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| Subject Categories: Chromatin & Transcription | Molecular Biology of Disease |
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| The EMBO Journal
(2005) 24, 2391–2402, doi:10.1038/sj.emboj.7600719 Published online 16 June 2005 |
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| Transforming activity of MECT1-MAML2 fusion oncoprotein is mediated by constitutive CREB activation |
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| Lizi Wu1, 2, Jingxuan Liu1, 2, Ping Gao1, 2, Makoto Nakamura1, 2, Yang Cao1, 2, Huangxuan Shen1, 2 and James D Griffin1, 2 |
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1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 2 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA To whom correspondence should be addressed Lizi Wu, Department of Medical Oncology, Dana-Farber Cancer Institute, Mayer 540, 44 Binney Street, Boston, MA 02115, USA. Tel.: +1 617 632 5451; Fax: +1 617 632 4388; E-mail: lizi_wu@dfci.harvard.edu Received 12 November 2004; Accepted 26 May 2005; Published online 16 June 2005. |
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| Abstract |
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| Salivary gland tumors, a group of histologically diverse benign and malignant neoplasms, represent a challenging problem for diagnosis and treatment. A specific recurring t(11;19)(q21;p13) translocation is associated with two types of salivary gland tumors, mucoepidermoid carcinomas and Warthin's tumors. This translocation generates a fusion protein comprised of the N-terminal CREB (cAMP response element-binding protein)-binding domain of the CREB regulator MECT1 (Mucoepidermoid carcinoma translocated-1) and the C-terminal transcriptional activation domain of the Notch coactivator Mastermind-like 2 (MAML2). Here, we demonstrate that the MECT1-MAML2 fusion protein induces expression of multiple genes known to be CREB transcriptional targets. MECT1-MAML2 was found to bind to CREB, recruit p300/CBP into the CREB complex through a binding domain on MAML2, and constitutively activate CREB-dependent transcription. The transforming activity of MECT1-MAML2 was markedly reduced by blocking CREB DNA binding. Thus, this fusion oncogene mimics constitutive activation of cAMP signaling, by activating CREB directly. This study has identified a novel, critical mechanism of transformation for an oncogene associated very specifically with salivary gland tumors, and identified potential targets for the development of novel therapies. |
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| Keywords: CREB, MECT1-MAML2 fusion, mucoepidermoid carcinoma, transformation, Warthin's tumor |
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