Transforming Activity of MECT1-MAML2 Fusion Oncoprotein is Mediated by Constitutive CREB Activation

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2005 Jun 18

PMID 15961999

Citations 60

Authors

Lizi Wu

Jingxuan Liu

Ping Gao

Makoto Nakamura

Yang Cao

Huangxuan Shen

James D Griffin

Affiliations

Soon will be listed here.

Abstract

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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