Mect1-maml2 fusion oncogene linked to the aberrant activation of cyclic AMP/CREB regulated genes
Mect1-maml2 fusion oncogene linked to the aberrant activation of cyclic AMP/CREB regulated genes
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DOI：
10.1158/0008-5472.can-05-1125
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发表时间：
2005-08-15
期刊：
影响因子：
11.2
通讯作者：
Kaye, FJ
中科院分区：
文献类型：
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作者：
Coxon, A;Rozenblum, E;Kaye, FJ
恶性涎腺肿瘤可能源于t(11；19)易位，该易位融合了Mect1/Torc1的42个残基，Mect1/Torc1是一种依赖于cAMP(CAMP)/cAMP反应元件结合蛋白(CREB)的转录共激活因子，而Mam12是一种缺口受体共激活因子，其982个残基融合在一起。为了确定Mect1-Mam12融合癌基因是否通过干扰cAMP/CREB信号而介导肿瘤发生，我们在Mect1/Torc1的CREB结合域中产生了框内缺失以测试转化活性，并开发了用于全球基因表达谱的多西环素调控的Mect1-Mam12哺乳动物表达载体。我们观察到，CREB结合域中的微小缺失完全取消了RK3E上皮细胞的转化活性。此外，我们已经证明，在HeLa细胞中异位诱导Mect1-Mam12强烈激活了一组已知的cAMP/CREB调节基因的表达。此外，我们在Mect1-Mam12表达激活的其他基因的转录起始点的100个核苷酸内检测到候选的cAMP反应元件位点。相反，在这些表达阵列图谱实验中，我们没有观察到已知的Notch调控的靶基因的变化。我们在HeLa、RK3E和H2009肺癌细胞以及内源性表达融合多肽的粘液表皮样癌细胞中通过逆转录-聚合酶链式反应验证了结果。虽然cAMP通路成分的过度表达与人类癌症的亚组分有关，但这些数据提供了cAMP/CREB通路的解除调控与上皮肿瘤发生之间的直接遗传联系，并建议了这组唾液腺肿瘤的未来治疗策略。
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 Mam12, a NOTCH receptor coactivator. To determine if the Mect1-Mam12 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-Mam12 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-Mam12 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-Mam12 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.