Cereblon: A Protein Crucial to the Multiple Functions of Immunomodulatory Drugs as well as Cell Metabolism and Disease Generation

Shi, Qinglin; Chen, Lijuan

doi:10.1155/2017/9130608

Cited by 43 publications

(36 citation statements)

References 64 publications

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“…Moreover, CRBN KO H1299 and CRBN KO MCF7 cells revealed marked increases of autophagy activation in response to LPS stimulation. Although the direct evidence of CRBN being capable of affecting cancer progression is insufficient, many reports have suggested that CRBN is closely related to the proliferation and metabolism of normal and tumor cells (6, 35–37). To expand the multifunctional roles of CRBN in cancer progression induced by autophagy, we examined the abilities of cancer cell migration and invasion in CRBN KO H1299 and CRBN KO MCF7 cells.…”

Section: Discussionmentioning

confidence: 99%

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CRBN Is a Negative Regulator of Bactericidal Activity and Autophagy Activation Through Inhibiting the Ubiquitination of ECSIT and BECN1

et al. 2019

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Cereblon (CRBN) as a multifunctional protein has been extensively studied. Here, we show that CRBN is a negative regulator of bactericidal activity and autophagy activation. Mitochondrial localization of CRBN was significantly increased in response to Toll-like receptor 4 (TLR4) stimulation. CRBN interrupted the association of evolutionarily conserved signaling intermediate in Toll pathways (ECSIT)-TNF-receptor associated factor 6 (TRAF6) complex, thereby inhibiting the ubiquitination of ECSIT, which plays a pivotal role for the production of mitochondrial reactive oxygen species (mROS). Subsequently, mROS levels were markedly elevated in CRBN-knockdown (CRBNKD) THP-1 cells, and that led to resistance against S. typhimurium infection, indicating CRBN is a negative regulator of bactericidal activity through the regulation of mROS. Additionally, CRBN inhibited TRAF6-induced ubiquitination of BECN1 (Beclin 1), and that induced autophagy activation in CRBNKD THP-1, CRBN-knockout (CRBNKO) H1299, and CRBNKO MCF7 cancer cells in response to TLR4 stimulation. Notably, we found that the ability of cancer migration and invasion was significantly enhanced in CRBNKO H1299 and CRBNKO MCF7 cancer cells, as compared with those of control cancer cells. Collectively, these results suggest that CRBN is a negative regulator of bactericidal activity and autophagy activation through inhibiting the TRAF6-induced ubiquitination of ECSIT and BECN1, respectively.

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Section: Discussionmentioning

confidence: 99%

“…So far, many studies on CRBN have focused on the multiple effects of immunomodulatory imide drugs (IMiDs) (6, 37–39). It has also been suggested that the cellular expression of CRBN influences cell metabolism and leads to disease in the absence of IMiDs, indicating the various functions and cellular mechanisms of CRBN (38).…”

Section: Discussionmentioning

confidence: 99%

CRBN Is a Negative Regulator of Bactericidal Activity and Autophagy Activation Through Inhibiting the Ubiquitination of ECSIT and BECN1

et al. 2019

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“…A recent x-ray structure of POI-PROTAC-E3 ternary complex provides strong evidence to support this mechanism [27]. Although there are > 600 E3 ubiquitin ligases, only several with small molecule ligands have been used for designing PROTACs, including Skp1-Cullin-F box complex containing Hrt1 (SCF) [28], Von Hippel-Lindau tumor suppressor (VHL) [29], Cereblon (CRBN) [30], inhibitor of apoptosis proteins (IAPs) [31], and mouse double minute 2 homolog (MDM2) [32]. Representative ligands of these E3s are showed in Fig.…”

Section: What Is Protac?mentioning

confidence: 99%

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

2020

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Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. A bifunctional PROTAC molecule consists of a ligand (mostly small-molecule inhibitor) of the protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3). Upon binding to the POI, the PROTAC can recruit E3 for POI ubiquitination, which is subjected to proteasome-mediated degradation. PROTAC complements nucleic acid-based gene knockdown/out technologies for targeted protein reduction and could mimic pharmacological protein inhibition. To date, PROTACs targeting~50 proteins, many of which are clinically validated drug targets, have been successfully developed with several in clinical trials for cancer therapy. This article reviews PROTAC-mediated degradation of critical oncoproteins in cancer, particularly those in hematological malignancies. Chemical structures, cellular and in vivo activities, pharmacokinetics, and pharmacodynamics of these PROTACs are summarized. In addition, potential advantages, challenges, and perspectives of PROTAC technology in cancer therapy are discussed.

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“…Considerable efforts have been made to identify new target proteins of CRBN and their roles in the normal and pathophysiology of the cell. Clinically, CRL4 Crbn have been recognized as an important therapeutic target for several diseases, including multiple myeloma, leprosy, and hematopoietic cancer ( 28 - 30 ). CRBN is likely to affect a variety of brain-related functions and diseases; however, the physiological function of CRBN in the brain is still unclear.…”

Section: Discussionmentioning

confidence: 99%

Susceptibility of pentylenetetrazole-induced seizures in mice with Cereblon gene knockout

et al. 2020

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Epilepsy is a neurological disorder characterized by unpredictable seizures, which are bursts of electrical activity that tempo-rarily affect the brain. Cereblon (CRBN), a DCAFs ( D DB1 and C UL4 a ssociated f actors), is a well-established protein associated with human mental retardation. Being a substrate receptor of the cullin-RING E3 ubiquitin ligase (CRL) 4 complex, CRBN mediates ubiquitination of several substrates and conducts multiple biological processes. In the central nervous system, the large-conductance Ca 2+ -activated K + (BK Ca ) channel, which is the substrate of CRBN, is an important regulator of epilepsy. Despite the functional role and importance of CRBN in the brain, di-rect injection of pentylenetetrazole (PTZ) to induce seizures in CRBN knock-out mice has not been challenged. In this study, we investigated the effect of PTZ in CRBN knock-out mice. Here, we demonstrate that, compared with WT mice, CRBN knock-out mice do not show the intensification of seizures by PTZ induction. Moreover, electroencephalography recordings were also performed in the brains of both WT and CRBN knockout mice to identify the absence of significant differences in the pattern of seizure activities. Consistently, immunoblot analysis for validating the protein level of the CRL4 complex containing CRBN (CRL4 Crbn ) in the mouse brain was carried out. Taken together, we found that the deficiency of CRBN does not affect PTZ-induced seizure.

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Cereblon: A Protein Crucial to the Multiple Functions of Immunomodulatory Drugs as well as Cell Metabolism and Disease Generation

Cited by 43 publications

References 64 publications

CRBN Is a Negative Regulator of Bactericidal Activity and Autophagy Activation Through Inhibiting the Ubiquitination of ECSIT and BECN1

CRBN Is a Negative Regulator of Bactericidal Activity and Autophagy Activation Through Inhibiting the Ubiquitination of ECSIT and BECN1

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

Susceptibility of pentylenetetrazole-induced seizures in mice with Cereblon gene knockout

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