Relevant bibliographies by topics / CHK2

Academic literature on the topic 'CHK2'

Author: Grafiati
Published: 4 June 2021
Last updated: 10 March 2023

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Journal articles on the topic "CHK2"

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Maioru, Ovidiu, Lucian Pop, Viorica Radoi, Radu Ursu, Nicolae Bacalbasa, Irina Balescu, and Ioan D. Suciu. "CHEK2 gene in breast cancer." Romanian Medical Journal 69, S3 (June 20, 2022): 15–16. http://dx.doi.org/10.37897/rmj.2022.s3.4.

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Checkpoint kinases (Chks) are serine/threonine kinases that are involved in the control of the cell cycle. Two subtypes have so far been identified, Chk1 and Chk2. They are essential components to delay cell cycle progression in all cells and act at all three cell cycle checkpoints. Here we provide more information regarding the CHEK2 gene and its role in breast cancer as well as known mutations that present a higher cancer risk.
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2

Yan, Tao, Anand B. Desai, James W. Jacobberger, R. Michael Sramkoski, Tamalette Loh, and Timothy J. Kinsella. "CHK1 and CHK2 are differentially involved in mismatch repair–mediated 6-thioguanine-induced cell cycle checkpoint responses." Molecular Cancer Therapeutics 3, no. 9 (September 1, 2004): 1147–57. http://dx.doi.org/10.1158/1535-7163.1147.3.9.

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Abstract The DNA mismatch repair (MMR) system plays an important role in mediating a G2-M checkpoint arrest and subsequent cell death following treatment with a variety of chemotherapeutic agents. In this study, using 6-thioguanine (6-TG) as a mismatch-inducing drug, we examine the role of ataxia telangiectasia mutated (ATM)/CHK2 and ATM and Rad-3 related (ATR)/CHK1 signaling pathways in MMR-mediated cell cycle responses in MMR-proficient human colorectal cancer RKO cells. We show that, in response to 6-TG (3 μmol/L × 24 hours), activating phosphorylation of CHK1 at Ser317 [CHK1(pS317)] and CHK2 at Thr68 [CHK2(pT68)] are induced differentially during a prolonged course (up to 6 days) of MMR-mediated cell cycle arrests following 6-TG treatment, with CHK1(pS317) being induced within 1 day and CHK2(pT68) being induced later. Using chemical inhibitors and small interfering RNA of the signaling kinases, we show that a MMR-mediated 6-TG-induced G2 arrest is ATR/CHK1 dependent but ATM/CHK2 independent and that ATR/CHK1 signaling is responsible for both initiation and maintenance of the G2 arrest. However, CHK2(pT68) seems to be involved in a subsequent tetraploid G1 arrest, which blocks cells that escape from the G2-M checkpoint following 6-TG treatment. Furthermore, we show that CHK2 is hyperphosphorylated at later times following 6-TG treatment and the phosphorylation of CHK2 seems to be ATM independent but up-regulated when ATR or CHK1 is reduced. Thus, our data suggest that CHK1(pS317) is involved in a MMR-mediated 6-TG-induced G2 arrest, whereas CHK2(pT68) seems to be involved in a subsequent tetraploid G1-S checkpoint. The two signaling kinases seem to work cooperatively to ensure that 6-TG damaged cells arrest at these cell cycle checkpoints.
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Kornepati, Anand V., Yilun Deng, Eloise Dray, Clare Murray, Suresh C. Kari, Erica Osta, Zexuan Liu, et al. "Intracellular PD-L1 regulates DNA damage checkpoints and suppresses Chk1 and PARP inhibitor synthetic lethality." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 67.15. http://dx.doi.org/10.4049/jimmunol.206.supp.67.15.

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Abstract Tumor PD-L1 mediates non-canonical, intracellular signals including the DNA damage response (DDR), of unclear significance and mechanisms. We show that genetic PD-L1 depletion (PD-L1KO) destabilized the Chk2 protein, a DNA damage response (DDR) factor, resulting in ATM/Chk2 pathway defects but not ATR/Chk1 in melanoma, bladder, breast, and ovarian cancer. Consistent with ATM/Chk2 defects, PD-L1 KO led to DNA damage (γH2AX) and impaired homologous recombination (HR) (p-RPA32, BRCA1, Rad51 foci). Thus, PD-L1 KO vs control cells were significantly more sensitive to DDR inhibitors (DDRi) against ATR, Chk1, and PARP in vitro and in vivo in NSG mice. Chk2 regulation by PD-L1 was independent of PD-L1 cytoplasmic tail yet required intracellular (vs surface) PD-L1 suggesting physical PD-L1/Chk2 interaction supported by IP and imaging. PD-L1 stabilized Chk2 protein by preventing its lysosomal degradation without altering Chek2 mRNA. αPD-L1 is thought to work by protecting PD-L1 induced anti-tumor T cell suppression via PD-1, but PD-L1 DDR effects were PD-1-independent. Intracellular PD-L1 suppressed DDRi induced cGAS/STING activation by immunoblots and qRT-PCR of type 1 IFN genes. In vivo in WT mice, genetic PD-L1 depletion but not αPD-L1, sensitized highly immunotherapy resistant 4T1 breast cancer to PARPi. Strikingly, PARPi had reduced effect on PD-L1KO tumors in RAG2KO mice despite treating WT mice, indicating a strong immune component to DDRi efficacy. Our work implicates a novel role of intracellular PD-L1 in DDR and tumor immunogenicity and identifies related therapeutic vulnerabilities exposed by intracellular PD-L1 targeting. Surface vs intracellular PD-L1, and specific DDR signals could be treatment response biomarkers.
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Rinaldi, Vera D., Jordana C. Bloom, and John C. Schimenti. "Oocyte Elimination Through DNA Damage Signaling from CHK1/CHK2 to p53 and p63." Genetics 215, no. 2 (April 9, 2020): 373–78. http://dx.doi.org/10.1534/genetics.120.303182.

