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  1. Book: Systems biology

    Kolch, Walter

    (Essays in biochemistry ; volume 62, issue 4 (October 2018))

    2018  

    Author's details guest editors Walter Kolch, Dirk Fey and Colm J. Ryan
    Series title Essays in biochemistry ; volume 62, issue 4 (October 2018)
    Collection
    Language English
    Size Seite 483-616, Illustrationen, Diagramme
    Publisher Portland Press
    Publishing place London
    Publishing country Great Britain
    Document type Book
    HBZ-ID HT019958541
    ISBN 978-1-85578-220-4 ; 1-85578-220-0
    Database Catalogue ZB MED Medicine, Health

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    In stock of ZB MED Cologne/Königswinter

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  2. Article ; Online: Dynamic regulation of RAS and RAS signaling.

    Kolch, Walter / Berta, Dénes / Rosta, Edina

    The Biochemical journal

    2023  Volume 480, Issue 1, Page(s) 1–23

    Abstract: RAS proteins regulate most aspects of cellular physiology. They are mutated in 30% of human cancers and 4% of developmental disorders termed Rasopathies. They cycle between active GTP-bound and inactive GDP-bound states. When active, they can interact ... ...

    Abstract RAS proteins regulate most aspects of cellular physiology. They are mutated in 30% of human cancers and 4% of developmental disorders termed Rasopathies. They cycle between active GTP-bound and inactive GDP-bound states. When active, they can interact with a wide range of effectors that control fundamental biochemical and biological processes. Emerging evidence suggests that RAS proteins are not simple on/off switches but sophisticated information processing devices that compute cell fate decisions by integrating external and internal cues. A critical component of this compute function is the dynamic regulation of RAS activation and downstream signaling that allows RAS to produce a rich and nuanced spectrum of biological outputs. We discuss recent findings how the dynamics of RAS and its downstream signaling is regulated. Starting from the structural and biochemical properties of wild-type and mutant RAS proteins and their activation cycle, we examine higher molecular assemblies, effector interactions and downstream signaling outputs, all under the aspect of dynamic regulation. We also consider how computational and mathematical modeling approaches contribute to analyze and understand the pleiotropic functions of RAS in health and disease.
    MeSH term(s) Humans ; Signal Transduction ; ras Proteins/chemistry ; Neoplasms ; Guanosine Triphosphate/metabolism
    Chemical Substances ras Proteins (EC 3.6.5.2) ; Guanosine Triphosphate (86-01-1)
    Language English
    Publishing date 2023-01-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BCJ20220234
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Reversing pathological cell states: the road less travelled can extend the therapeutic horizon.

    Kholodenko, Boris N / Kolch, Walter / Rukhlenko, Oleksii S

    Trends in cell biology

    2023  Volume 33, Issue 11, Page(s) 913–923

    Abstract: Acquisition of omics data advances at a formidable pace. Yet, our ability to utilize these data to control cell phenotypes and design interventions that reverse pathological states lags behind. Here, we posit that cell states are determined by core ... ...

    Abstract Acquisition of omics data advances at a formidable pace. Yet, our ability to utilize these data to control cell phenotypes and design interventions that reverse pathological states lags behind. Here, we posit that cell states are determined by core networks that control cell-wide networks. To steer cell fate decisions, core networks connecting genotype to phenotype must be reconstructed and understood. A recent method, cell state transition assessment and regulation (cSTAR), applies perturbation biology to quantify causal connections and mechanistically models how core networks influence cell phenotypes. cSTAR models are akin to digital cell twins enabling us to purposefully convert pathological states back to physiologically normal states. While this capability has a range of applications, here we discuss reverting oncogenic transformation.
    MeSH term(s) Humans ; Gene Regulatory Networks ; Cell Differentiation ; Phenotype ; Genotype ; Cell Transformation, Neoplastic
    Language English
    Publishing date 2023-05-30
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 30122-x
    ISSN 1879-3088 ; 0962-8924
    ISSN (online) 1879-3088
    ISSN 0962-8924
    DOI 10.1016/j.tcb.2023.04.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: A Systems Biology Approach to Understand the Racial Disparities in Colorectal Cancer.

    Nwaokorie, Annabelle / Kolch, Walter / Fey, Dirk

    Cancer research communications

    2023  Volume 4, Issue 1, Page(s) 103–117

    Abstract: Racial disparities between Black/African Americans (AA) and White patients in colorectal cancer are an ever-growing area of concern. Black/AA show the highest incidence and have the highest mortality among major U.S. racial groups. There is no definite ... ...

