTG1 from an inhibitor into an activator of separase. In agreement with this, PTTG1 lacking H(134) was able to trigger premature sister chromatid separation. Conversely, introduction of H(134) into PTTG2 is sufficient to allow it to bind separase. These data demonstrate that while the motif containing H(134) has a strong affinity for separase and is involved in inhibiting separase, other domain(s) is involved in activating separase and has a relatively weaker affinity for separase. Although PTTG2 lacks securin function, its differences with PTTG1 provide evidence of independent inhibitory and activating functions of PTTG1 on separase.
    Molecular and Cellular Biology 06/2013; · 5.04 Impact Factor
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    Randy Y C Poon
    Cell cycle (Georgetown, Tex.) 03/2013; 12(7). · 5.24 Impact Factor
  • J P H Chow, R Y C Poon
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    ABSTRACT: Inhibition of cyclin-dependent kinase 1 (CDK1) by phosphorylation is a key regulatory mechanism for both the unperturbed cell cycle and the DNA damage checkpoint. Although both WEE1 and MYT1 can phosphorylate CDK1, little is known about the contribution of MYT1. We found that in contrast to WEE1, MYT1 was not important for the normal cell cycle or checkpoint activation. Time-lapse microscopy indicated that MYT1 did, however, have a rate-determining role during checkpoint recovery. Depletion of MYT1 induced precocious mitotic entry when the checkpoint was abrogated with inhibitors of either CHK1 or WEE1, indicating that MYT1 contributes to checkpoint recovery independently of WEE1. The acceleration of checkpoint recovery in MYT1-depleted cells was due to a lowering of threshold for CDK1 activation. The kinase activity of MYT1 was high during checkpoint activation and reduced during checkpoint recovery. Importantly, although depletion of MYT1 alone did not affect long-term cell growth, it potentiated with DNA damage to inhibit cell growth in clonogenic survival and tumor xenograft models. These results reveal the functions of MYT1 in checkpoint recovery and highlight the potential of MYT1 as a target for anti-cancer therapies.Oncogene advance online publication, 12 November 2012; doi:10.1038/onc.2012.504.
    Oncogene 11/2012; · 8.56 Impact Factor
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    ABSTRACT: Aurora kinases are overexpressed in many cancers and are targets for anticancer drugs. The yeast homolog of Aurora B kinase, IPL1, was found to be a ploidy-specific lethality gene. Given that polyploidization is a common feature of many cancers, we hypothesized polyploidization also sensitizes mammalian cells to inhibition of Aurora kinases. Using two models of apparent diploid vs. tetraploid cell lines (one based on the hepatocellular carcinoma cell line Hep3B and another on untransformed mouse fibroblasts), we found that tetraploid cells were more sensitive to Aurora B inhibition than their diploid counterparts. Apoptosis could be induced in tetraploid cells by two different Aurora B inhibitors. Furthermore, tetraploid cells were sensitive to Aurora B inhibition but were not affected by Aurora A inhibition. Interestingly, the underlying mechanism was due to mitotic slippage and the subsequent excessive genome reduplication. In support of this, abolition of cytokinesis with dihydrocytochalasin B resulted in similar effects on tetraploid cells as Aurora B inhibition. These results indicate that inhibition of Aurora B or cytokinesis can promote apoptosis effectively in polyploid cancer cells.
    Cell cycle (Georgetown, Tex.) 07/2012; 11(13):2567-77. · 5.24 Impact Factor
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    ABSTRACT: Antimitotic spindle poisons are among the most important chemotherapeutic agents available. However, precocious mitotic exit by mitotic slippage limits the cytotoxicity of spindle poisons. The MAD2-binding protein p31(comet) is implicated in silencing the spindle assembly checkpoint after all kinetochores are attached to spindles. In this study, we report that the levels of p31(comet) and MAD2 in different cell lines are closely linked with susceptibility to mitotic slippage. Down-regulation of p31(comet) increased the sensitivity of multiple cancer cell lines to spindle poisons, including nocodazole, vincristine, and Taxol. In the absence of p31(comet), lower concentrations of spindle poisons were required to induce mitotic block. The delay in checkpoint silencing was induced by an accumulation of mitotic checkpoint complexes. The increase in the duration of mitotic block after p31(comet) depletion resulted in a dramatic increase in mitotic cell death upon challenge with spindle poisons. Significantly, cells that are normally prone to mitotic slippage and resistant to spindle disruption-mediated mitotic death were also sensitized after p31(comet) depletion. These results highlight the importance of p31(comet) in checkpoint silencing and its potential as a target for antimitotic therapies.