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Eukaryotic organisms have evolved mechanisms to prevent the accumulation of cells bearing genetic aberrations. This is especially crucial for the germline, because fecundity and fitness of progeny would be adversely affected by an excessively high mutational incidence. The process of meiosis poses unique problems for mutation avoidance because of the requirement for SPO11-induced programmed double-strand breaks (DSBs) in recombination-driven pairing and segregation of homologous chromosomes. Mouse meiocytes bearing unrepaired meiotic DSBs or unsynapsed chromosomes are eliminated before completing meiotic prophase I. In previous work, we showed that checkpoint kinase 2 (CHK2; CHEK2), a canonical DNA damage response protein, is crucial for eliminating not only oocytes defective in meiotic DSB repair (e.g., Trip13Gt mutants), but also Spo11−/− oocytes that are defective in homologous chromosome synapsis and accumulate a threshold level of spontaneous DSBs. However, rescue of such oocytes by Chk2 deficiency was incomplete, raising the possibility that a parallel checkpoint pathway(s) exists. Here, we show that mouse oocytes lacking both p53 (TRP53) and the oocyte-exclusive isoform of p63, TAp63, protects nearly all Spo11−/− and Trip13Gt/Gt oocytes from elimination. We present evidence that checkpoint kinase I (CHK1; CHEK1), which is known to signal to TRP53, also becomes activated by persistent DSBs in oocytes, and to an increased degree when CHK2 is absent. The combined data indicate that nearly all oocytes reaching a threshold level of unrepaired DSBs are eliminated by a semiredundant pathway of CHK1/CHK2 signaling to TRP53/TAp63.
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Zachos, George, Michael D. Rainey, and David A. F. Gillespie. "Chk1-Dependent S-M Checkpoint Delay in Vertebrate Cells Is Linked to Maintenance of Viable Replication Structures." Molecular and Cellular Biology 25, no. 2 (January 15, 2005): 563–74. http://dx.doi.org/10.1128/mcb.25.2.563-574.2005.

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ABSTRACT We investigated mitotic delay during replication arrest (the S-M checkpoint) in DT40 B-lymphoma cells deficient in the Chk1 or Chk2 kinase. We show here that cells lacking Chk1, but not those lacking Chk2, enter mitosis with incompletely replicated DNA when DNA synthesis is blocked, but only after an initial delay. This initial delay persists when S-M checkpoint failure is induced in Chk2−/− cells with the Chk1 inhibitor UCN-01, indicating that it does not depend on Chk1 or Chk2 activity. Surprisingly, dephosphorylation of tyrosine 15 did not accompany Cdc2 activation during premature entry to mitosis in Chk1−/− cells, although mitotic phosphorylation of cyclin B2 did occur. Previous studies have shown that Chk1 is required to stabilize stalled replication forks during replication arrest, and strikingly, premature mitosis occurs only in Chk1-deficient cells which have lost the capacity to synthesize DNA as a result of progressive replication fork inactivation. These results suggest that Chk1 maintains the S-M checkpoint indirectly by preserving the viability of replication structures and that it is the continued presence of such structures, rather than the activation of Chk1 per se, which delays mitosis until DNA replication is complete.
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Ou, Yi-Hung, Pei-Han Chung, Te-Ping Sun, and Sheau-Yann Shieh. "p53 C-Terminal Phosphorylation by CHK1 and CHK2 Participates in the Regulation of DNA-Damage-induced C-Terminal Acetylation." Molecular Biology of the Cell 16, no. 4 (April 2005): 1684–95. http://dx.doi.org/10.1091/mbc.e04-08-0689.

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The tumor suppressor protein p53 mediates stress-induced growth arrest or apoptosis and plays a major role in safeguarding genome integrity. In response to DNA damage, p53 can be modified at multiple sites by phosphorylation and acetylation. We report on the characterization of p53 C-terminal phosphorylation by CHK1 and CHK2, two serine/threonine (Ser/Thr) protein kinases, previously implicated in the phosphorylation of the p53 N terminus. Using tryptic phosphopeptide mapping, we have identified six additional CHK1 and CHK2 sites residing in the final 100 amino acids of p53. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage, and the induction at Ser366 and Thr387 was abrogated by small interfering RNA targeting chk1 and chk2. Furthermore, mutation of these phosphorylation sites has a different impact on p53 C-terminal acetylation and on the activation of p53-targeted promoters. Our results demonstrate a possible interplay between p53 C-terminal phosphorylation and acetylation, and they provide an additional mechanism for the control of the activity of p53 by CHK1 and CHK2.
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Martínez-Marchal, Ana, Yan Huang, Maria Teresa Guillot-Ferriols, Mònica Ferrer-Roda, Anna Guixé, Montserrat Garcia-Caldés, and Ignasi Roig. "The DNA damage response is required for oocyte cyst breakdown and follicle formation in mice." PLOS Genetics 16, no. 11 (November 18, 2020): e1009067. http://dx.doi.org/10.1371/journal.pgen.1009067.

