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

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FältnamnIndikatorerMetadata
00004866naa a2200349 4500
001oai:DiVA.org:liu-101872
003SwePub
008131124s2007 | |||||||||||000 ||eng|
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-1018722 URI
0247 a https://doi.org/10.1074/jbc.M6089522002 DOI
040 a (SwePub)liu
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Plaza-Menacho, Ivánu 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 Kingdom4 aut
2451 0a 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.
264 1c 2007
338 a print2 rdacarrier
520 a 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.
7001 a van der Sluis, Tinekeu Department of Pathology, Hanzeplein 1, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands4 aut
7001 a Hollema, Harryu Department of Pathology, Hanzeplein 1, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands4 aut
7001 a Gimm, Oliveru Department of Surgery, Martin Luther University, Ernst Grube Strasse 40, 06097 Halle-Wittenberg, Germany4 aut0 (Swepub:liu)oligi51
7001 a Buys, Charles H C Mu Department of Genetics, Hanzeplein 1, 9700 RB, Groningen, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands4 aut
7001 a Magee, Anthony Iu Section of Molecular and Cellular Medicine, Imperial College, London SW7 2AZ, United Kingdom4 aut
7001 a Isacke, Clare Mu Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, United Kingdom4 aut
7001 a Hofstra, Robert M Wu Department of Genetics, Hanzeplein 1, 9700 RB, Groningen, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands4 aut
7001 a Eggen, Bart J Lu Developmental Genetics, Groningen Biomolecular Science and Biotechnology Institute, University of Groningen, Kerklaan 30, 9751 NN Haren, The Netherlands4 aut
7102 a 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 Kingdomb Department of Pathology, Hanzeplein 1, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands4 org
7730 t Journal of Biological Chemistryg 282:9, s. 6415-24q 282:9<6415-24x 0021-9258x 1083-351X
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-101872
8564 8u https://doi.org/10.1074/jbc.M608952200

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