    Abstract Racial disparities between Black/African Americans (AA) and White patients in colorectal cancer are an ever-growing area of concern. Black/AA show the highest incidence and have the highest mortality among major U.S. racial groups. There is no definite cause other than possible sociodemographic, socioeconomic, education, nutrition, delivery of healthcare, screening, and cultural factors. A primary limitation in this field is the lack of and small sample size of Black/AA studies. Thus, this study aimed to investigate whether differences in gene expression contribute to this ongoing unanswered racial disparity issue. In this study, we examined transcriptomic data of Black/AA and White patient cohorts using a bioinformatic and systems biology approach. We performed a Kaplan-Meier overall survival analysis between both patient cohorts across critical colorectal cancer signal transduction networks (STN), to determine the differences in significant genes across each cohort. Other bioinformatic analyses performed included PROGENy (pathway responsive genes for activity inference), RNA sequencing differential expression using DESeq2, multivariable-adjusted regression, and other associated Kaplan-Meier analyses. These analyses identified novel prognostic genes independent from each cohort, 176 differentially expressed genes, and specific patient cohort STN survival associations. Despite the overarching limitation, the results revealed several novel differences in gene expression between the colorectal cancer Black/AA and White patient cohorts, which allows one to dive deeper into and understand the behavior on a systems level of what could be driving this racial difference across colorectal cancer. Concretely, this information can guide precision medicine approaches tailored specifically for colorectal cancer racial disparities.
    Significance: The purpose of this work is to investigate the racial disparities in colorectal cancer between Black/AA and White patient cohorts using a systems biology and bioinformatic approach. Our study investigates the underlying biology of each patient cohort. Concretely, the findings of this study include disparity-associated genes and pathways, which provide a tangible starting point to guide precision medicine approaches tailored specifically for colorectal cancer racial disparities.
    MeSH term(s) Humans ; Black or African American/genetics ; Colorectal Neoplasms/epidemiology ; Colorectal Neoplasms/genetics ; Delivery of Health Care ; Racial Groups/genetics ; Systems Biology ; Health Status Disparities ; White
    Language English
    Publishing date 2023-12-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2767-9764
    ISSN (online) 2767-9764
    DOI 10.1158/2767-9764.CRC-22-0464
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Analysis of Alternative mRNA Splicing in Vemurafenib-Resistant Melanoma Cells.

    Bokharaie, Honey / Kolch, Walter / Krstic, Aleksandar

    Biomolecules

    2022  Volume 12, Issue 7

    Abstract: Alternative mRNA splicing is common in cancers. In BRAF V600E-mutated malignant melanoma, a frequent mechanism of acquired resistance to BRAF inhibitors involves alternative splicing (AS) of BRAF. The resulting shortened BRAF protein constitutively ... ...

    Abstract Alternative mRNA splicing is common in cancers. In BRAF V600E-mutated malignant melanoma, a frequent mechanism of acquired resistance to BRAF inhibitors involves alternative splicing (AS) of BRAF. The resulting shortened BRAF protein constitutively dimerizes and conveys drug resistance. Here, we have analysed AS in SK-MEL-239 melanoma cells and a BRAF inhibitor (vemurafenib)-resistant derivative that expresses an AS, shortened BRAF V600E transcript. Transcriptome analysis showed differential expression of spliceosome components between the two cell lines. As there is no consensus approach to analysing AS events, we used and compared four common AS softwares based on different principles, DEXSeq, rMATS, ASpli, and LeafCutter. Two of them correctly identified the BRAF V600E AS in the vemurafenib-resistant cells. Only 12 AS events were identified by all four softwares. Testing the AS predictions experimentally showed that these overlapping predictions are highly accurate. Interestingly, they identified AS caused alterations in the expression of melanin synthesis and cell migration genes in the vemurafenib-resistant cells. This analysis shows that combining different AS analysis approaches produces reliable results and meaningful, biologically testable hypotheses.
    MeSH term(s) Alternative Splicing ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics ; Humans ; Indoles/pharmacology ; Melanoma/drug therapy ; Melanoma/genetics ; Melanoma/pathology ; Mutation ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins B-raf/genetics ; RNA, Messenger/metabolism ; Sulfonamides/pharmacology ; Vemurafenib/pharmacology ; Vemurafenib/therapeutic use
    Chemical Substances Antineoplastic Agents ; Indoles ; Protein Kinase Inhibitors ; RNA, Messenger ; Sulfonamides ; Vemurafenib (207SMY3FQT) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
    Language English
    Publishing date 2022-07-17
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2701262-1
    ISSN 2218-273X ; 2218-273X
    ISSN (online) 2218-273X
    ISSN 2218-273X
    DOI 10.3390/biom12070993
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  6. Article: All over the place: deciphering HRAS signaling from different subcellular compartments.