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Mammalian oogonia proliferate without completing cytokinesis, forming cysts. Within these, oocytes differentiate and initiate meiosis, promoting double-strand break (DSBs) formation, which are repaired by homologous recombination (HR) causing the pairing and synapsis of the homologs. Errors in these processes activate checkpoint mechanisms, leading to apoptosis. At the end of prophase I, in contrast with what is observed in spermatocytes, oocytes accumulate unrepaired DSBs. Simultaneously to the cyst breakdown, there is a massive oocyte death, which has been proposed to be necessary to enable the individualization of the oocytes to form follicles. Based upon all the above-mentioned information, we hypothesize that the apparently inefficient HR occurring in the oocytes may be a requirement to first eliminate most of the oocytes and enable cyst breakdown and follicle formation. To test this idea, we compared perinatal ovaries from control and mutant mice for the effector kinase of the DNA Damage Response (DDR), CHK2. We found that CHK2 is required to eliminate ~50% of the fetal oocyte population. Nevertheless, the number of oocytes and follicles found in Chk2-mutant ovaries three days after birth was equivalent to that of the controls. These data revealed the existence of another mechanism capable of eliminating oocytes. In vitro inhibition of CHK1 rescued the oocyte number in Chk2-/- mice, implying that CHK1 regulates postnatal oocyte death. Moreover, we found that CHK1 and CHK2 functions are required for the timely breakdown of the cyst and to form follicles. Thus, we uncovered a novel CHK1 function in regulating the oocyte population in mice. Based upon these data, we propose that the CHK1- and CHK2-dependent DDR controls the number of oocytes and is required to properly break down oocyte cysts and form follicles in mammals.
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Feijoo, Carmen, Clare Hall-Jackson, Rong Wu, David Jenkins, Jane Leitch, David M. Gilbert, and Carl Smythe. "Activation of mammalian Chk1 during DNA replication arrest." Journal of Cell Biology 154, no. 5 (September 3, 2001): 913–24. http://dx.doi.org/10.1083/jcb.200104099.

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Checkpoints maintain order and fidelity in the cell cycle by blocking late-occurring events when earlier events are improperly executed. Here we describe evidence for the participation of Chk1 in an intra-S phase checkpoint in mammalian cells. We show that both Chk1 and Chk2 are phosphorylated and activated in a caffeine-sensitive signaling pathway during S phase, but only in response to replication blocks, not during normal S phase progression. Replication block–induced activation of Chk1 and Chk2 occurs normally in ataxia telangiectasia (AT) cells, which are deficient in the S phase response to ionizing radiation (IR). Resumption of synthesis after removal of replication blocks correlates with the inactivation of Chk1 but not Chk2. Using a selective small molecule inhibitor, cells lacking Chk1 function show a progressive change in the global pattern of replication origin firing in the absence of any DNA replication. Thus, Chk1 is apparently necessary for an intra-S phase checkpoint, ensuring that activation of late replication origins is blocked and arrested replication fork integrity is maintained when DNA synthesis is inhibited.
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Tsoi, Ho, Wai-Chung Tsang, Ellen P. S. Man, Man-Hong Leung, Chan-Ping You, Sum-Yin Chan, Wing-Lok Chan, and Ui-Soon Khoo. "Checkpoint Kinase 2 Inhibition Can Reverse Tamoxifen Resistance in ER-Positive Breast Cancer." International Journal of Molecular Sciences 23, no. 20 (October 14, 2022): 12290. http://dx.doi.org/10.3390/ijms232012290.

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Breast cancer is a heterogeneous disease. Tamoxifen is frequently used to treat ER-positive breast cancer. Our team has identified a novel splice variant of NCOR2, BQ323636.1 (BQ), that mediates tamoxifen resistance. However, the upstream factors that modulate BQ expression are not apparent. This study reveals that tamoxifen treatment causes induction of DNA damage which can enhance BQ expression. We show that DNA damage can activate the ATM/CHK2 and ATR/CHK1 signalling cascades and confirm that ATM/CHK2 signalling is responsible for enhancing the protein stability of BQ. siRNA or a small inhibitor targeting CHK2 resulted in the reduction in BQ expression through reduced phosphorylation and enhanced poly-ubiquitination of BQ. Inhibition of CHK2 by CCT241533 could reverse tamoxifen resistance in vitro and in vivo. Using clinical samples in the tissue microarray, we confirmed that high p-CHK2 expression was significantly associated with high nuclear BQ expression, tamoxifen resistance and poorer overall and disease-specific survival. In conclusion, tamoxifen treatment can enhance BQ expression in ER-positive breast cancer by activating the ATM/CHK2 axis. Targeting CHK2 is a promising approach to overcoming tamoxifen resistance in ER-positive breast cancer.
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Kim, Hyeon Ho, Kotb Abdelmohsen, and Myriam Gorospe. "Regulation of HuR by DNA Damage Response Kinases." Journal of Nucleic Acids 2010 (2010): 1–8. http://dx.doi.org/10.4061/2010/981487.

