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

Shaunna L Beedie; Phoebe A Huang; Emily M Harris; Jonathan D Strope; Christopher Mahony; Cindy H Chau; Neil Vargesson; William D Figg

doi:10.1096/fj.201903060RR

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

Shaunna L Beedie, Phoebe A Huang, Emily M Harris, Jonathan D Strope, Christopher Mahony, Cindy H Chau, Neil Vargesson, William D Figg^* (Corresponding Author)

^*Corresponding author for this work

School of Medicine, Medical Sciences & Nutrition

Research output: Contribution to journal › Article › peer-review

12 Citations (Scopus)

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.

Original language	English
Pages (from-to)	11395-11404
Number of pages	10
Journal	The FASEB Journal
Volume	34
Issue number	9
Early online date	17 Jul 2020
DOIs	https://doi.org/10.1096/fj.201903060RR
Publication status	Published - Sept 2020

Bibliographical note

The authors thank Prof. Lynda Erskine and Dr Lucas Rosa Fraga for discussions on cereblon and Dr Tristan Sissung for advice on primers and genotyping, and to Afua Akuffo for helpful discussion. We are especially grateful to Drs. Pearlie Burnette (Moffitt Cancer Institute, FL) and Anjali Rajadhyaksha (Weill Cornell Medical College, NY) for providing the cereblon knockout mice. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the US Government. This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (ZIA SC006538) and a Wellcome Trust‐NIH PhD Studentship to SB, WDF, and NV (Grant number 098252/Z/12/Z).

Keywords

angiogenesis
cereblon
immunomodulatory drugs
endothelial cell
argonaute-2
SALL4

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10.1096/fj.201903060RRLicence: Unspecified

Cite this

@article{d83421e0b18a4d8f86482cb7e6839af9,

title = "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.",

keywords = "angiogenesis, cereblon, immunomodulatory drugs, endothelial cell, argonaute-2, SALL4",

author = "Beedie, {Shaunna L} and Huang, {Phoebe A} and Harris, {Emily M} and Strope, {Jonathan D} and Christopher Mahony and Chau, {Cindy H} and Neil Vargesson and Figg, {William D}",

note = "The authors thank Prof. Lynda Erskine and Dr Lucas Rosa Fraga for discussions on cereblon and Dr Tristan Sissung for advice on primers and genotyping, and to Afua Akuffo for helpful discussion. We are especially grateful to Drs. Pearlie Burnette (Moffitt Cancer Institute, FL) and Anjali Rajadhyaksha (Weill Cornell Medical College, NY) for providing the cereblon knockout mice. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the US Government. This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (ZIA SC006538) and a Wellcome Trust‐NIH PhD Studentship to SB, WDF, and NV (Grant number 098252/Z/12/Z).",

year = "2020",

month = sep,

doi = "10.1096/fj.201903060RR",

language = "English",

volume = "34",

pages = "11395--11404",

journal = "The FASEB Journal",

issn = "0892-6638",

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T1 - Role of cereblon in angiogenesis and in mediating the antiangiogenic activity of immunomodulatory drugs

AU - Beedie, Shaunna L

AU - Huang, Phoebe A

AU - Harris, Emily M

AU - Strope, Jonathan D

AU - Mahony, Christopher

AU - Chau, Cindy H

AU - Vargesson, Neil

AU - Figg, William D

N1 - The authors thank Prof. Lynda Erskine and Dr Lucas Rosa Fraga for discussions on cereblon and Dr Tristan Sissung for advice on primers and genotyping, and to Afua Akuffo for helpful discussion. We are especially grateful to Drs. Pearlie Burnette (Moffitt Cancer Institute, FL) and Anjali Rajadhyaksha (Weill Cornell Medical College, NY) for providing the cereblon knockout mice. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the US Government. This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (ZIA SC006538) and a Wellcome Trust‐NIH PhD Studentship to SB, WDF, and NV (Grant number 098252/Z/12/Z).

PY - 2020/9

Y1 - 2020/9

N2 - 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.

AB - 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.

KW - angiogenesis

KW - cereblon

KW - immunomodulatory drugs

KW - endothelial cell

KW - argonaute-2

KW - SALL4

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U2 - 10.1096/fj.201903060RR

DO - 10.1096/fj.201903060RR

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C2 - 32677118

SN - 0892-6638

VL - 34

SP - 11395

EP - 11404

JO - The FASEB Journal

JF - The FASEB Journal

IS - 9

ER -

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

Abstract

Bibliographical note

Keywords

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Neil Vargesson

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

Abstract

Bibliographical note

Keywords

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Fingerprint

Profiles

Neil Vargesson

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