Research Topics
Genomes and Genes | K W KohnSummaryAffiliation: National Institutes of Health Country: USA Publications
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Publications
A formal MIM specification and tools for the common exchange of MIM diagrams: an XML-Based format, an API, and a validation methodAugustin Luna
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
BMC Bioinformatics 12:167. 2011..A lack of software tools for the notation restricts wider usage of the notation. Development of software is facilitated by a more detailed specification regarding software requirements than has previously existed for the MIM notation...- Molecular and biological determinants of the cytotoxic actions of camptothecins. Perspective for the development of new topoisomerase I inhibitorsK W Kohn
Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Ann N Y Acad Sci 922:11-26. 2000..This is made possible by current concepts based, for the most part, on a sound experimental foundation, which points the way towards optimally effective therapy... - Chromatin challenges during DNA replication: a systems representationKurt W Kohn
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Mol Biol Cell 19:1-7. 2008..on the complexities of chromatin replication, thereby providing a tool for system-level comprehension of the effects of genetic mutations, altered gene expression, and pharmacologic intervention... - Depicting combinatorial complexity with the molecular interaction map notationKurt W Kohn
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
Mol Syst Biol 2:51. 2006..These comparisons may help cell and systems biologists adopt a graphical language that is unambiguous and generally understood... - Molecular interaction map of the mammalian cell cycle control and DNA repair systemsK W Kohn
Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland 20892, USA
Mol Biol Cell 10:2703-34. 1999..The map shows how multiprotein complexes could assemble and function at gene promoter sites and at sites of DNA damage. It also portrays the richness of connections between the p53-Mdm2 subsystem and other parts of the network... - Molecular interaction maps of bioregulatory networks: a general rubric for systems biologyKurt W Kohn
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Mol Biol Cell 17:1-13. 2006..Drawing a MIM diagram, adhering to the rules of notation, imposes a logical discipline that sharpens one's understanding of the structure and function of a network... - Molecular interaction map of the p53 and Mdm2 logic elements, which control the Off-On switch of p53 in response to DNA damageKurt W Kohn
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Biochem Biophys Res Commun 331:816-27. 2005..We also used molecular interaction maps to propose a p53 Off-On switch in response to DNA damage... - Beyond DNA cross-linking: history and prospects of DNA-targeted cancer treatment--fifteenth Bruce F. Cain Memorial Award LectureK W Kohn
Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland 20892, USA
Cancer Res 56:5533-46. 1996..Panels of human tumor cell lines may serve to link the molecular defects with specific drug sensitivities. Such correlations could guide the selection of drugs for therapy based on molecular diagnosis of individual tumors... - An information-intensive approach to the molecular pharmacology of cancerJ N Weinstein
Laboratory of Molecular Pharmacology LMP, Division of Basic Science, National Cancer Institute NCI, National Institutes of Health, Bethesda, MD 20892, USA
Science 275:343-9. 1997..It remains to be seen how effective this information-intensive strategy will be at generating new clinically active agents... - p21CDKN1A allows the repair of replication-mediated DNA double-strand breaks induced by topoisomerase I and is inactivated by the checkpoint kinase inhibitor 7-hydroxystaurosporineT Furuta
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Oncogene 25:2839-49. 2006..However, these breaks are not related to apoptotic DNA fragmentation. We propose that p21(CDKN1A) prevents the collapse of replication forks damaged by stabilized topoisomerase I cleavage complexes... - Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA:DNA-PK complexesR G Shao
Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 4255, USA
EMBO J 18:1397-406. 1999..Keywords: camptothecin/DNA damage/DNA-dependent protein kinase/RPA2 phosphorylation.. - Ataxia telangiectasia mutated activation by transcription- and topoisomerase I-induced DNA double-strand breaksOlivier Sordet
Laboratory of Molecular Pharmacology, National Cancer Institute, NIH, Bethesda, MD 20892 4255, USA
EMBO Rep 10:887-93. 2009..Thus, we propose that Top1cc produce transcription arrests with R-loop formation and generate DSBs that activate ATM in post-mitotic cells... - Death receptor-induced activation of the Chk2- and histone H2AX-associated DNA damage response pathwaysStéphanie Solier
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892 4255, USA
Mol Cell Biol 29:68-82. 2009..Together, our findings suggest that nuclear activation of Chk2 by TRAIL acts as a positive feedback loop involving the mitochondrion-dependent activation of caspases, independently of p53... - Functional capabilities of molecular network components controlling the mammalian G1/S cell cycle phase transitionK W Kohn
Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Oncogene 16:1065-75. 1998..The results show how network simulations, carried out by means of the methods described, can assist in the design and interpretation of experiments probing the control of the G1/S phase transition... - Characterization of the p53 tumor suppressor pathway in cell lines of the National Cancer Institute anticancer drug screen and correlations with the growth-inhibitory potency of 123 anticancer agentsP M O'Connor
Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA
Cancer Res 57:4285-300. 1997..This information also allows for the large-scale analysis of the more than 60,000 compounds tested against these lines for novel agents that might exploit defective p53 function as a means of preferential toxicity... - Quantitative structure-antitumor activity relationships of camptothecin analogues: cluster analysis and genetic algorithm-based studiesY Fan
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
J Med Chem 44:3254-63. 2001..The cross-validated r(2) for the final GFA model was 0.783, indicating a predictive QSAR model... - Transcriptional regulation of mitotic genes by camptothecin-induced DNA damage: microarray analysis of dose- and time-dependent effectsYi Zhou
Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA
Cancer Res 62:1688-95. 2002.... - G2 delay induced by nitrogen mustard in human cells affects cyclin A/cdk2 and cyclin B1/cdc2-kinase complexes differentlyP M O'Connor
Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
J Biol Chem 268:8298-308. 1993..Furthermore, we found that pentoxifylline disrupts the signal transduction pathway that regulates these complexes when damaged DNA is present, resulting in abrogation of cell cycle arrest... - UCN-01 inhibits p53 up-regulation and abrogates gamma-radiation-induced G(2)-M checkpoint independently of p53 by targeting both of the checkpoint kinases, Chk2 and Chk1Qiang Yu
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255, USA
Cancer Res 62:5743-8. 2002..Taken together, these observations indicate that UCN-01 can modulate both Chk1 and Chk2 in intact cells and enhance IR-induced apoptosis in p53-deficient, and consequently p21-deficient, cells... - Dose-response transition from cell cycle arrest to apoptosis with selective degradation of Mdm2 and p21WAF1/CIP1 in response to the novel anticancer agent, aminoflavone (NSC 686,288)L H Meng
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 4255, USA
Oncogene 26:4806-16. 2007.... - Genome-wide analysis of novel splice variants induced by topoisomerase I poisoning shows preferential occurrence in genes encoding splicing factorsStéphanie Solier
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892 4255, USA
Cancer Res 70:8055-65. 2010..The preferential effect of CPT on genes encoding splicing factors may explain the abnormal splicing of a large number of genes in response to Top1cc... - Comparative pharmacokinetics of DNA lesion formation and removal following treatment of L1210 cells with nitrogen mustardsP M O'Connor
Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
Cancer Commun 2:387-94. 1990..QM was the only compound that produced detectable SSB, and the SSB were so numerous that ISC could not be quantitated.(ABSTRACT TRUNCATED AT 250 WORDS).. - DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinataY Pommier
Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 4255, USA
Biochemistry 35:13303-9. 1996..These data indicate that ecteinascidin 743 is a novel DNA minor groove, guanine-specific alkylating agent... - Network architecture of signaling from uncoupled helicase-polymerase to cell cycle checkpoints and trans-lesion DNA synthesisKurt W Kohn
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Cell Cycle 8:2281-99. 2009..In addition, the network architecture disclosed by the hierarchical map, suggested a speculative model for how molecular crowding and the granular localization of network components in the cell nucleus can facilitate function... - Chk2 molecular interaction map and rationale for Chk2 inhibitorsYves Pommier
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892 4255, USA
Clin Cancer Res 12:2657-61. 2006..Visualizing the regulatory circuits underlying cellular signaling may help identify key regulatory reactions and defects that can serve as targets for anticancer drugs... - Cancers as wounds that do not heal: differences and similarities between renal regeneration/repair and renal cell carcinomaJoseph Riss
Laboratory of Biosystems and Cancer, Comparative Oncology Program, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA
Cancer Res 66:7216-24. 2006..The observations reported here provide a conceptual framework for further efforts to understand the biology and to develop more effective diagnostic biomarkers and therapeutic strategies for renal tumors and renal ischemia... - mRNA and microRNA expression profiles of the NCI-60 integrated with drug activitiesHongfang Liu
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
Mol Cancer Ther 9:1080-91. 2010..The data sets presented here will facilitate the identification of groups of mRNAs, microRNAs, and drugs that potentially affect and interact with one another... - A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of the topoisomerase I-DNA covalent complexChristophe Marchand
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Building 37, Room 5068, Bethesda, MD 20892-4255, USA
Mol Cancer Ther 5:287-95. 2006..Stabilization of such conformational states results in uncompetitive inhibition and exemplifies the relevance of screening for ligands and drugs that stabilize ("trap") these macromolecular complexes... - Targeting chk2 kinase: molecular interaction maps and therapeutic rationaleYves Pommier
Center for Cancer Research, National Cancer Institute, National Institute of Health, DHHS, Bethesda, Maryland, USA
Curr Pharm Des 11:2855-72. 2005..Chk2 inhibitors might be used to enhance the tumor selectivity of DNA targeted agents in p53-deficient tumors, and for the treatment of tumors whose growth depends on enhanced Chk2 activity... - Apoptotic susceptibility of cancer cells selected for camptothecin resistance: gene expression profiling, functional analysis, and molecular interaction mappingWilliam C Reinhold