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As many DNA-damaging conditions repress transcription, posttranscriptional processes critically influence gene expression during the genotoxic stress response. The RNA-binding protein HuR robustly influences gene expression following DNA damage. HuR function is controlled in two principal ways: (1) by mobilizing HuR from the nucleus to the cytoplasm, where it modulates the stability and translation of target mRNAs and (2) by altering its association with target mRNAs. Here, we review evidence that two main effectors of ataxia-telangiectasia-mutated/ATM- and Rad3-related (ATM/ATR), the checkpoint kinases Chk1 and Chk2, jointly influence HuR function. Chk1 affects HuR localization by phosphorylating (hence inactivating) Cdk1, a kinase that phosphorylates HuR and thereby blocks HuR's cytoplasmic export. Chk2 modulates HuR binding to target mRNAs by phosphorylating HuR's RNA-recognition motifs (RRM1 and RRM2). We discuss how HuR phosphorylation by kinases including Chk1/Cdk1 and Chk2 impacts upon gene expression patterns, cell proliferation, and survival following genotoxic injury.
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Dissertations / Theses on the topic "CHK2"

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Oehler, Verena. "Role of Chk1 and Chk2 in mitotic checkpoint control in vertebrate cells." Thesis, University of Glasgow, 2008. http://theses.gla.ac.uk/148/.

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Two conserved protein kinases, Chk1 and Chk2, are activated in response to genotoxic stress and mediate multiple cell cycle checkpoint mechanisms that ensure genomic integrity. The establishment of mitotic checkpoint delay in response to DNA damage or incompletely replicated DNA is conventionally thought to be accomplished through inhibition of the cyclin-dependent kinase, Cdc2. Both Chk1 and Chk2 have the potential to operate in this pathway. Therefore, the initial aim of this study was to investigate the relative requirement of Chk1 and Chk2 for mitotic delay mechanisms triggered by DNA damage and DNA replication arrest in avian and human cells. These studies demonstrated that Chk1 is the principal regulator of the G2/M checkpoint with a direct role in the establishment and maintenance of the mitotic delay in response to DNA damage. Chk1 was also found to be required for the S/M checkpoint in response to DNA replication arrest; however, detailed analysis indicated that its role is to maintain rather than initiate this checkpoint, as cells lacking functional Chk1 can initially delay mitosis for many hours before they enter a premature mitosis with unreplicated DNA. In avian cells, mitotic phosphorylation of cyclinB2 was found to be mediated by cyclin dependent kinases and suppressed by checkpoint signalling. However, accumulation of potentially active phospho-cyclinB2/Cdc2 complexes was observed during the initial mitotic delay in the absence of functional Chk1, suggesting that other factors apart from the conventionally known mechanisms can restrain mitotic Cdc2 activity. In addition, avian cells were able to delay mitosis effectively during replication arrest in the presence of the ATM/ATR inhibitor caffeine, further emphasizing the possibility of mitotic delay mechanisms that operate independently of ATM/ATR and Chk1. Furthermore, this study revealed that endogenous Cdc6 accumulates in a Chk1-dependent manner during replication arrest. To test whether Cdc6 might function upstream or downstream of Chk1 in the replication checkpoint pathway, Cdc6 was ectopically expressed in both checkpoint-proficient and checkpoint-deficient Chk1-depleted cells. The results from these intervention experiments give preliminary evidence that places Cdc6 downstream of Chk1 in the S/M checkpoint response. The ability of cells to delay the onset of mitosis while DNA replication is stalled independently of ATM/ATR/Chk1 is consistent with the general idea of an inherent relationship between the process of DNA replication and mitosis. The replication machinery might be able to signal either normal DNA replication in progress or the presence of stalled replication structures and thereby intrinsically link the successful completion of DNA synthesis to progression into mitosis.
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Höglund, Andreas. "Regulation of DNA damage responses by the Myc oncogene : implications for future anti-cancer therapies." Doctoral thesis, Umeå universitet, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet), 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-44284.

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Myc is a transcription factor frequently found deregulated in human cancer. Cells with deregulated expression of Myc carry a selective advantage against its neighbours due to the fact that Myc-mediated transcription governs crucial cellular events such as proliferation and growth. In addition, Myc has been implicated in several other aspects of tumour biology like cellular immortality, the formation of new blood vessels and the colonization of distant tissues through the process of metastasis. Therapy aimed at disrupting essential pathways regulated by Myc is important because of the many different types of cancers that depend on continued signalling along these pathways.  This thesis describes new treatment opportunities for cancers with a high Myc signature. In Paper Ι, we describe a new role for the DNA methyltransferase inhibitor Decitabine in the treatment of Myc transformed tumours cells. We show that the therapeutic potential of Decitabine in the treatment of Burkitt Lymphoma relies not only on its ability to cause reactivation of silenced genes such as pro-apoptotic PUMA, but also on the DNA damage that this drug induces. In vivo, Decitabine delays disease progression of transplanted lymphoma cells. In Paper ΙΙ, we identify the DNA damage checkpoint kinase Chk1 as a therapeutic target in Myc overexpressing cancers. We show that targeting Chk1 with shRNA or with a novel small molecule inhibitor cause a delay in disease progression of transplanted lymphoma cells in vivo. In Paper ΙΙΙ, the Chk1-related kinase Chk2 is evaluated as a therapeutic target in Myc overexpressing cancers. Myc overexpressing cells are not dependent on Chk2 but we show that Chk2 abrogation using shRNA causes polyploidization and protection against DNA damage. However, Chk2-targeted therapy elicits a synergistic lethal response in combination with inhibition of the DNA repair associated protein PARP. In conclusion, this thesis shows the potential of targeting the DNA damage machinery and the functional hubs important for maintenance of genomic stability in tumours with a deregulated expression of Myc.
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Qin, Dongyan. "Specificity and structural modeling of FHA domain of CHK2 and a general characterization of FHA domain of caenorhabditis elegans CHK2." The Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=osu1061304007.

