role of stat3 in in vitro transformation triggered by trk oncogenesstat3在体外转换触发trk致癌基因.pdfVIP

Role of STAT3 in In Vitro Transformation Triggered by TRK Oncogenes 1 1 1 1 1 Claudia Miranda *, Tiziana Fumagalli , Maria Chiara Anania , Maria Grazia Vizioli , Sonia Pagliardini , 2 1 Marco A. Pierotti , Angela Greco * 1 Operative Unit ‘‘Molecular Mechanisms’’, Department of Experimental Oncology and Molecular Medicine, IRCCS Foundation, Istituto Nazionale dei Tumori, Milan, Italy, 2 Scientific Directorate, IRCCS Foundation, Istituto Nazionale dei Tumori, Milan, Italy Abstract TRK oncoproteins are chimeric versions of the NTRK1/NGF receptor and display constitutive tyrosine kinase activity leading to transformation of NIH3T3 cells and neuronal differentiation of PC12 cells. Signal Transducer and Activator of Transcription (STAT) 3 is activated in response to cytokines and growth factors and it has been recently identified as a novel signal transducer for TrkA, mediating the functions of NGF in nervous system. In this paper we have investigated STAT3 involvement in signalling induced by TRK oncogenes. We showed that TRK oncogenes trigger STAT3 phosphorylation both on Y705 and S727 residues and STAT3 transcriptional activity. MAPK pathway was involved in the induction of STAT3 phosphorylation. Interestingly, we have shown reduced STAT3 protein level in NIH3T3 transformed foci expressing TRK oncogenes. Overall, we have unveiled a dual role for STAT3 in TRK oncogenes-induced NIH3T3 transformation: i) decreased STAT3 protein levels, driven by TRK oncoproteins activity, are associated to morphological transformation; ii) residual STAT3 transcriptional activity is required for cell growth. Citation: Mir