Unmasking the mammalian SET domain-containing protein 4.
Unmasking the mammalian SET domain-containing protein 4.
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SET结构域蛋白4 （SETD4）是一类独特的蛋白质赖氨酸甲基转移酶的成员。本文介绍了SETD4的基本特征，总结了近年来研究的主要发现，重点介绍了SETD4在组织发育和肿瘤发生中的作用及其甲基化底物。SETD4在干细胞/祖细胞中表达。消融Setd4+细胞会阻碍胰腺损伤后腺泡细胞的再生。小鼠Setd4缺失通过增强骨髓生态位功能，促进放射诱导的骨髓（BM）衰竭的恢复，促进心脏内皮细胞的生成和毛细血管新生，增强BM间充质干细胞的增殖，破坏BM源性巨噬细胞的TLR4信号。SETD4的表达也与静止乳腺癌干细胞的维持有关。虽然小鼠敲除Setd4会延迟辐射诱导的t淋巴瘤的形成，但在一些增生性癌细胞中观察到Setd4表达升高，并与促进生存的潜力有关。虽然罕见，但SETD4的致癌融合也在癌症中被发现。此外，SETD4在KU70的c端球状结构域甲基化赖氨酸-570，使KU70易位到细胞质，从而抑制细胞凋亡。
SET domain-containing protein 4 (SETD4) is a member of a unique class of protein lysine methyltransferases. Here, we introduce the basic features of SETD4 and summarize the key findings from recent studies with emphases on its roles in tissue development and tumorigenesis, and its methylation substrates. SETD4 is expressed in stem/progenitor cells. Ablation of Setd4+ cells impedes the repopulation of acinar cells after pancreatic injury. Setd4 deletion in mice promotes the recovery of radiation-induced bone marrow (BM) failure by boosting the function of BM niche, facilitates the generation of endothelial cells and neovascularization of capillary vessels in the heart, enhances the proliferation of BM mesenchymal stem cells and disrupts the TLR4 signaling in BM-derived macrophages. SETD4 expression is also associated with the maintenance of quiescent breast cancer stem cells. While mouse Setd4 knockout delays radiation-induced T-lymphoma formation, elevated SETD4 expression has been observed in some proliferative cancer cells and is associated with a pro-survival potential. Oncogenic fusions of SETD4 have also been identified in cancer, albeit rare. In addition, SETD4 methylates lysine-570 in the C-terminal globular domain of KU70, which enables KU70 translocation to cytoplasm to suppress apoptosis.