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Freeman, Alyson. "CHK2 is Negatively Regulated by Protein Phosphatase 2A." Scholar Commons, 2010. http://scholarcommons.usf.edu/etd/3443.

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Checkpoint kinase 2 (CHK2) is an effector kinase of the DNA damage response pathway and although its mechanism of activation has been well studied, the attenuation of its activity following DNA damage has not been explored. Here, we identify the B'α subunit of protein phosphatase 2A (PP2A), a major protein serine/threonine phosphatase of the cell, as a CHK2 binding partner and show that their interaction is modulated by DNA damage. B'α binds to the SQ/TQ cluster domain of CHK2, which is a target of ATM phosphorylation. CHK2 is able to bind to many B' subunits as well as the PP2A C subunit, indicating that it can bind to the active PP2A enzyme. The induction of DNA double-strand breaks by ionizing radiation (IR) as well as treatment with doxorubicin causes dissociation of the B'α and CHK2 proteins, however, it does not have an effect on the binding of B'α to CHK1. IR-induced dissociation is an early event and occurs in a dose-dependent manner. CHK2 and B'α can re-associate hours after DNA damage and this is not dependent upon the repair of the DNA. Dissociation is dependent on ATM activity and correlates with an increase in the ATM-dependent phosphorylation of CHK2 at serines 33 and 35 in the SQ/TQ region. Indeed, mutating these sites to mimic phosphorylation increases the dissociation after IR. CHK2 is able to phosphorylate B'α in vitro; however, in vivo, irradiation has no effect on PP2A activity or localization. Alternatively, PP2A negatively regulates CHK2 phosphorylation at multiple sites, as well as its kinase activity and protein stability. These data reveal a novel mechanism for PP2A to keep CHK2 inactive under normal conditions while also allowing for a rapid release from this regulation immediately following DNA damage. This is followed by a subsequent reconstitution of the PP2A/CHK2 complex in later time points after damage, which may help to attenuate the signal. This mechanism of CHK2 negative regulation by PP2A joins a growing list of negative regulations of DNA damage response proteins by protein serine/threonine phosphatases.
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Ghelli, Luserna di Rorà Andrea <1987&gt. "The Inhibition of Chk1/Chk2 and Wee-1 Kinases as a Promising Therapy for the Treatment of Adult Acute Lymphoblastic Leukemia." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2016. http://amsdottorato.unibo.it/7529/1/Ghelli_Luserna_di_Rora%27_Andrea_Tesi.pdf.

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Due to inadequate treatments, the survival rate of adult patients with acute lymphoblastic leukemia (ALL) is still very poor. Thus there is a need to improve the efficacy of conventional therapy. In this study we evaluated the effectiveness of checkpoint kinase inhibitors (Chk-i) in single agent and in combination with different compounds conventionally used for the treatment of B-/T-ALL. We showed that Chk1 and Chk2 kinases are highly expressed and hyper-activated in tumor samples in comparison to normal tissue. On these bases we speculate that the inhibition of these kinases could mine the genetic stability and enhance cell death in ALL cells. We firstly evaluate the efficacy in single agent of the Chk1/Chk2 (PF-0477736 and LY2606368) and of the Wee1 (MK-1775) inhibitors on different cell lines and on primary cells isolated from adult B-ALL patients. We demonstrated that the inhibition of Chk1/Chk2 kinases reduces of the cell viability, activates the apoptosis and modify the expression of different elements of the G2/M checkpoint. To assess the chemo-sensitizer activity of different checkpoint kinase inhibitors, several combination studies were performed. To this purpose, LY2606368 and MK-1775 were combined with different tyrosine kinase inhibitors (imatinb, dasatinib and bosutinib) and with the purine nucleoside analogue, clofarabine. The efficacy of the combinations was not only evaluated in term of reduction of the cell viability but also in term of induction of apoptosis and induction of DNA damages. The results found were then confirmed on primary cells of B-ALL patients. Finally different class of checkpoint kinase inhibitors were combined together in order to evaluate their interaction. In our opinion the preclinical data presented in this study are the basis for a future evaluation of this class of compound in clinical trials in the treatment of adult ALL patients.
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Ghelli, Luserna di Rorà Andrea <1987&gt. "The Inhibition of Chk1/Chk2 and Wee-1 Kinases as a Promising Therapy for the Treatment of Adult Acute Lymphoblastic Leukemia." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2016. http://amsdottorato.unibo.it/7529/.

