Oncogene database

23373

CRTC1

CREB regulated transcription coactivator 1;CRTC1;CREB regulated transcription coactivator 1

CREB-regulated transcription coactivator 1|mucoepidermoid carcinoma translocated protein 1|transducer of regulated cAMP response element-binding protein (CREB) 1

19p13.11

protein-coding

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.

Malignant salivary gland tumors can arise from a t(11;19) translocation that fuses 42 residues from Mect1/Torc1, a cyclic AMP (cAMP)/cAMP-responsive element binding protein (CREB)-dependent transcriptional coactivator, with 982 residues from Maml2, a NOTCH receptor coactivator. To determine if the Mect1-Maml2 fusion oncogene mediates tumorigenicity by disrupting cAMP/CREB signaling, we have generated in-frame deletions within the CREB-binding domain of Mect1/Torc1 for testing transformation activity and have also developed a doxycycline-regulated Mect1-Maml2 mammalian expression vector for global gene expression profiling. We observed that small deletions within the CREB-binding domain completely abolished transforming activity in RK3E epithelial cells. Further, we have shown that the ectopic induction of Mect1-Maml2 in HeLa cells strongly activated the expression of a group of known cAMP/CREB-regulated genes. In addition, we detected candidate cAMP-responsive element sites within 100 nucleotides of the transcriptional start sites of other genes activated by Mect1-Maml2 expression. In contrast, we did not observe alterations of known Notch-regulated target genes in these expression array profile experiments. We validated the results by reverse transcription-PCR in transfected HeLa, RK3E, and H2009 lung tumor cells and in mucoepidermoid cancer cells that endogenously express the fusion oncopeptide. Whereas overexpression of components of the cAMP pathway has been associated with a subset of human carcinomas, these data provide a direct genetic link between deregulation of cAMP/CREB pathways and epithelial tumorigenesis and suggest future therapeutic strategies for this group of salivary gland tumors.

Mucoepidermoid carcinomas (MECs) of the salivary and bronchial glands are characterized by a recurrent t(11;19)(q21;p13) translocation resulting in a MECT1-MAML2 fusion in which the CREB-binding domain of the CREB coactivator MECT1 (also known as CRTC1, TORC1 or WAMTP1) is fused to the transactivation domain of the Notch coactivator MAML2. To gain further insights into the molecular pathogenesis of MECs, we cytogenetically and molecularly characterized a series of 29 MECs. A t(11;19) and/or an MECT1-MAML2 fusion was detected in more than 55% of the tumors. Several cases with cryptic rearrangements that resulted in gene fusions were detected. In fusion-negative MECs, the most common aberration was a single or multiple trisomies. Western blot and immunohistochemical studies demonstrated that the MECT1-MAML2 fusion protein was expressed in ALL MEC-specific cell types. In addition, cotransfection experiments showed that the fusion protein colocalized with CREB in homogeneously distributed nuclear granules. Analyses of potential downstream targets of the fusion revealed differential expression of the cAMP/CREB (FLT1 and NR4A2) and Notch (HES1 and HES5) target genes in fusion-positive and fusion-negative MECs. Moreover, clinical follow-up studies revealed that fusion-positive patients had a significantly lower risk of local recurrence, metastases, or tumor-related death compared to fusion-negative patients (P = 0.0012). When considering tumor-related deaths only, the estimated median survival for fusion-positive patients was greater than 10 years compared to 1.6 years for fusion-negative patients. These findings suggest that molecularly classifying MECs on the basis of an MECT1-MAML2 fusion is histopathologically and clinically relevant and that the fusion is a useful marker in predicting the biological behavior of MECs.

Mucoepidermoid carcinoma (MEC) is a relatively uncommon carcinoma of variable histology that can involve many tissue types, most commonly major and minor salivary glands and the tracheo-bronchial tree. In a significant number of cases a recurring t(11;19) translocation with an associated novel fusion oncogene (CRTC1-MAML2) is present. This translocation is also found in Warthin s tumour and clear cell hidradenoma of the skin. The CRTC1-MAML2 oncogene acts as a transcription factor on Notch and CREB regulatory pathways, disrupting normal cell-cycle and differentiation, contributing to tumour development. Data suggest that in MEC, the presence of CRTC1-MAML2 may have some prognostic value. An understanding of these mechanisms extends our knowledge of the role of fusion oncogenes in epithelial malignancy. A review of CRTC1-MAML2 in MEC is presented.

Recent reports of a clinical response to gefitinib in pulmonary mucoepidermoid carcinoma (MEC) in the absence of sensitizing EGFR mutations suggest that tyrosine kinase inhibitors (TKIs) may be effective in this tumor type. Although not documented in these reports, MEC of the lung may harbor a t(11;19) translocation with an associated novel fusion oncogene (CRTC1-MAML2). Furthermore, MECs arising in the salivary glands carry this mutation in a high proportion of cases. In vitro data has shown that MEC cell-lines with t(11;19) are sensitive to gefitinib and that this may be mediated by the action of CRTC1-MAML2 in up-regulating the EGFR ligand, amphiregulin. Data also shows that gefitinib demonstrates amphiregulin-dependant activity in NSCLC cell-lines. As such, it may be speculated that MEC from lung and salivary glands expressing CRTC1-MAML2 present a valid target for treatment with gefitinib, even in the absence of sensitizing EGFR mutations. Clinical studies are required to test this hypothesis.