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Cullin-RING Ligases and Protein Neddylation pp 297–315Cite as

Targeting Protein Neddylation for Cancer Therapy

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1217))

Abstract

Neddylation is a posttranslational modification that conjugates a ubiquitin-like protein NEDD8 to substrate proteins. The best-characterized substrates of neddylation are the cullin subunits of cullin-RING E3 ubiquitin ligase complexes (CRLs). CRLs as the largest family of E3 ubiquitin ligases control many important biological processes, including tumorigenesis, through promoting ubiquitylation and subsequent degradation of a variety of key regulatory proteins. The process of protein neddylation is overactivated in multiple types of human cancers, providing a sound rationale as an attractive anticancer therapeutic strategy, evidenced by the development of the NEDD8-activating enzyme (NAE) inhibitor MLN4924 (also known as pevonedistat). Recently, increasing evidence strongly indicates that neddylation inhibition by MLN4924 exerts anticancer effects mainly by triggering cell apoptosis, senescence, and autophagy and causing angiogenesis suppression, inflammatory responses, and chemo-/radiosensitization in a context-dependent manner. Here, we briefly summarize the latest progresses in this field, focusing on the preclinical studies to validate neddylation modification as a promising anticancer target.

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Abbreviations

4E-BP1:

Eukaryotic translation initiation factor 4E-binding protein 1

AICD:

APP intracellular domain

APPBP1:

Amyloid beta precursor protein binding protein 1

ATF4:

Activating transcription factor 4

BAX:

BCL2-associated X, apoptosis regulator

BCA3:

Breast cancer-associated protein 3

BIK:

BCL2 Interacting killer

CAM:

Chorioallantoic membrane

c-CBL:

Casitas B-lineage lymphoma

CDT1/2:

Chromatin licensing and DNA replication factor 1/2

c-FLIP:

CASP8 and FADD-like apoptosis regulator

CRLs:

Cullin-RING ligases

CSN:

COP9 signalosome complex

DCN1:

Defective in cullin neddylation 1

DCNL:

DCN1-like protein

Deptor:

DEP domain-containing mTOR-interacting protein

DR5:

Death receptor 5

E2F-1:

E2F transcriptional factor 1

EGFR:

Epidermal growth factor receptor

FANCD2:

FA complementation group D2

FBXO11:

F-box protein 11

HIF1α/2α:

Hypoxia-inducible factor 1α/2α

HUR:

Hu antigen R

HUVECs:

Human umbilical vein endothelial cells

IAPs:

Inhibitors of apoptosis

IL-6:

Interleukin 6

MAPK:

Mitogen-activated protein kinase

MDM2:

Murine double minute 2

mTOR:

Mammalian target of rapamycin

NAC:

N-acetyl cysteine

NAE1:

NEDD8-activating enzyme E1 subunit 1

NAEβ:

NEDD8-activating enzyme E1 subunit β

NEDD8:

Neural precursor cell expressed, developmentally downregulated 8

NEDP1:

NEDD8-specific protease 1

NF-κB:

Nuclear factor-κB

ORC1:

Origin recognition complex subunit 1

PAMPs:

Pathogen-associated molecular patterns

PfUCH54:

54-kDa plasmodium falciparum ubiquitin C-terminal hydrolase

PINK1:

PTEN-induced putative kinase 11

pIκB:

p-inhibitor of nuclear factor kappa B

PONY:

Potentiating neddylation

pVHL:

p-von Hippel-Lindau

RBX1/2:

RING box protein 1/2

RhoA:

Ras homolog family member A

RING:

Really interesting new gene

RNF111:

Ring finger protein 111

ROS:

Reactive oxygen species

S6K1:

Ribosomal protein S6 kinase B1

SKP1/2:

S-phase kinase-associated protein 1/2

SMURF1:

SMAD-specific E3 ubiquitin protein ligase 1

TGFβ-RII:

Transforming growth factor β type II receptor

TNFα:

Tumor necrosis factor α

TRAIL:

Tumor necrosis factor-related apoptosis-inducing ligand

TRIM40:

Tripartite motif containing 40

TSC1:

TSC complex subunit 1

UBA3:

Ubiquitin-like modifier activating enzyme 3

UBC12:

Ubiquitin-conjugating enzyme 12

UBE2F:

Ubiquitin-conjugating enzyme E2F

UBE2M:

Ubiquitin-conjugating enzyme E2M

UCH-L1/3:

Ubiquitin carboxyl-terminal esterase L1/3

USP21:

Ubiquitin-specific peptidase 21

VEGF:

Vascular endothelial growth factor

WEE1:

WEE1 G2 checkpoint kinase 1

β-Trcp:

β-Transducin repeat containing E3 ubiquitin protein ligase

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Acknowledgments

The Chinese Minister of Science and Technology grant (2016YFA0501800), National Natural Science Foundation of China (Grant Nos. 81820108022, 81625018, 81572340, 81772470, 81602072, 81401893, 81702244, and 81871870), Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-10-E00056), National Thirteenth Five-Year Science and Technology Major Special Project for New Drug and Development (2017ZX09304001), and Program of Shanghai Academic/Technology Research Leader (18XD1403800) supported this work.

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Authors and Affiliations

  1. Department of Biochemistry, Medical College, Taizhou University, Taizhou, China

    Lisha Zhou

  2. Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Lijun Jia

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  1. Lisha Zhou
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  2. Lijun Jia
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Correspondence to Lisha Zhou or Lijun Jia .

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  1. Radiation Oncology, University of Michigan, Ann Arbor, MI, USA

    Yi Sun

  2. Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Wenyi Wei

  3. Life Science Institute, Zhejiang University, Hangzhou, China

    Jianping Jin

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Zhou, L., Jia, L. (2020). Targeting Protein Neddylation for Cancer Therapy. In: Sun, Y., Wei, W., Jin, J. (eds) Cullin-RING Ligases and Protein Neddylation. Advances in Experimental Medicine and Biology, vol 1217. Springer, Singapore. https://doi.org/10.1007/978-981-15-1025-0_18

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