Transforming activity of MECT1-MAML2 fusion oncoprotein is mediated by constitutive CREB activation.
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.
Wu
Lizi
L
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. lizi_wu@dfci.harvard.edu
Liu
Jingxuan
J
Gao
Ping
P
Nakamura
Makoto
M
Cao
Yang
Y
Shen
Huangxuan
H
Griffin
James D
JD
D002453:Cell Cycle; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D000242:Cyclic AMP / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C495418:MECT1-MAML2 fusion protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D014157:Transcription Factors; D000242:Cyclic AMP