Anovel ubiquitin ligase, which targets TSLC-1

在本研究中，我们探讨了以Notch配体和TSLC1为靶点的瘦骨素的病理生物学特性。有趣的是，瘦骨素介导的单泛素化随后是靶表面膜蛋白的内吞作用。骨骼肌蛋白的CM/mina' RING motif，也被称为心智炸弹-2 (mib2)，是底物单泛素化所必需的。我们还确定了瘦素基因的启动子区域，并发现异常的高甲基化是导致恶性黑色素瘤和肺癌中瘦素表达沉默的原因。单泛素化后的内吞作用似乎在配体依赖性Notch激活中起重要作用。这些最近的发现可能表明，骨营养因子表达的异常或沉默通过癌间质相互作用促进了肿瘤的发展。我希望本研究结果能够为癌症-间质反应的基础认识做出贡献，并进一步发展恶性黑色素瘤和肺癌的新方法。

In the present study, we explore the pathobiological property of skeletrophin, which targets to Notch ligands and TSLC1. Interestingly, skeletrophin mediated mono-ubiquitination followed by endocytosis of the target surface membrane protein. CM/mina' RING motif of the skeletrophin, also described as mind bomb-2 (mib2), is necessary for monoubiquitination of the substrates. We also identified the promoter region of the skeletrophin gene and found that aberrant hypermethylation is responsible for silencing of skeletrophin expression in malignant melanoma and lung cancer. Monoubiquitination followed by the endocytosis appeared to play an important role of ligands-dependent Notch activation. These resent findings may indicated that aberrant or silencing of skeletrophin expression contribute the tumor development through cancer-stromal interaction.I expect that the present findings may contribute the fundamental understandings of cancer-stromal reaction, further develop the new approach for malignant melanoma and lung cancer.