RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis

Key Points

  • RING finger ubiquitin-protein ligases (E3s) are the most abundant class of E3 that mediate protein ubiquitylation (also known as ubiquitination). They regulate crucial cellular functions, such as the cell cycle, DNA repair, cell signalling and responses to hypoxia. Genetic alterations, including activating and inactivating mutations, gene amplifications, translocations and deletions, have been described for many RING finger E3s. RING finger E3s are validated oncogenes (such as MDM2) or tumour suppressor genes (such as BRCA1 and von Hippel–Lindau tumour suppressor (VHL)) because of their role in regulating crucial cell functions.

  • The cell cycle is regulated by the S phase kinase-associated protein 1 (SKP1)–cullin 1 (CUL1)–F-box protein (SCF) and anaphase-promoting complex/cyclosome (APC/C) multisubunit RING finger E3s. These complexes are targeted to specific substrates via interchangeable substrate recognition subunits, including F-box proteins for SCF and cell division cycle 20 (CDC20) and CDH1 for APC/C. These multisubunit E3s have a large number of substrates with oncogenic and tumour suppressive effects. Genetic alterations to components of these E3 complexes that result in loss of function (such as FBW7, CDH1 and CDC20) or gain of function (such as SKP2 and β-transducin repeat-containing protein (β-TrCP)) are implicated in the development of cancer.

  • RING finger E3s have central roles in DNA damage responses and DNA repair. For example, MDM2 targets p53 for degradation. MDM2 is amplified, overexpressed or activated in other ways in cancers and is a means of inactivating the tumour suppressor p53. The BRCA1 and the Fanconi anaemia (FANC) E3s have essential roles in the repair of DNA damage; both E3s function as tumour suppressors.

  • RING finger E3s have important roles in both positively and negatively regulating signal transduction. A prominent example of negative regulation is the CBL family of RING finger E3s that target activated receptor tyrosine kinases (RTKs) for degradation. Mutations that inactivate CBL E3 function have been described in myeloid neoplasms and result in the hyperactivation of RTKs and intracellular signalling pathways.

  • The response to hypoxia is regulated by the multisubunit CRL2VHL RING finger E3 and the single subunit RING finger E3 SIAH. The VHL complex targets the hypoxia-inducible factor-α (HIFα) transcription factors for proteasomal degradation, which prevents the expression of angiogenic and growth-promoting genes under normoxic conditions. Inactivating mutations of VHL are found in familial and sporadic clear cell cancer of the kidney, resulting in the stabilization of the HIFα transcription factor subunits and consequently abnormally high expression of angiogenic and growth genes. By contrast, the SIAH RING finger E3s stabilize HIFα under hypoxic conditions.

  • Targeting RING finger E3s for the treatment of cancer is being actively explored. For example, small-molecule inhibitors have been developed that interfere with the MDM2–p53 interaction or that inhibit MDM2 E3 activity, thus stabilizing p53. These approaches have demonstrated antitumour activity in preclinical studies, but the clinical efficacy of interfering with MDM2 function remains to be determined. Targeting the loss of activity of RING finger E3s that are tumour suppressors will require novel approaches such as the synthetic lethality that is induced by poly(ADP-ribose) polymerase (PARP) inhibition in cells that are deficient in BRCA1 or BRCA2.

Abstract

The ubiquitin-proteasome system has numerous crucial roles in physiology and pathophysiology. Fundamental to the specificity of this system are ubiquitin-protein ligases (E3s). Of these, the majority are RING finger and RING finger-related E3s. Many RING finger E3s have roles in processes that are central to the maintenance of genomic integrity and cellular homeostasis, such as the anaphase promoting complex/cyclosome (APC/C), the SKP1–cullin 1–F-box protein (SCF) E3s, MDM2, BRCA1, Fanconi anaemia proteins, CBL proteins, von Hippel–Lindau tumour suppressor (VHL) and SIAH proteins. As a result, many RING finger E3s are implicated in either the suppression or the progression of cancer. This Review summarizes current knowledge in this area.

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Figure 1: MDM2.
Figure 2: CBL.
Figure 3: Hypoxia.

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Acknowledgements

The authors apologize to the many scientists whose contributions to this extensive and exponentially growing field of research could not be directly cited because of space limitations. They are indebted to their colleagues whose outstanding reviews on individual RING finger E3s and RING finger E3 families summarize and cite much of this important research. The authors thank R. Das (Structural Biophysics Laboratory, National Cancer Institute, USA) for invaluable assistance in generating the RING finger-E2 ribbon diagram. The authors' research programmes are supported by the National Institutes of Health, National Cancer Institute, Center for Cancer Research, USA.

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Supplementary information

Supplementary information S1 (table)

Established and Proposed E3s for p53 (PDF 385 kb)

Supplementary information S2 (table)

RING Finger E3s Implicated in Regulating Cell Cycle in Response to DNA Damage (PDF 173 kb)

Supplementary information S3 (table)

RING E3s Implicated in DNA repair* (PDF 187 kb)

Glossary

Oncogenes

Genes with protein products that can promote cancer development. Oncogenes frequently undergo amplification or activating mutations and act in a genetically dominant manner.

Tumour suppressor genes

(TSGs). Genes whose protein products, when lost or mutated, are permissive for the development of cancer. TSGs frequently undergo deletion or inactivating mutations of both alleles and act in a genetically recessive manner.

Aneuploidy

Abnormal number of chromosomes resulting in more or less than the normal diploid number of chromosomes. Cancer cells are frequently aneuploid.

Cyclins

Proteins that control the progression of the cell cycle by activating cyclin-dependent kinases.

Securin

A protein that forms a complex with separase and thereby inhibits separase activity and prevents chromosome separation at anaphase. Securin is dephosphorylated and degraded by APC/CCDC20 at the onset of anaphase.

Haploinsufficient TSG

A gene for which the loss of one allele is sufficient to promote cancer development.

Amplification

Increased copy number of a gene within the genome; this is a common mechanism to increase the activity of oncogenes.

Anergy

When lymphocytes fail to mount an immune response to an antigen.

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Lipkowitz, S., Weissman, A. RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis. Nat Rev Cancer 11, 629–643 (2011). https://doi.org/10.1038/nrc3120

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