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Sökning: WFRF:(Plaza J.) > (2005-2009) > Ras/ERK1/2-mediated...

  • Plaza-Menacho, IvánDepartment of Genetics, Hanzeplein 1, 9700 RB, Groningen, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands / Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, United Kingdom (författare)

Ras/ERK1/2-mediated STAT3 Ser727 phosphorylation by familial medullary thyroid carcinoma-associated RET mutants induces full activation of STAT3 and is required for c-fos promoter activation, cell mitogenicity, and transformation.

  • Artikel/kapitelEngelska2007

Förlag, utgivningsår, omfång ...

  • 2007
  • printrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:liu-101872
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-101872URI
  • https://doi.org/10.1074/jbc.M608952200DOI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • The precise role of STAT3 Ser(727) phosphorylation in RET-mediated cell transformation and oncogenesis is not well understood. In this study, we have shown that familial medullary thyroid carcinoma (FMTC) mutants RET(Y791F) and RET(S891A) induced, in addition to Tyr(705) phosphorylation, constitutive STAT3 Ser(727) phosphorylation. Using inhibitors and dominant negative constructs, we have demonstrated that RET(Y791F) and RET(S891A) induce STAT3 Ser(727) phosphorylation via a canonical Ras/ERK1/2 pathway and that integration of the Ras/ERK1/2/ELK-1 and STAT3 pathways was required for up-regulation of the c-fos promoter by FMTC-RET. Moreover, inhibition of ERK1/2 had a more severe effect on cell proliferation and cell phenotype in HEK293 cells expressing RET(S891A) compared with control and RET(WT)-transfected cells. The transforming activity of RET(Y791F) and RET(S891A) in NIH-3T3 cells was also inhibited by U0126, indicating a role of the ERK1/2 pathway in RET-mediated transformation. To investigate the biological significance of Ras/ERK1/2-induced STAT3 Ser(727) phosphorylation for cell proliferation and transformation, N-Ras-transformed NIH-3T3 cells were employed. These cells displayed elevated levels of activated ERK1/2 and Ser(727)-phosphorylated STAT3, which were inhibited by treatment with U0126. Importantly, overexpression of STAT3, in which the Ser(727) was mutated into Ala (STAT3(S727A)), rescued the transformed phenotype of N-Ras-transformed cells. Immunohistochemistry in tumor samples from FMTC patients showed strong nuclear staining of phosphorylated ERK1/2 and Ser(727) STAT3. These data show that FMTC-RET mutants activate a Ras/ERK1/2/STAT3 Ser(727) pathway, which plays an important role in cell mitogenicity and transformation.

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • van der Sluis, TinekeDepartment of Pathology, Hanzeplein 1, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands (författare)
  • Hollema, HarryDepartment of Pathology, Hanzeplein 1, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands (författare)
  • Gimm, OliverDepartment of Surgery, Martin Luther University, Ernst Grube Strasse 40, 06097 Halle-Wittenberg, Germany(Swepub:liu)oligi51 (författare)
  • Buys, Charles H C MDepartment of Genetics, Hanzeplein 1, 9700 RB, Groningen, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands (författare)
  • Magee, Anthony ISection of Molecular and Cellular Medicine, Imperial College, London SW7 2AZ, United Kingdom (författare)
  • Isacke, Clare MBreakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, United Kingdom (författare)
  • Hofstra, Robert M WDepartment of Genetics, Hanzeplein 1, 9700 RB, Groningen, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands (författare)
  • Eggen, Bart J LDevelopmental Genetics, Groningen Biomolecular Science and Biotechnology Institute, University of Groningen, Kerklaan 30, 9751 NN Haren, The Netherlands (författare)
  • Department of Genetics, Hanzeplein 1, 9700 RB, Groningen, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands / Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, United KingdomDepartment of Pathology, Hanzeplein 1, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Journal of Biological Chemistry282:9, s. 6415-240021-92581083-351X

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