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Due to inadequate treatments, the survival rate of adult patients with acute lymphoblastic leukemia (ALL) is still very poor. Thus there is a need to improve the efficacy of conventional therapy. In this study we evaluated the effectiveness of checkpoint kinase inhibitors (Chk-i) in single agent and in combination with different compounds conventionally used for the treatment of B-/T-ALL. We showed that Chk1 and Chk2 kinases are highly expressed and hyper-activated in tumor samples in comparison to normal tissue. On these bases we speculate that the inhibition of these kinases could mine the genetic stability and enhance cell death in ALL cells. We firstly evaluate the efficacy in single agent of the Chk1/Chk2 (PF-0477736 and LY2606368) and of the Wee1 (MK-1775) inhibitors on different cell lines and on primary cells isolated from adult B-ALL patients. We demonstrated that the inhibition of Chk1/Chk2 kinases reduces of the cell viability, activates the apoptosis and modify the expression of different elements of the G2/M checkpoint. To assess the chemo-sensitizer activity of different checkpoint kinase inhibitors, several combination studies were performed. To this purpose, LY2606368 and MK-1775 were combined with different tyrosine kinase inhibitors (imatinb, dasatinib and bosutinib) and with the purine nucleoside analogue, clofarabine. The efficacy of the combinations was not only evaluated in term of reduction of the cell viability but also in term of induction of apoptosis and induction of DNA damages. The results found were then confirmed on primary cells of B-ALL patients. Finally different class of checkpoint kinase inhibitors were combined together in order to evaluate their interaction. In our opinion the preclinical data presented in this study are the basis for a future evaluation of this class of compound in clinical trials in the treatment of adult ALL patients.
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Zannini, Laura. "Analysis of the functional domains of the cell cycle checkpoint kinase Chk2." Thesis, Open University, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441156.

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LeBron, Cynthia. "Regulation of MDMX nuclear import and degradation by Chk2 and 14-3-3." [Tampa, Fla.] : University of South Florida, 2007. http://purl.fcla.edu/usf/dc/et/SFE0001992.

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Wroble, Brian Noel. "The Role of Chk2 and Wee1 Protein Kinases during the Early Embryonic Development of Xenopus laevis." Diss., Virginia Tech, 2005. http://hdl.handle.net/10919/29723.

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In somatic cells, when DNA is damaged or incompletely replicated, checkpoint pathways arrest the cell cycle prior to M or S phases by inhibiting cyclin-dependent kinases (Cdks). In Xenopus laevis, embryonic cellular divisions (2-12) consist of rapid cleavage cycles in which gap phases, checkpoint engagement, and apoptosis are absent. Upon the completion of the 12th cellular division, the midblastula transition (MBT) begins and the cell cycle lengthens, acquiring gap phases. In addition, cell cycle checkpoint pathways and an apoptotic program become functional. The studies described here were performed to better understand the roles of two protein kinases, Chk2/Cds1 and Wee1, during checkpoint signaling in the developing embryo. The DNA damage checkpoint is mediated by the Chk2/Cds1 kinase. Conflicting evidence implicates Chk2 as an inhibitor or promoter of apoptosis. To better understand the developmental function of Chk2 and its role in apoptosis, we expressed wild-type (wt) and dominant-negative (DN) Chk2 in Xenopus embryos. Wt-Chk2 created a pre-MBT checkpoint by promoting degradation of Cdc25A and phosphorylation of Cdks. Embryos expressing DN-Chk2 developed normally until gastrulation and then underwent apoptosis. Conversely, low doses of wt-Chk2 blocked radiation-induced apoptosis. These data indicate that Chk2 inhibits apoptosis in the early embryo. Therefore, Chk2 operates as a switch between cell cycle arrest and apoptosis in response to genomic assaults. In Xenopus laevis, Wee1 kinase phosphorylates and inhibits Cdks. To determine the role of Wee1 in cell cycle checkpoint signaling and remodeling at the MBT, exogenous Wee1 was expressed in one-cell stage embryos. Modest overexpression of Wee1 created a pre-MBT cell cycle checkpoint, similar to Chk2, characterized by cell cycle delay and phosphorylation of Cdks. Furthermore, overexpression of Wee1 disrupted remodeling events that normally occur at the MBT, including degradation of Cdc25A, cyclin E, and Wee1. Interestingly, overexpression of Wee1 also resulted in post-MBT apoptosis. Taken together, these data suggest the importance of Wee1 as not only a Cdk inhibitory kinase, but also potentially as a promoter of apoptosis during early development of Xenopus laevis. The studies described here provide evidence that Chk2 and Wee1 have both similar and distinct roles in the developing embryo.
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Lopergolo, A. "CHK2 PHOSPHORYLATION OF SURVIVIN-DEX3 CONTRIBUTES TO A DNA DAMAGE-SENSING CHECKPOINT IN CANCER." Doctoral thesis, Università degli Studi di Milano, 2012. http://hdl.handle.net/2434/171952.

