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Cereblon: promise and challenges for combating human diseases

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Abstract

Cereblon (CRBN) is a substrate recognition protein in the E3-ligase ubiquitin complex. The binding target of CRBN varies according to tissues and cells, and the protein regulates various biological functions by regulating tissue-specific targets. As new endogenous targets of CRBN have been identified over the past decade, the physiological and pathological functions of CRBN and its potential as a therapeutic target in various diseases have greatly expanded. For this purpose, in this review article, we introduce the basic principle of the ubiquitin–proteasome system, the regulation of physiological/pathological functions related to the endogenous substrate of CRBN, and the discovery of immunomodulatory imide drug-mediated neo-substrates of CRBN. In addition, the development of CRBN-based proteolysis-targeting chimeras, which has been actively researched recently, and strategies for developing therapeutic agents using them are introduced. These recent updates on CRBN will be useful in the establishment of strategies for disease treatment and utilization of CRBNs in biomedical engineering and clinical medicine.

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Abbreviations

AML:

Acute myeloid leukemia

ARID2:

AT-rich interactive domain 2

BKCa :

Large conductance Ca2+-activated K+ channel

CDK:

Cyclin-dependent kinase

CLC:

Voltage-gated chloride channel

CRBN:

Cereblon

CRL:

Cullin-RING E3 ligase

DCAF:

DDB1-CUL4-associated factor

DDB1:

DNA damage-binding protein 1

FAK:

Focal adhesion kinase

FGF:

Fibroblast growth factor

FKBP12:

FK506 binding protein 12

GS:

Glutamine synthetase

GSK-3β:

Glycogen synthase kinase 3 beta

GSPT1:

G1 to S phase transition 1

HMGCR:

HMG-CoA reductase

IKZF:

Ikaros family zinc finger protein

IMiDs:

Immunomodulatory imide drugs

IRF:

Interferon regulatory factor

MAPK:

p38 mitogen-activated protein kinase

MEFs:

Mouse embryonic fibroblasts

MEIS2:

Myeloid ecotropic insertion site 2

NLRP3:

NOD-like receptor pyrin domain-containing protein 3

PHD-finger:

Plant homeodomain-finger

PLK1:

Polo-like kinase 1

PLZF:

Promyelocytic leukemia zinc finger

PROTAC:

Proteolysis-targeting chimera

SALL4:

Spalt like transcription factor 4

SKP1:

S-phase kinase associated protein 1

TLR4:

Toll-like receptor 4

VHL:

Von Hippel-Lindau

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Acknowledgements

We thank all scientists of Cereblon Open Research Excellence (CORE) for their expertise and achievements throughout all aspects in the research field of cereblon.

Funding

This work was supported by the Basic Research Lab program and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Korean government (2020R1A4A1018943, 2018R1A2A3074998, and 2018R1D1A1A09081767), and by the 2018 Inje University research grant.

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Authors and Affiliations

  1. Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Smart Marine Therapeutic Center, Department of Health Sciences and Technology, Graduate School, Inje University, 47392, Busan, Korea

    Hyoung Kyu Kim, Jung Eun Seol, Seungje Jeon & Jin Han

  2. Department of Dermatology, Inje University Busan Paik Hospital, Inje University, 47392, Busan, Korea

    Jung Eun Seol & Sang Woo Ahn

  3. School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea

    Seungje Jeon & Chul-Seung Park

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  1. Hyoung Kyu Kim
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  2. Jung Eun Seol
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Correspondence to Jin Han.

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Kim, H.K., Seol, J.E., Ahn, S.W. et al. Cereblon: promise and challenges for combating human diseases. Pflugers Arch - Eur J Physiol 473, 1695–1711 (2021). https://doi.org/10.1007/s00424-021-02624-0

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