Role of Ubiquitin Ligases and the Proteasome in Oncogenesis: Novel Targets for Anticancer Therapies

Overview

Journal J Clin Oncol

Specialty Oncology

Date 2013 Jan 30

PMID 23358974

Citations 92

Authors

Lindsey N Micel

John J Tentler

Peter G Smith

Gail S Eckhardt

Affiliations

Soon will be listed here.

Abstract

The ubiquitin proteasome system (UPS) regulates the ubiquitination, and thus degradation and turnover, of many proteins vital to cellular regulation and function. The UPS comprises a sequential series of enzymatic processes using four key enzyme families: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-carrier proteins), E3 (ubiquitin-protein ligases), and E4 (ubiquitin chain assembly factors). Because the UPS is a crucial regulator of the cell cycle, and abnormal cell-cycle control can lead to oncogenesis, aberrancies within the UPS pathway can result in a malignant cellular phenotype and thus has become an attractive target for novel anticancer agents. This article will provide an overall review of the mechanics of the UPS, describe aberrancies leading to cancer, and give an overview of current drug therapies selectively targeting the UPS.

Citing Articles

Tripartite motif 8 promotes the progression of hepatocellular carcinoma via mediating ubiquitination of HNF1α.

Peng Y, Qian H, Xu W, Xiao M, Ding C, Liu F Cell Death Dis. 2024; 15(6):416.

PMID: 38879600 PMC: 11180176. DOI: 10.1038/s41419-024-06819-y.

Role of microRNA-363 during tumor progression and invasion.

Shad A, Akhlaghipour I, Alshakarchi H, Saburi E, Moghbeli M J Physiol Biochem. 2024; 80(3):481-499.

PMID: 38691273 DOI: 10.1007/s13105-024-01022-1.

In vivo activity of the second-generation proteasome inhibitor ixazomib against pediatric T-cell acute lymphoblastic leukemia xenografts.

Randall J, Evans K, Watts B, Kosasih H, Smith C, Earley E Exp Hematol. 2024; 132:104176.

PMID: 38320689 PMC: 10978271. DOI: 10.1016/j.exphem.2024.104176.

Parkin regulates IGF2BP3 through ubiquitination in the tumourigenesis of cervical cancer.

Sun X, Ye G, Li J, Shou H, Bai G, Zhang J Clin Transl Med. 2023; 13(10):e1457.

PMID: 37877353 PMC: 10599278. DOI: 10.1002/ctm2.1457.

Development and validation of a ubiquitin-proteasome system gene signature for prognostic prediction and immune microenvironment evaluation in hepatocellular carcinoma.

Liu Z, Li Y, Zhang Q, Li B, Xin L J Cancer Res Clin Oncol. 2023; 149(14):13363-13382.

PMID: 37490101 DOI: 10.1007/s00432-023-05189-w.

References

Kubbutat M, Jones S, Vousden K . Regulation of p53 stability by Mdm2. Nature. 1997; 387(6630):299-303. DOI: 10.1038/387299a0. View

Haas A, WARMS J, Hershko A, Rose I . Ubiquitin-activating enzyme. Mechanism and role in protein-ubiquitin conjugation. J Biol Chem. 1982; 257(5):2543-8. View

Koegl M, Hoppe T, Schlenker S, Ulrich H, Mayer T, Jentsch S . A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. Cell. 1999; 96(5):635-44. DOI: 10.1016/s0092-8674(00)80574-7. View

Jin J, Arias E, Chen J, Harper J, Walter J . A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol Cell. 2006; 23(5):709-21. DOI: 10.1016/j.molcel.2006.08.010. View

Carter S, Bischof O, Dejean A, Vousden K . C-terminal modifications regulate MDM2 dissociation and nuclear export of p53. Nat Cell Biol. 2007; 9(4):428-35. DOI: 10.1038/ncb1562. View

Rodriguez M, Desterro J, Lain S, Lane D, Hay R . Multiple C-terminal lysine residues target p53 for ubiquitin-proteasome-mediated degradation. Mol Cell Biol. 2000; 20(22):8458-67. PMC: 102152. DOI: 10.1128/MCB.20.22.8458-8467.2000. View

