Endothelial deletion of Sag/Rbx2/Roc2 E3 ubiquitin ligase causes embryonic lethality and blocks tumor angiogenesis.
Endothelial deletion of Sag/Rbx2/Roc2 E3 ubiquitin ligase causes embryonic lethality and blocks tumor angiogenesis.
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SAG（细胞凋亡敏感基因），也称为 RBX2 或 ROC2，是 Cullin-RING 连接酶 (CRL) 活性所需的 RING 蛋白。我们最近的研究表明，Sag 完全敲除会导致 E11.5-12.5 天的胚胎死亡，并伴有血管生成的相关缺陷。 Sag 是否是胚胎血管新生和肿瘤血管生成所必需的尚不清楚。在这里，我们报告 Sag 内皮缺失也会导致 E15.5 胚胎死亡，血管生成不良。原代内皮细胞中的下垂缺失或 MS-1 内皮细胞中的敲低会抑制迁移、增殖和管形成，其中 p27 积累负责抑制迁移和增殖。此外，Sag 缺失显着抑制体内基质胶塞测定中的血管生成，以及 B16F10 黑色素瘤模型中的肿瘤血管生成和肿瘤发生。最后，MLN4924 是一种正在研究的 NEDD8 激活酶 (NAE) 小分子抑制剂，可抑制 CRL，抑制体外迁移、增殖和管形成，以及体内血管生成和肿瘤发生。总而言之，我们的研究使用遗传和药物方法，证明了 Sag 对于胚胎血管生成和肿瘤血管生成至关重要，并提供了概念验证证据，表明靶向 Sag E3 泛素连接酶可能对人类癌症的抗血管生成治疗具有临床价值。
SAG (Sensitive to Apoptosis Gene), also known as RBX2 or ROC2, is a RING protein required for the activity of Cullin-RING ligase (CRL). Our recent study showed that Sag total knockout caused embryonic lethality at E11.5–12.5 days with associated defects in vasculogenesis. Whether Sag is required for de novo vasculogenesis in embryos and angiogenesis in tumors is totally unknown. Here, we report that Sag endothelial deletion also causes embryonic lethality at E15.5 with poor vasculogenesis. Sag deletion in primary endothelial cells or knockdown in MS-1 endothelial cells inhibits migration, proliferation and tube formation with p27 accumulation being responsible for the suppression of migration and proliferation. Furthermore, Sag deletion significantly inhibits angiogenesis in an in vivo Matrigel plug assay, and tumor angiogenesis and tumorigenesis in a B16F10 melanoma model. Finally, MLN4924, an investigational small molecule inhibitor of NEDD8-activating enzyme (NAE) that inhibits CRL, suppresses in vitro migration, proliferation, and tube formation, as well as in vivo angiogenesis and tumorigenesis. Taken together, our study, using both genetic and pharmaceutical approaches, demonstrates that Sag is essential for embryonic vasculogenesis and tumor angiogenesis, and provides the proof-of-concept evidence that targeting Sag E3 ubiquitin ligase may have clinical value for anti-angiogenesis therapy of human cancer.
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影响因子：
64.5
作者：
Duda, David M.;Borg, Laura A.;Scott, Daniel C.;Hunt, Harold W.;Hammel, Michal;Schulman, Brenda A.
通讯作者：
Schulman, Brenda A.
影响因子：
7.8
作者：
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影响因子：
50.3
作者：
Baldassarre, G;Belletti, B;Colombatti, A
通讯作者：
Colombatti, A
影响因子：
8
作者：
Bockbrader, KM;Tan, MJ;Sun, Y
通讯作者：
Sun, Y
影响因子：
3
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Jia L;Sun Y
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