Molecular basis of crosstalk between oncogenic Ras and the master regulator of hematopoiesis GATA-2
Identifieur interne : 002D93 ( Pmc/Curation ); précédent : 002D92; suivant : 002D94Molecular basis of crosstalk between oncogenic Ras and the master regulator of hematopoiesis GATA-2
Auteurs : Koichi R. Katsumura [États-Unis] ; Chenxi Yang [États-Unis] ; Meghan E. Boyer [États-Unis] ; Lingjun Li [États-Unis] ; Emery H. Bresnick [États-Unis]Source :
- EMBO Reports [ 1469-221X ] ; 2014.
Abstract
Disease mutations provide unique opportunities to decipher protein and cell function. Mutations in the master regulator of hematopoiesis GATA-2 underlie an immunodeficiency associated with myelodysplastic syndrome and leukemia. We discovered that a GATA-2 disease mutant (T354M) defective in chromatin binding was hyperphosphorylated by p38 mitogen-activated protein kinase. p38 also induced multisite phosphorylation of wild-type GATA-2, which required a single phosphorylated residue (S192). Phosphorylation of GATA-2, but not T354M, stimulated target gene expression. While crosstalk between oncogenic Ras and GATA-2 has been implicated as an important axis in cancer biology, its mechanistic underpinnings are unclear. Oncogenic Ras enhanced S192-dependent GATA-2 phosphorylation, nuclear foci localization, and transcriptional activation. These studies define a mechanism that controls a key regulator of hematopoiesis and a dual mode of impairing GATA-2-dependent genetic networks: mutational disruption of chromatin occupancy yielding insufficient GATA-2, and oncogenic Ras-mediated amplification of GATA-2 activity.
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DOI: 10.15252/embr.201438808
PubMed: 25056917
PubMed Central: 4198037
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Boyer</name><affiliation wicri:level="1"><nlm:aff id="au1"><institution>UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Carbone Cancer Center, Wisconsin Institutes for Medical Research, University of Wisconsin School of Medicine and Public Health</institution><addr-line>Madison, WI, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Madison, WI</wicri:regionArea></affiliation></author><author><name sortKey="Li, Lingjun" sort="Li, Lingjun" uniqKey="Li L" first="Lingjun" last="Li">Lingjun Li</name><affiliation wicri:level="1"><nlm:aff id="au2"><institution>Department of Chemistry, University of Wisconsin</institution><addr-line>Madison, WI, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Madison, WI</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="au3"><institution>University of Wisconsin School of Pharmacy</institution><addr-line>Madison, WI, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Madison, WI</wicri:regionArea></affiliation></author><author><name sortKey="Bresnick, Emery H" sort="Bresnick, Emery H" uniqKey="Bresnick E" first="Emery H" last="Bresnick">Emery H. Bresnick</name><affiliation wicri:level="1"><nlm:aff id="au1"><institution>UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Carbone Cancer Center, Wisconsin Institutes for Medical Research, University of Wisconsin School of Medicine and Public Health</institution><addr-line>Madison, WI, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Madison, WI</wicri:regionArea></affiliation></author></analytic><series><title level="j">EMBO Reports</title><idno type="ISSN">1469-221X</idno><idno type="eISSN">1469-3178</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Disease mutations provide unique opportunities to decipher protein and cell function. Mutations in the master regulator of hematopoiesis GATA-2 underlie an immunodeficiency associated with myelodysplastic syndrome and leukemia. We discovered that a GATA-2 disease mutant (T354M) defective in chromatin binding was hyperphosphorylated by p38 mitogen-activated protein kinase. p38 also induced multisite phosphorylation of wild-type GATA-2, which required a single phosphorylated residue (S192). Phosphorylation of GATA-2, but not T354M, stimulated target gene expression. While crosstalk between oncogenic Ras and GATA-2 has been implicated as an important axis in cancer biology, its mechanistic underpinnings are unclear. Oncogenic Ras enhanced S192-dependent GATA-2 phosphorylation, nuclear foci localization, and transcriptional activation. These studies define a mechanism that controls a key regulator of hematopoiesis and a dual mode of impairing GATA-2-dependent genetic networks: mutational disruption of chromatin occupancy yielding insufficient GATA-2, and oncogenic Ras-mediated amplification of GATA-2 activity.