Roh J, Kang S, Minn I, Califano J, Sidransky D, Koch W . p53-Reactivating small molecules induce apoptosis and enhance chemotherapeutic cytotoxicity in head and neck squamous cell carcinoma. Oral Oncol. 2010; 47(1):8-15. PMC: 3032831. DOI: 10.1016/j.oraloncology.2010.10.011. View

Hakem A, Bohgaki M, Lemmers B, Tai E, Salmena L, Matysiak-Zablocki E . Role of Pirh2 in mediating the regulation of p53 and c-Myc. PLoS Genet. 2011; 7(11):e1002360. PMC: 3219591. DOI: 10.1371/journal.pgen.1002360. View

Le Cam L, Linares L, Paul C, Julien E, Lacroix M, Hatchi E . E4F1 is an atypical ubiquitin ligase that modulates p53 effector functions independently of degradation. Cell. 2006; 127(4):775-88. DOI: 10.1016/j.cell.2006.09.031. View

10.

Wilkinson K . Ubiquitin: a Nobel protein. Cell. 2004; 119(6):741-5. DOI: 10.1016/j.cell.2004.12.001. View

11.

Sterz J, von Metzler I, Hahne J, Lamottke B, Rademacher J, Heider U . The potential of proteasome inhibitors in cancer therapy. Expert Opin Investig Drugs. 2008; 17(6):879-95. DOI: 10.1517/13543784.17.6.879. View

12.

Cohen P, Tcherpakov M . Will the ubiquitin system furnish as many drug targets as protein kinases?. Cell. 2010; 143(5):686-93. DOI: 10.1016/j.cell.2010.11.016. View

13.

Brzovic P, Keeffe J, Nishikawa H, Miyamoto K, Fox 3rd D, Fukuda M . Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex. Proc Natl Acad Sci U S A. 2003; 100(10):5646-51. PMC: 156255. DOI: 10.1073/pnas.0836054100. View

14.

Bedford L, Lowe J, Dick L, Mayer R, Brownell J . Ubiquitin-like protein conjugation and the ubiquitin-proteasome system as drug targets. Nat Rev Drug Discov. 2010; 10(1):29-46. PMC: 7097807. DOI: 10.1038/nrd3321. View

15.

Kapuria V, Peterson L, Showalter H, Kirchhoff P, Talpaz M, Donato N . Protein cross-linking as a novel mechanism of action of a ubiquitin-activating enzyme inhibitor with anti-tumor activity. Biochem Pharmacol. 2011; 82(4):341-9. DOI: 10.1016/j.bcp.2011.05.012. View

16.

Hershko A . The ubiquitin system for protein degradation and some of its roles in the control of the cell division cycle. Cell Death Differ. 2005; 12(9):1191-7. DOI: 10.1038/sj.cdd.4401702. View

17.

Liakopoulos D, Busgen T, Brychzy A, Jentsch S, Pause A . Conjugation of the ubiquitin-like protein NEDD8 to cullin-2 is linked to von Hippel-Lindau tumor suppressor function. Proc Natl Acad Sci U S A. 1999; 96(10):5510-5. PMC: 21890. DOI: 10.1073/pnas.96.10.5510. View

18.

Gstaiger M, Jordan R, Lim M, Catzavelos C, Mestan J, Slingerland J . Skp2 is oncogenic and overexpressed in human cancers. Proc Natl Acad Sci U S A. 2001; 98(9):5043-8. PMC: 33160. DOI: 10.1073/pnas.081474898. View

19.

Polsky D, Bastian B, Hazan C, Melzer K, Pack J, Houghton A . HDM2 protein overexpression, but not gene amplification, is related to tumorigenesis of cutaneous melanoma. Cancer Res. 2001; 61(20):7642-6. View

20.

Zhou H, Aujay M, Bennett M, Dajee M, Demo S, Fang Y . Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047). J Med Chem. 2009; 52(9):3028-38. DOI: 10.1021/jm801329v. View