    Journal of Biological Chemistry 04/2012; 287(25):21561-9. · 4.65 Impact Factor
  • Yue Chen, Jeremy P H Chow, Randy Y C Poon
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    ABSTRACT: The G(2) DNA damage checkpoint is activated by genotoxic agents and is particularly important for cancer therapies. Overriding the checkpoint can trigger precocious entry into mitosis, causing cells to undergo mitotic catastrophe. But some checkpoint-abrogated cells can remain viable and progress into G(1) phase, which may contribute to further genome instability. Our previous studies reveal that the effectiveness of the spindle assembly checkpoint and the duration of mitosis are pivotal determinants of mitotic catastrophe after checkpoint abrogation. In this study, we tested the hypothesis whether mitotic catastrophe could be enhanced by combining genotoxic stress, checkpoint abrogation, and the inhibition of the mitotic kinesin protein Eg5. We found that mitotic catastrophe induced by ionizing radiation and a CHK1 inhibitor (UCN-01) was exacerbated after Eg5 was inhibited with either siRNAs or monastrol. The combination of DNA damage, UCN-01, and monastrol sensitized cancer cells that were normally resistant to checkpoint abrogation. Importantly, a relatively low concentration of monastrol, alone not sufficient in causing mitotic arrest, was already effective in promoting mitotic catastrophe. These experiments suggest that it is possible to use sublethal concentrations of Eg5 inhibitors in combination with G(2) DNA damage checkpoint abrogation as an effective therapeutic approach.
    Molecular Cancer Research 04/2012; 10(5):626-35. · 4.35 Impact Factor
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    ABSTRACT: Replication stress- and DNA damage-induced cell cycle checkpoints are critical for maintaining genome stability. To identify protein phosphatases involved in the activation and maintenance of the checkpoints, we have carried out RNA interference-based screens with a human phosphatome shRNA library. Several phosphatases, including SHP2 (also called PTPN11) were found to be required for cell survival upon hydroxyurea-induced replicative stress in HeLa cells. More detailed studies revealed that SHP2 was also important for the maintenance of the checkpoint after DNA damage induced by cisplatin or ionizing radiation in HeLa cells. Furthermore, SHP2 was activated after replicative stress and DNA damage. Although depletion of SHP2 resulted in a delay in cyclin E accumulation and an extension of G(1) phase, these cell cycle impairments were not responsible for the increase in apoptosis after DNA damage. Depletion of SHP2 impaired CHK1 activation, checkpoint-mediated cell cycle arrest, and DNA repair. These effects could be rescued with a shRNA-resistant SHP2. These results underscore the importance of protein phosphatases in checkpoint control and revealed a novel link between SHP2 and cell cycle checkpoints.
    PLoS ONE 01/2012; 7(11):e49943. · 3.53 Impact Factor
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    ABSTRACT: Cdc25A, which is one of the three mammalian CDK-activating Cdc25 protein phosphatases (Cdc25A, B and C), is degraded through SCF(βTrCP)-mediated ubiquitylation following genomic insult; however, the regulation of the stability of the other two Cdc25 proteins is not well understood. Previously, we showed that Cdc25B is primarily degraded by cellular stresses that activate stress-activated MAPKs, such as Jun NH(2)-terminal kinase (JNK) and p38. Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104). Point mutation of these Ser residues to alanine (Ala) abolished the JNK-induced ubiquitylation by SCF(βTrCP), and point mutation of DAG to AAG or DAA eradicated both βTrCP binding and ubiquitylation. Further analysis of the mode of βTrCP binding to this region revealed that the PEST-like sequence from E(82)SS to D(94)AG is crucially involved in both the βTrCP binding and ubiquitylation of Cdc25B. Furthermore, the phospho-mimetic replacement of all 10 Ser residues in the E(82)SS to SPSP(104) region with Asp resulted in βTrCP binding. Collectively, these results indicate that stress-induced Cdc25B ubiquitylation by SCF(βTrCP) requires the phosphorylation of S(101)PS(103)P in the βTrCP-binding-motif-like and adjacent PEST-like sequences.
    Journal of Cell Science 08/2011; 124(Pt 16):2816-25. · 5.88 Impact Factor
  • Hoi Tang Ma, Randy Y C Poon
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    ABSTRACT: Mitosis is associated with profound changes in cell physiology and a spectacular surge in protein phosphorylation. To accomplish these, a remarkably large portion of the kinome is involved in the process. In the present review, we will focus on classic mitotic kinases, such as cyclin-dependent kinases, Polo-like kinases and Aurora kinases, as well as more recently characterized players such as NIMA (never in mitosis in Aspergillus nidulans)-related kinases, Greatwall and Haspin. Together, these kinases co-ordinate the proper timing and fidelity of processes including centrosomal functions, spindle assembly and microtubule-kinetochore attachment, as well as sister chromatid separation and cytokinesis. A recurrent theme of the mitotic kinase network is the prevalence of elaborated feedback loops that ensure bistable conditions. Sequential phosphorylation and priming phosphorylation on substrates are also frequently employed. Another important concept is the role of scaffolds, such as centrosomes for protein kinases during mitosis. Elucidating the entire repertoire of mitotic kinases, their functions, regulation and interactions is critical for our understanding of normal cell growth and in diseases such as cancers.