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Cancer Res 63:1000-11. 2003..This model is analogous to one suggested previously for the relationship between oncogene function and apoptosis in carcinogenesis... - [Cell cycle and checkpoints in oncology: new therapeutic targets]Yves Pommier
Laboratoire de Pharmacologie Moleculaire, Center for Cancer Research, National Cancer Institute, Bldg 37, Room 5068, NIH, Bethesda, MD 20892 4255, USA
Med Sci (Paris) 19:173-86. 2003..This review is an update of the molecular networks driving the cell cycle and its regulation, and of the importance of this knowledge for understanding the mechanisms driving oncogenesis and therapeutic developments... - Apoptosis defects and chemotherapy resistance: molecular interaction maps and networksYves Pommier
Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, DHHS, Bethesda, MD 20892, USA
Oncogene 23:2934-49. 2004..They complement the p53, Chk2 and c-Abl maps published recently. We will also introduce the 'permissive apoptosis-resistance' model for the selection of multidrug-resistant cells... - Molecular interaction maps--a diagrammatic graphical language for bioregulatory networksMirit I Aladjem
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
Sci STKE 2004:pe8. 2004.... - Repair of and checkpoint response to topoisomerase I-mediated DNA damageYves Pommier
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute NIH, Building 37, Room 5068, Bethesda, MD 20892 4255, USA
Mutat Res 532:173-203. 2003..Defects in these repair/checkpoint pathways, which promote tumor development, explain, at least in part, the selectivity of camptothecins and other Top1 inhibitors for cancer cells... - Hereditary ataxia SCAN1 cells are defective for the repair of transcription-dependent topoisomerase I cleavage complexesZe Hong Miao
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
DNA Repair (Amst) 5:1489-94. 2006.... - Differential induction of topoisomerase I-DNA cleavage complexes by the indenoisoquinoline MJ-III-65 (NSC 706744) and camptothecin: base sequence analysis and activity against camptothecin-resistant topoisomerases ISmitha Antony
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute/NIH, 37 Convent Drive, Bethesda, MD 20892-4255, USA
Cancer Res 63:7428-35. 2003..This study shows the specific molecular interactions of MJ-III-65 with top1 and demonstrates that MJ-III-65 is a potentially useful top1 inhibitor that enhances and traps top1 cleavage sites not sensitive to CPTs... - 4-nitroquinoline-1-oxide induces the formation of cellular topoisomerase I-DNA cleavage complexesZe-Hong Miao
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute/NIH, Bethesda, MD 20892, USA
Cancer Res 66:6540-5. 2006..Induction of Top1cc and histone gamma-H2AX by 4NQO may contribute to the cellular effects of 4NQO, including its selective activity toward RecQ helicase BLM-deficient cells... - Properties of switch-like bioregulatory networks studied by simulation of the hypoxia response control systemKurt W Kohn
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA
Mol Biol Cell 15:3042-52. 2004..The studies disclosed the mechanism responsible for the sharp transitions. We show how parameter sets giving switch-like behavior can be found and how this type of behavior provides a foundation for quantitative studies in cells... - Apoptosis induced by topoisomerase inhibitorsOlivier Sordet
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255, USA
Curr Med Chem Anticancer Agents 3:271-90. 2003..Finally, we will review the recent observations that support a role for topoisomerases in chromatin fragmentation during the execution phase of apoptosis... - The gadd and MyD genes define a novel set of mammalian genes encoding acidic proteins that synergistically suppress cell growthQ Zhan
Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, Maryland 20892
Mol Cell Biol 14:2361-71. 1994..Taken together, these observations indicate that these genes define a novel class of mammalian genes encoding acidic proteins involved in the control of cellular growth... - Predicted functions of MdmX in fine-tuning the response of p53 to DNA damageSohyoung Kim
Laboratory of Molecular Pharmacology, National Cancer Institute, National Institute of Health, Bethesda, Maryland, United States of America
PLoS Comput Biol 6:e1000665. 2010..Our study suggests how MdmX may participate in the response of p53 to DNA damage either by increasing dependency of p53 on Mdm2 or by dampening oscillations of p53 activity and presents a model for experimental investigation... - Impact of p53 knockout and topotecan treatment on gene expression profiles in human colon carcinoma cells: a pharmacogenomic studySayed S Daoud
Department of Pharmaceutical Sciences, Washington State University, Pullman, Washington 99164, USA
Cancer Res 63:2782-93. 2003..The new experimental design and gene expression map analysis introduced here are applicable to a wide range of studies that encompass both treatment effects and genotypic or phenotypic differences... - Circuit diagrams for biological networksKurt W Kohn
Mol Syst Biol 2:2006.0002. 2006 - Importance of the fourth alpha-helix within the CAP homology domain of type II topoisomerase for DNA cleavage site recognition and quinolone actionDirk Strumberg
Department of Internal Medicine and Medical Oncology, West German Cancer Center, University Medical School of Essen, 45122 Essen, Germany
Antimicrob Agents Chemother 46:2735-46. 2002..It also demonstrates that selective amino acid residues in the alpha4-helix are important in determining the activity and possibly the binding of quinolones to the topoisomerase II-DNA complexes...