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p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression

p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression

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AMELIO, Ivano, Mara MANCINI, Varvara PETROVA, Rob A. CAIRNS, Polina VIKHREVA, Sara NICOLAI, Alberto MARINI, Alexey A. ANTONOV, John LE QUESNE, Gerry MELINO, 2018. p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression. In: Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences. 115(46), pp. E10869-E10878. ISSN 0027-8424. eISSN 1091-6490. Available under: doi: 10.1073/pnas.1808314115

@article{Amelio2018mutan-57060, title={p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression}, year={2018}, doi={10.1073/pnas.1808314115}, number={46}, volume={115}, issn={0027-8424}, journal={Proceedings of the National Academy of Sciences of the United States of America}, pages={E10869--E10878}, author={Amelio, Ivano and Mancini, Mara and Petrova, Varvara and Cairns, Rob A. and Vikhreva, Polina and Nicolai, Sara and Marini, Alberto and Antonov, Alexey A. and Le Quesne, John and Melino, Gerry} }

<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bibo="http://purl.org/ontology/bibo/" xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#" xmlns:foaf="http://xmlns.com/foaf/0.1/" xmlns:void="http://rdfs.org/ns/void#" xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > <rdf:Description rdf:about="https://kops.uni-konstanz.de/rdf/resource/123456789/57060"> <dc:creator>Mancini, Mara</dc:creator> <dc:creator>Amelio, Ivano</dc:creator> <dc:creator>Petrova, Varvara</dc:creator> <dc:contributor>Vikhreva, Polina</dc:contributor> <dc:contributor>Mancini, Mara</dc:contributor> <dc:creator>Marini, Alberto</dc:creator> <dcterms:rights rdf:resource="http://creativecommons.org/licenses/by-nc-nd/4.0/"/> <dcterms:title>p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression</dcterms:title> <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/57060"/> <dc:contributor>Marini, Alberto</dc:contributor> <dc:contributor>Antonov, Alexey A.</dc:contributor> <dc:creator>Vikhreva, Polina</dc:creator> <dc:creator>Melino, Gerry</dc:creator> <dc:contributor>Nicolai, Sara</dc:contributor> <dc:creator>Antonov, Alexey A.</dc:creator> <foaf:homepage rdf:resource="http://localhost:8080/jspui"/> <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <dc:contributor>Petrova, Varvara</dc:contributor> <dc:creator>Nicolai, Sara</dc:creator> <dc:contributor>Amelio, Ivano</dc:contributor> <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <dc:rights>Attribution-NonCommercial-NoDerivatives 4.0 International</dc:rights> <dc:contributor>Le Quesne, John</dc:contributor> <dcterms:abstract xml:lang="eng">Mutations in the TP53 gene and microenvironmentally driven activation of hypoxia-inducible factor-1 (HIF-1) typically occur in later stages of tumorigenesis. An ongoing challenge is the identification of molecular determinants of advanced cancer pathogenesis to design alternative last-line therapeutic options. Here, we report that p53 mutants influence the tumor microenvironment by cooperating with HIF-1 to promote cancer progression. We demonstrate that in non-small cell lung cancer (NSCLC), p53 mutants exert a gain-of-function (GOF) effect on HIF-1, thus regulating a selective gene expression signature involved in protumorigenic functions. Hypoxia-mediated activation of HIF-1 leads to the formation of a p53 mutant/HIF-1 complex that physically binds the SWI/SNF chromatin remodeling complex, promoting expression of a selective subset of hypoxia-responsive genes. Depletion of p53 mutants impairs the HIF-mediated up-regulation of extracellular matrix (ECM) components, including type VIIa1 collagen and laminin-γ2, thus affecting tumorigenic potential of NSCLC cells in vitro and in mouse models in vivo. Analysis of surgically resected human NSCLC revealed that expression of this ECM gene signature was highly correlated with hypoxic tumors exclusively in patients carrying p53 mutations and was associated with poor prognosis. Our data reveal a GOF effect of p53 mutants in hypoxic tumors and suggest synergistic activities of p53 and HIF-1. These findings have important implications for cancer progression and might provide innovative last-line treatment options for advanced NSCLC.</dcterms:abstract> <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/> <dc:contributor>Cairns, Rob A.</dc:contributor> <dc:contributor>Melino, Gerry</dc:contributor> <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2022-03-30T07:30:02Z</dc:date> <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/57060/1/Amelio_2-1sg916xx4uyu95.pdf"/> <dc:creator>Le Quesne, John</dc:creator> <dc:creator>Cairns, Rob A.</dc:creator> <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/57060/1/Amelio_2-1sg916xx4uyu95.pdf"/> <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2022-03-30T07:30:02Z</dcterms:available> <dc:language>eng</dc:language> <dcterms:issued>2018</dcterms:issued> </rdf:Description> </rdf:RDF>

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