    Biochemical Journal 04/2011; 435(1):17-31. · 4.65 Impact Factor
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    ABSTRACT: Genotoxic stress such as ionizing radiation halts entry into mitosis by activation of the G(2) DNA damage checkpoint. The CHK1 inhibitor 7-hydroxystaurosporine (UCN-01) can bypass the checkpoint and induce unscheduled mitosis in irradiated cells. Precisely, how cells behave following checkpoint abrogation remains to be defined. In this study, we tracked the fates of individual cells after checkpoint abrogation, focusing in particular on whether they undergo mitotic catastrophe. Surprisingly, while a subset of UCN-01-treated cells were immediately eliminated during the first mitosis after checkpoint abrogation, about half remained viable and progressed into G(1). Both the delay of mitotic entry and the level of mitotic catastrophe were dependent on the dose of radiation. Although the level of mitotic catastrophe was specific for different cell lines, it could be promoted by extending the mitosis. In supporting this idea, weakening of the spindle-assembly checkpoint, by either depleting MAD2 or overexpressing the MAD2-binding protein p31(comet), suppressed mitotic catastrophe. Conversely, delaying of mitotic exit by depleting either p31(comet) or CDC20 tipped the balance toward mitotic catastrophe. These results underscore the interplay between the level of DNA damage and the effectiveness of the spindle-assembly checkpoint in determining whether checkpoint-abrogated cells are eliminated during mitosis.
    Molecular Cancer Therapeutics 03/2011; 10(5):784-94. · 5.60 Impact Factor
  • Hoi Tang Ma, Randy Y C Poon
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    ABSTRACT: Anaphase is promoted by the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) only when all the chromosomes have achieved bipolar attachment to the mitotic spindles. Unattached kinetochores or the absence of tension between the paired kinetochores activates a surveillance mechanism termed the spindle-assembly checkpoint. A fundamental principle of the checkpoint is the activation of mitotic arrest deficient 2 (MAD2). MAD2 then forms a diffusible complex called mitotic checkpoint complex (designated as MAD2(MCC)) before it is recruited to APC/C (designated as MAD2(APC/C)). Large gaps in our knowledge remain on how MAD2 is inactivated after the checkpoint is satisfied. In this study, we have investigated the regulation of MAD2-containing complexes during mitotic progression. Using selective immunoprecipitation of checkpoint components and gel filtration chromatography, we found that MAD2(MCC) and MAD2(APC/C) were regulated very differently during mitotic exit. Temporally, MAD2(MCC) was broken down ahead of MAD2(APC/C). The inactivation of the two complexes also displayed different requirements of proteolysis; although APC/C and proteasome activities were dispensable for MAD2(MCC) inactivation, they are required for MAD2(APC/C) inactivation. In fact, the degradation of CDC20 is inextricably linked to the breakdown of MAD2(APC/C). These data extended our understanding of the checkpoint complexes during checkpoint silencing.
    Journal of Biological Chemistry 02/2011; 286(15):13052-9. · 4.65 Impact Factor
  • Jeremy P.H. Chow, Randy Y.C. Poon
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    ABSTRACT: A growing body of evidence indicates that polyploidization triggers chromosomal instability and contributes to tumorigenesis. DNA damage is increasingly being recognized for its roles in promoting polyploidization. Although elegant mechanisms known as the DNA damage checkpoints are responsible for halting the cell cycle after DNA damage, agents that uncouple the checkpoints can induce unscheduled entry into mitosis. Likewise, defects of the checkpoints in several disorders permit mitotic entry even in the presence of DNA damage. Forcing cells with damaged DNA into mitosis causes severe chromosome segregation defects, including lagging chromosomes, chromosomal fragments and chromosomal bridges. The presence of these lesions in the cleavage plane is believed to abort cytokinesis. It is postulated that if cytokinesis failure is coupled with defects of the p53-dependent postmitotic checkpoint pathway, cells can enter S phase and become polyploids. Progress in the past several years has unraveled some of the underlying principles of these pathways and underscored the important role of DNA damage in polyploidization. Furthermore, polyploidization per se may also be an important determinant of sensitivity to DNA damage, thereby may offer an opportunity for novel therapies.
    01/2011: pages 57-71;

Publication Stats

2k Citations
493.98 Total Impact Points


  • 1997–2014
    • The Hong Kong University of Science and Technology
      • Division of Life Science
      Chiu-lung, Kowloon City, Hong Kong
    • Torrey Pines Institute for Molecular Studies
      Port St. Lucie, Florida, United States
  • 2009
    • The University of Hong Kong
      • Department of Surgery
      Hong Kong, Hong Kong
  • 1999
    • University of Oxford
      • Department of Biochemistry
      Oxford, ENG, United Kingdom
  • 1995–1997
    • Salk Institute
      • Molecular Biology and Virology Laboratory
      La Jolla, California, United States