Role of cereblon in angiogenesis and in mediating the antiangiogenic activity of immunomodulatory drugs.
Role of cereblon in angiogenesis and in mediating the antiangiogenic activity of immunomodulatory drugs.
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DOI：
10.1096/fj.201903060rr
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Figg WD
中科院分区：
文献类型：
--
作者：
Beedie SL;Huang PA;Harris EM;Strope JD;Mahony C;Chau CH;Vargesson N;Figg WD
Cereblon （CRBN）是E3 cullin 4-RING泛素连接酶复合物的底物招募元件，也是免疫调节剂（IMiDs）的结合靶点。CRBN对IMiDs的多效作用负责，但其在血管生成和介导IMiDs的抗血管生成作用中的功能尚不清楚。我们在体外研究了CRBN在血管生成过程中的作用，以及在IMiDs抗血管生成作用中的作用。在人内皮细胞（HUVEC和HMVEC-L）中，sirna介导的CRBN敲低不影响内皮细胞的增殖、迁移或管的形成。利用crbn缺陷小鼠，我们进一步证明了在离体小鼠主动脉环模型中，微血管形成可以独立于小脑发生。小脑E3泛素连接酶复合物可以招募内皮细胞特异性因子AGO2（与血管生成相关）和SALL4（与胚胎发生/血管生成相关），用于泛素介导的降解。CRBN的敲低引起AGO2和SALL4蛋白表达的相应增加，IMiD处理能够挽救siCRBN的作用，增加CRBN的表达。这些发现提示了一种潜在的作用机制，可能涉及到CRBN与内皮细胞靶点的紧密协调调节，并强调需要进一步阐明其机制，其中可能包括不依赖小脑的途径，IMiDs通过该途径发挥其抗血管生成作用。
Cereblon (CRBN) is a substrate recruiter element of the E3 cullin 4-RING ubiquitin ligase complex, and a binding target of immunomodulatory agents (IMiDs). CRBN is responsible for the pleiotropic effects of IMiDs, yet its function in angiogenesis and in mediating the antiangiogenic effects of IMiDs remains unclear. We investigated the role of CRBN in the angiogenic process and in propagating the antiangiogenic effects of IMiDs in vitro. siRNA-mediated CRBN knock down in human endothelial cells (HUVEC and HMVEC-L), did not affect endothelial cell proliferation, migration, or tube formation. Using CRBN-deficient mice, we further demonstrated that microvessal formation can occur independently of cereblon in the ex vivo mouse aortic ring model. The cereblon E3 ubiquitin ligase complex can recruit endothelial cell-specific factors, AGO2 (associated with angiogenesis), and SALL4 (associated with embryogenesis/angiogenesis), for ubiquitin-mediated degradation. Knockdown of CRBN caused a corresponding increase in AGO2 and SALL4 protein expression and IMiD treatment was able to rescue the siCRBN effect to increase the CRBN expression. These findings suggest one potential mechanism of action that likely involves a tightly coordinated regulation of CRBN with endothelial cell targets and highlight the need to further elucidate the mechanism(s), which could include cereblon-independent pathways, through which IMiDs exert their antiangiogenic effects.
影响因子：
2.4
作者：
Mahony C;McMenemy S;Rafipay AJ;Beedie SL;Fraga LR;Gütschow M;Figg WD;Erskine L;Vargesson N
通讯作者：
Vargesson N