Identification of Y-box binding protein 1 as a core regulator of MEK/ERK pathway-dependent gene signatures in colorectal cancer cells.
Transcriptional signatures are an indispensible source of correlative information on disease-related molecular alterations on a genome-wide level. Numerous candidate genes involved in disease and in factors of predictive, as well as of prognostic, value have been deduced from such molecular portrait...
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Public Library of Science (PLoS)
2010-12-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1001231&type=printable |
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| author | Karsten Jürchott Ralf-Jürgen Kuban Till Krech Nils Blüthgen Ulrike Stein Wolfgang Walther Christian Friese Szymon M Kiełbasa Ute Ungethüm Per Lund Thomas Knösel Wolfgang Kemmner Markus Morkel Johannes Fritzmann Peter M Schlag Walter Birchmeier Tammo Krueger Silke Sperling Christine Sers Hans-Dieter Royer Hanspeter Herzel Reinhold Schäfer |
| author_facet | Karsten Jürchott Ralf-Jürgen Kuban Till Krech Nils Blüthgen Ulrike Stein Wolfgang Walther Christian Friese Szymon M Kiełbasa Ute Ungethüm Per Lund Thomas Knösel Wolfgang Kemmner Markus Morkel Johannes Fritzmann Peter M Schlag Walter Birchmeier Tammo Krueger Silke Sperling Christine Sers Hans-Dieter Royer Hanspeter Herzel Reinhold Schäfer |
| author_sort | Karsten Jürchott |
| collection | DOAJ |
| description | Transcriptional signatures are an indispensible source of correlative information on disease-related molecular alterations on a genome-wide level. Numerous candidate genes involved in disease and in factors of predictive, as well as of prognostic, value have been deduced from such molecular portraits, e.g. in cancer. However, mechanistic insights into the regulatory principles governing global transcriptional changes are lagging behind extensive compilations of deregulated genes. To identify regulators of transcriptome alterations, we used an integrated approach combining transcriptional profiling of colorectal cancer cell lines treated with inhibitors targeting the receptor tyrosine kinase (RTK)/RAS/mitogen-activated protein kinase pathway, computational prediction of regulatory elements in promoters of co-regulated genes, chromatin-based and functional cellular assays. We identified commonly co-regulated, proliferation-associated target genes that respond to the MAPK pathway. We recognized E2F and NFY transcription factor binding sites as prevalent motifs in those pathway-responsive genes and confirmed the predicted regulatory role of Y-box binding protein 1 (YBX1) by reporter gene, gel shift, and chromatin immunoprecipitation assays. We also validated the MAPK-dependent gene signature in colorectal cancers and provided evidence for the association of YBX1 with poor prognosis in colorectal cancer patients. This suggests that MEK/ERK-dependent, YBX1-regulated target genes are involved in executing malignant properties. |
| format | Article |
| id | doaj-art-374dde0b6ad640c3b6dc0984ca6ebe07 |
| institution | DOAJ |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2010-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-374dde0b6ad640c3b6dc0984ca6ebe072025-08-20T03:00:57ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042010-12-01612e100123110.1371/journal.pgen.1001231Identification of Y-box binding protein 1 as a core regulator of MEK/ERK pathway-dependent gene signatures in colorectal cancer cells.Karsten JürchottRalf-Jürgen KubanTill KrechNils BlüthgenUlrike SteinWolfgang WaltherChristian FrieseSzymon M KiełbasaUte UngethümPer LundThomas KnöselWolfgang KemmnerMarkus MorkelJohannes FritzmannPeter M SchlagWalter BirchmeierTammo KruegerSilke SperlingChristine SersHans-Dieter RoyerHanspeter HerzelReinhold SchäferTranscriptional signatures are an indispensible source of correlative information on disease-related molecular alterations on a genome-wide level. Numerous candidate genes involved in disease and in factors of predictive, as well as of prognostic, value have been deduced from such molecular portraits, e.g. in cancer. However, mechanistic insights into the regulatory principles governing global transcriptional changes are lagging behind extensive compilations of deregulated genes. To identify regulators of transcriptome alterations, we used an integrated approach combining transcriptional profiling of colorectal cancer cell lines treated with inhibitors targeting the receptor tyrosine kinase (RTK)/RAS/mitogen-activated protein kinase pathway, computational prediction of regulatory elements in promoters of co-regulated genes, chromatin-based and functional cellular assays. We identified commonly co-regulated, proliferation-associated target genes that respond to the MAPK pathway. We recognized E2F and NFY transcription factor binding sites as prevalent motifs in those pathway-responsive genes and confirmed the predicted regulatory role of Y-box binding protein 1 (YBX1) by reporter gene, gel shift, and chromatin immunoprecipitation assays. We also validated the MAPK-dependent gene signature in colorectal cancers and provided evidence for the association of YBX1 with poor prognosis in colorectal cancer patients. This suggests that MEK/ERK-dependent, YBX1-regulated target genes are involved in executing malignant properties.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1001231&type=printable |
| spellingShingle | Karsten Jürchott Ralf-Jürgen Kuban Till Krech Nils Blüthgen Ulrike Stein Wolfgang Walther Christian Friese Szymon M Kiełbasa Ute Ungethüm Per Lund Thomas Knösel Wolfgang Kemmner Markus Morkel Johannes Fritzmann Peter M Schlag Walter Birchmeier Tammo Krueger Silke Sperling Christine Sers Hans-Dieter Royer Hanspeter Herzel Reinhold Schäfer Identification of Y-box binding protein 1 as a core regulator of MEK/ERK pathway-dependent gene signatures in colorectal cancer cells. PLoS Genetics |
| title | Identification of Y-box binding protein 1 as a core regulator of MEK/ERK pathway-dependent gene signatures in colorectal cancer cells. |
| title_full | Identification of Y-box binding protein 1 as a core regulator of MEK/ERK pathway-dependent gene signatures in colorectal cancer cells. |
| title_fullStr | Identification of Y-box binding protein 1 as a core regulator of MEK/ERK pathway-dependent gene signatures in colorectal cancer cells. |
| title_full_unstemmed | Identification of Y-box binding protein 1 as a core regulator of MEK/ERK pathway-dependent gene signatures in colorectal cancer cells. |
| title_short | Identification of Y-box binding protein 1 as a core regulator of MEK/ERK pathway-dependent gene signatures in colorectal cancer cells. |
| title_sort | identification of y box binding protein 1 as a core regulator of mek erk pathway dependent gene signatures in colorectal cancer cells |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1001231&type=printable |
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