    Kolch, Walter / Matallanas, David

    Molecular & cellular oncology

    2019  Volume 6, Issue 5, Page(s) e1605821

    Abstract: ... ...

    Abstract RAS
    Language English
    Publishing date 2019-05-20
    Publishing country United States
    Document type Journal Article
    ISSN 2372-3556
    ISSN 2372-3556
    DOI 10.1080/23723556.2019.1605821
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  7. Article ; Online: The Ins and Outs of RAS Effector Complexes.

    Kiel, Christina / Matallanas, David / Kolch, Walter

    Biomolecules

    2021  Volume 11, Issue 2

    Abstract: RAS oncogenes are among the most commonly mutated proteins in human cancers. They regulate a wide range of effector pathways that control cell proliferation, survival, differentiation, migration and metabolic status. Including aberrations in these ... ...

    Abstract RAS oncogenes are among the most commonly mutated proteins in human cancers. They regulate a wide range of effector pathways that control cell proliferation, survival, differentiation, migration and metabolic status. Including aberrations in these pathways, RAS-dependent signaling is altered in more than half of human cancers. Targeting mutant RAS proteins and their downstream oncogenic signaling pathways has been elusive. However, recent results comprising detailed molecular studies, large scale omics studies and computational modeling have painted a new and more comprehensive portrait of RAS signaling that helps us to understand the intricacies of RAS, how its physiological and pathophysiological functions are regulated, and how we can target them. Here, we review these efforts particularly trying to relate the detailed mechanistic studies with global functional studies. We highlight the importance of computational modeling and data integration to derive an actionable understanding of RAS signaling that will allow us to design new mechanism-based therapies for RAS mutated cancers.
    MeSH term(s) Computer Simulation ; Genes, ras ; Humans ; Molecular Structure ; Mutation ; Neoplasms/genetics ; Neoplasms/metabolism ; Precision Medicine ; Protein Binding ; Signal Transduction
    Language English
    Publishing date 2021-02-07
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2701262-1
    ISSN 2218-273X ; 2218-273X
    ISSN (online) 2218-273X
    ISSN 2218-273X
    DOI 10.3390/biom11020236
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Proteomic Mapping of the Interactome of KRAS Mutants Identifies New Features of RAS Signalling Networks and the Mechanism of Action of Sotorasib.

    Nolan, Aoife / Raso, Cinzia / Kolch, Walter / Kriegsheim, Alex von / Wynne, Kieran / Matallanas, David

    Cancers

    2023  Volume 15, Issue 16

    Abstract: RAS proteins are key regulators of cell signalling and control different cell functions including cell proliferation, differentiation, and cell death. Point mutations in the genes of this family are common, particularly ... ...

    Abstract RAS proteins are key regulators of cell signalling and control different cell functions including cell proliferation, differentiation, and cell death. Point mutations in the genes of this family are common, particularly in
    Language English
    Publishing date 2023-08-17
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers15164141
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  9. Article ; Online: From oncogenic mutation to dynamic code.

    Kolch, Walter / Kiel, Christina

    Science (New York, N.Y.)

    2018  Volume 361, Issue 6405, Page(s) 844–845

    MeSH term(s) Genetic Code ; Mutation
    Language English
    Publishing date 2018-08-30
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.aau8059
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  10. Article ; Online: Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity.

    Lee, Shannon / Rauch, Jens / Kolch, Walter

    International journal of molecular sciences

    2020  Volume 21, Issue 3

    Abstract: Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Here, we focus on the role of MAPK pathways in modulating drug sensitivity and ... ...

    Abstract Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Here, we focus on the role of MAPK pathways in modulating drug sensitivity and resistance in cancer. We briefly discuss new findings in the extracellular signaling-regulated kinase (ERK) pathway, but mainly focus on the mechanisms how stress activated MAPK pathways, such as p38 MAPK and the Jun N-terminal kinases (JNK), impact the response of cancer cells to chemotherapies and targeted therapies. In this context, we also discuss the role of metabolic and epigenetic aberrations and new therapeutic opportunities arising from these changes.
    MeSH term(s) Animals ; Drug Resistance, Neoplasm ; Epigenesis, Genetic ; Humans ; MAP Kinase Signaling System ; Molecular Targeted Therapy/methods ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; p38 Mitogen-Activated Protein Kinases/genetics ; p38 Mitogen-Activated Protein Kinases/metabolism
    Chemical Substances p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24)
    Language English
    Publishing date 2020-02-07
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms21031102
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