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Survivin is a pivotal cancer gene with multiple roles in cell viability and mitosis, but the function(s) of its alternatively spliced isoforms has remained elusive. Here, we show that a survivin spliced variant that lacks exon 3 and contains a unique -COOH terminus sequence, survivin-DEx3, is differentially expressed in cancer, compared to normal tissues, and correlates with aggressive disease and markers of unfavorable prognosis, by genome-wide bioinformatics analysis. Unlike other survivin variants, survivin-DEx3 localizes exclusively to nuclei in tumor cells, and is phosphorylated by the DNA damage checkpoint kinase, Chk2, on residues located in its unique -COOH terminus. Ala mutagenesis of the Chk2 phosphorylation sites prolongs survivin-DEx3 stability in tumor cells, inhibits the expression of Ser139 phosphorylated H2AX in response to double strand DNA breaks, and impairs colony formation in soft agar after DNA damage. Active Chk2 was detected at the earliest stages of the colorectal adenoma-to-carcinoma transition, persisted in advanced tumors, and correlated with increased survivin expression, in vivo. These data suggest that Chk2 phosphorylation of survivin-DEx3 contributes to a DNA damage-sensing checkpoint in tumor cells, which may affect sensitivity to genotoxic therapies.
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Books on the topic "CHK2"

1

Hoàng, Viuet. Khoa xem chki tay. Glendale, CA: Đại Nam, 1995.

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Wolongsheng. Đàn chki thsan công. Hà Nuoi: NXB Lao đuong, 2004.

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Trsan, Ngọc. Cũng chki là phi vụ. [California]: Đông, 1999.

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Sekretarʹ Moskovskoĭ ChK. Moskva: Galerei︠a︡, 2006.

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Dukel'skii, S. ChK na Ukraine. Benson (Vt.): Chalidze, 1989.

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S, Agabekov G. ChK za rabotoĭ. Moskva: Assot͡s︡iat͡s︡ii͡a︡ "Kniga, Prosveshchenie, Miloserdie", 1992.

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Dukelʹskiĭ, Semen Semenovich. ChK na Ukraine. Benson, Vt: Chalidze Publications, 1989.

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Chku-nghĩa hòa-bình: Luuan thuyret. Santa Ana, CA: The Author, 2006.

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Lê, Bi. Địa chki ckua muot ngưxoi: Thơ. [Garden Grove, CA]: Tân Thư, 1996.

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Yinzhenren. Tính muenh khuê chki toàn thư. Costa Mesa, Calif: Nhân Tyu Văn, 2002.

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Book chapters on the topic "CHK2"

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Zhang, Haiying, Zhan Xiao, and Tom Sowin. "Chk1 and Chk2 as Checkpoint Targets." In Checkpoint Controls and Targets in Cancer Therapy, 245–59. Totowa, NJ: Humana Press, 2009. http://dx.doi.org/10.1007/978-1-60761-178-3_16.

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Collins, Ian, and Michelle D. Garrett. "Preclinical Profiles and Contexts for CHK1 and CHK2 Inhibitors." In Cancer Drug Discovery and Development, 241–76. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-75836-7_10.

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Yu, Jing Jie, Xiaobing Liang, Qing-Wu Yan, Eddie Reed, Antonio Tito Fojo, Ying Guo, Qi He, and Michael D. Mueller. "CHK2 and ERCC1 in the DNA Adduct Repair Pathway that Mediates Acquired Cisplatin Resistance." In Platinum and Other Heavy Metal Compounds in Cancer Chemotherapy, 189–94. Totowa, NJ: Humana Press, 2009. http://dx.doi.org/10.1007/978-1-60327-459-3_23.

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Beckwith, A. L. J. "4.3.4 Secondary alkyl radicals, type R1–CH2–ĊH–CHR2." In Inorganic Radicals, Metal Complexes and Nonconjugated Carbon Centered Radicals. Part 1, 377–82. Berlin, Heidelberg: Springer Berlin Heidelberg, 2007. http://dx.doi.org/10.1007/978-3-540-48466-0_93.

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Goto, Hidemasa, Hironori Inaba, and Masaki Inagaki. "Chk1." In Encyclopedia of Signaling Molecules, 1091–97. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-67199-4_101557.

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Buscemi, Giacomo, and Laura Zannini. "CHEK2." In Encyclopedia of Signaling Molecules, 1056–65. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-67199-4_101559.

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Goto, Hidemasa, Hironori Inaba, and Masaki Inagaki. "Chk1." In Encyclopedia of Signaling Molecules, 1–7. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4614-6438-9_101557-1.

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Buscemi, Giacomo, and Laura Zannini. "CHEK2." In Encyclopedia of Signaling Molecules, 1–10. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4614-6438-9_101559-1.

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Brown, J. M. "CHF2." In Landolt-Börnstein - Group II Molecules and Radicals, 1–3. Berlin, Heidelberg: Springer Berlin Heidelberg, 2005. http://dx.doi.org/10.1007/11313410_79.

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Kuhlmei, Eckehard. "chi2-Tests." In Lerne mit uns Statistik!, 93–116. Berlin, Heidelberg: Springer Berlin Heidelberg, 2018. http://dx.doi.org/10.1007/978-3-662-56082-2_9.

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Conference papers on the topic "CHK2"

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Jobson, Andrew, George T. Lountos, Philip Lorenzi, John Connelly, Joseph E. Tropea, Gabriele Zoppoli, Sudhir Kondapaka, et al. "Abstract A120: Cellular inhibition of Chk2 kinase and potentiation of camptothecins and radiation by the novel Chk2 inhibitor PV1019." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 15-19, 2009; Boston, MA. American Association for Cancer Research, 2009. http://dx.doi.org/10.1158/1535-7163.targ-09-a120.