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">EMBO Rep</journal-id><journal-id journal-id-type="iso-abbrev">EMBO Rep</journal-id><journal-id journal-id-type="publisher-id">embr</journal-id><journal-title-group><journal-title>EMBO Reports</journal-title></journal-title-group><issn pub-type="ppub">1469-221X</issn><issn pub-type="epub">1469-3178</issn><publisher><publisher-name>BlackWell Publishing Ltd</publisher-name><publisher-loc>Oxford, UK</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25056917</article-id><article-id pub-id-type="pmc">4198037</article-id><article-id pub-id-type="doi">10.15252/embr.201438808</article-id><article-categories><subj-group subj-group-type="heading"><subject>Scientific Reports</subject></subj-group></article-categories><title-group><article-title>Molecular basis of crosstalk between oncogenic Ras and the master regulator of hematopoiesis GATA-2</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Katsumura</surname><given-names>Koichi R</given-names></name><xref ref-type="aff" rid="au1">1</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Chenxi</given-names></name><xref ref-type="aff" rid="au2">2</xref></contrib><contrib contrib-type="author"><name><surname>Boyer</surname><given-names>Meghan E</given-names></name><xref ref-type="aff" rid="au1">1</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Lingjun</given-names></name><xref ref-type="aff" rid="au2">2</xref><xref ref-type="aff" rid="au3">3</xref></contrib><contrib contrib-type="author"><name><surname>Bresnick</surname><given-names>Emery H</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><aff id="au1"><label>1</label><institution>UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Carbone Cancer Center, Wisconsin Institutes for Medical Research, University of Wisconsin School of Medicine and Public Health</institution><addr-line>Madison, WI, USA</addr-line></aff><aff id="au2"><label>2</label><institution>Department of Chemistry, University of Wisconsin</institution><addr-line>Madison, WI, USA</addr-line></aff><aff id="au3"><label>3</label><institution>University of Wisconsin School of Pharmacy</institution><addr-line>Madison, WI, USA</addr-line></aff></contrib-group><author-notes><corresp id="cor1">*Corresponding author. Tel: +1 608 265 6446; E-mail: <email>ehbresni@wisc.edu</email></corresp></author-notes><pub-date pub-type="ppub"><month>9</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>23</day><month>7</month><year>2014</year></pub-date><volume>15</volume><issue>9</issue><fpage>938</fpage><lpage>947</lpage><history><date date-type="received"><day>21</day><month>3</month><year>2014</year></date><date date-type="rev-recd"><day>19</day><month>6</month><year>2014</year></date><date date-type="accepted"><day>23</day><month>6</month><year>2014</year></date></history><permissions><copyright-statement>© 2014 The Authors</copyright-statement><copyright-year>2014</copyright-year></permissions><abstract><p>Disease mutations provide unique opportunities to decipher protein and cell function. Mutations in the master regulator of hematopoiesis GATA-2 underlie an immunodeficiency associated with myelodysplastic syndrome and leukemia. We discovered that a GATA-2 disease mutant (T354M) defective in chromatin binding was hyperphosphorylated by p38 mitogen-activated protein kinase. p38 also induced multisite phosphorylation of wild-type GATA-2, which required a single phosphorylated residue (S192). Phosphorylation of GATA-2, but not T354M, stimulated target gene expression. While crosstalk between oncogenic Ras and GATA-2 has been implicated as an important axis in cancer biology, its mechanistic underpinnings are unclear. Oncogenic Ras enhanced S192-dependent GATA-2 phosphorylation, nuclear foci localization, and transcriptional activation. These studies define a mechanism that controls a key regulator of hematopoiesis and a dual mode of impairing GATA-2-dependent genetic networks: mutational disruption of chromatin occupancy yielding insufficient GATA-2, and oncogenic Ras-mediated amplification of GATA-2 activity.</p></abstract><kwd-group><kwd>GATA factor</kwd><kwd>GATA-2</kwd><kwd>p38</kwd><kwd>Ras</kwd><kwd>transcription</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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