Transforming activity of MECT1-MAML2 fusion oncoprotein is mediated by constitutive CREB activation
Transforming activity of MECT1-MAML2 fusion oncoprotein is mediated by constitutive CREB activation
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DOI：
10.1038/sj.emboj.7600719
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发表时间：
2005-07-06
期刊：
影响因子：
11.4
通讯作者：
Griffin, JD
中科院分区：
文献类型：
--
作者：
Wu, LZ;Liu, JX;Griffin, JD
涎腺肿瘤是一组组织学类型多样的良性和恶性肿瘤，其诊断和治疗一直是一个具有挑战性的问题。一种特异性的复发性t（11; 19）（q21; p13）易位与两种类型的涎腺肿瘤相关，粘液表皮样癌和沃辛瘤。该易位产生融合蛋白，其由CREB调节因子MECT 1（粘液表皮样癌易位-1）的N-末端CREB（cAMP反应元件结合蛋白）结合结构域和Notch共激活因子Mastermind样2（MAML 2）的C-末端转录激活结构域组成。在这里，我们证明了MECT 1-MAML 2融合蛋白诱导多个已知为CREB转录靶基因的表达。发现MECT 1-MAML 2与CREB结合，通过MAML 2上的结合结构域将p300/CBP募集到CREB复合物中，并组成性地激活CREB依赖性转录。通过阻断CREB DNA结合，MECT 1-MAML 2的转化活性显著降低。因此，这种融合癌基因通过直接激活CREB模拟cAMP信号传导的组成性激活。这项研究已经确定了一种新的，关键的转化机制的癌基因非常具体地与唾液腺肿瘤，并确定了潜在的目标，为发展新的疗法。
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.