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Ghelli Luserna di Rora, Andrea, Ilaria Iacobucci, Enrica Imbrogno, Enrico Derenzini, Anna Ferrari, Valentina Robustelli, Viviana Guadagnuolo, et al. "Abstract 2723: The synergistic efficacy of Chk1/Chk2 inhibitors and doxorubicin in the treatment of acute lymphoblastic leukemia." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-2723.

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Derenzini, Enrico, Ilaria Iacobucci, Elisa Brighenti, Federica Cattina, Beatrice Casadei, Richard Eric Davis, Stefano Pileri, Giovanni Martinelli, Michele Baccarani, and Pier Luigi Zinzani. "Abstract 4694: The small molecule CHK1/CHK2 inhibitor PF-0477736 (Pfizer) demonstrates single agent activity in diffuse large B-cell lymphoma." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-4694.

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Iacobucci, Ilaria, Federica Cattina, Silvia Pomella, Elisa Brighenti, Cristina Papayannidis, Enrico Derenzini, Annalisa Lonetti, et al. "Abstract 1772: Inhibition of DNA repair by the small molecule Chk1/Chk2 inhibitor PF-0477736 (Pfizer) in B-acute lymphoblastic leukemia (ALL)." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-1772.

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Muñoz-Maldonado, Carmen, Aurélie Quintin, Daniel M. Aebersold, Yitzhak Zimmer, and Michaela Medová. "Abstract PO-026: DNA damage response and repair characterization in CHK2-deficient cancers." In Abstracts: AACR Virtual Special Conference on Radiation Science and Medicine; March 2-3, 2021. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1557-3265.radsci21-po-026.

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Iacobucci, Ilaria, Andrea Ghelli Luserna Di Rorà, Maria Vittoria Verga Falzacappa, Enrico Derenzini, Anna Ferrari, Enrica Imbrogno, Cristina Papayannidis, et al. "Abstract 705: Inhibition of Checkpoint Kinase 1 (Chk1) and 2 (Chk2) is a novel therapeutic strategy in B- and T-Acute Lymphoblastic Leukemia (ALL)." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-705.

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Powell, Simon N. "Abstract IA20: Phosphorylation of BRCA1 by CHK2 mediates resection activity and recruitment of BRCA2." In Abstracts: AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; November 2-5, 2016; Montreal, QC, Canada. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1557-3125.dnarepair16-ia20.

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Liang, Xiaobing, Michael D. Mueller, and Jing Jie Yu. "Abstract 2982: Activation of checkpoint kinase Chk2 by cisplatin and its role in cisplatin resistance." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-2982.

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Panda, Rupayana, Satya Narayan Sahu, Fahmida Khan, and Subrat Kumar Pattanayak. "Binding performance of phytochemicals with mutant threonine-protein kinase Chk2 protein: An in silico study." In PROCEEDINGS OF ADVANCED MATERIAL, ENGINEERING & TECHNOLOGY. AIP Publishing, 2020. http://dx.doi.org/10.1063/5.0019655.

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Meraz, Ismail M., Abdul R. Khokhar, and Zahid H. Siddik. "Abstract 2507: Defective Chk2 expression in cisplatin-resistant ovarian tumor cells impedes wild-type p53 function." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-2507.

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Reports on the topic "CHK2"

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Tsvetkov, Lyuben. Identification of New Chk2 Substrates. Fort Belvoir, VA: Defense Technical Information Center, July 2002. http://dx.doi.org/10.21236/ada410391.

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Zhenkun, Lou. Functional Analysis of Chk2-Kiaa0170 Interaction. Fort Belvoir, VA: Defense Technical Information Center, September 2005. http://dx.doi.org/10.21236/ada449840.

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Lou, Zhenkun. Functional Analysis of Chk2-Kiaa0170 Interaction. Fort Belvoir, VA: Defense Technical Information Center, September 2004. http://dx.doi.org/10.21236/ada429482.

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Liu, Wanguo. CHK2, A Candidate Prostate Cancer Susceptibility Gene. Fort Belvoir, VA: Defense Technical Information Center, January 2005. http://dx.doi.org/10.21236/ada443052.

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Elledge, Stephen J. The Role of Chk2 in Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, April 2006. http://dx.doi.org/10.21236/ada455288.

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Liu, Wanguo. CHK2, A Candidate Prostate Cancer Susceptibility Gene. Fort Belvoir, VA: Defense Technical Information Center, January 2003. http://dx.doi.org/10.21236/ada413554.

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Liu, Wanguo. CHK2, A Candidate Prostate Cancer Susceptibility Gene. Fort Belvoir, VA: Defense Technical Information Center, January 2004. http://dx.doi.org/10.21236/ada423213.

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Elledge, Stephan J. The Role of Chk2 in Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, April 2004. http://dx.doi.org/10.21236/ada425809.

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Godwin, Andrew K. Susceptibility to Breast Cancer in CHK2 Mutation Carriers. Fort Belvoir, VA: Defense Technical Information Center, October 2001. http://dx.doi.org/10.21236/ada399192.

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Godwin, Andrew K. Susceptibility to Breast Cancer in CHK2 Mutation Carriers. Fort Belvoir, VA: Defense Technical Information Center, October 2002. http://dx.doi.org/10.21236/ada411670.

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