Role of cereblon in angiogenesis and in mediating the antiangiogenic activity of immunomodulatory drugs

Abstract

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.

Antiangiogenic Activity and in Silico Cereblon Binding Analysis of Novel Thalidomide Analogs

“…Overall, the in silico cereblon docking experiments suggest that cereblon binding alone does not account for the antiangiogenic activity of all the tested thalidomide analogs. Our recent findings demonstrate that loss of cereblon does not prevent thalidomide-induced antiangiogenesis, though downstream cereblon targets are upregulated [64]. Thalidomide itself appears to have one target [6], but analogs and metabolites of thalidomide could have multiple targets.…”

Cereblon contributes to the development of pulmonary fibrosis via inactivation of adenosine monophosphate-activated protein kinase α1

“…This might have been because other intracellular signaling cascades, including the non-SMAD (SMAD-independent) TGF-β signaling pathway, are involved in the upregulation of ECM protein expression 24 and because CRBN might not block all pathways associated with the expression of ECM genes. Several types of lung cells, such as epithelial cells, macrophages, endothelial cells, and fibroblasts, express CRBN 25 – 27 . In evaluating the role of CRBN in lung fibrosis, we tested the effect of cigarette smoke extract (CSE) on CRBN expression in lung epithelial cells since epithelial cell injury is considered as an initiating event in lung fibrosis and cigarette smoking is the most consistent environmental risk factor.…”

Comparative Genomics Identifies Putative Interspecies Mechanisms Underlying Crbn-Sall4-Linked Thalidomide Embryopathy

“…Ikaros, the protein encoded by Ikzf1 , degradation is demonstrated to be an important event in thalidomide therapeutics in multiple myeloma ( Krönke et al, 2014 ). Furthermore, thalidomide anti-angiogenic property is suggested as independent of Cereblon binding ( Beedie et al, 2020 ; Peach et al, 2020 ). Hence, the differential co-expression correlations and variants encountered in insensitive species might help to understand thalidomide anti-angiogenic effects in these animals.…”