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Ubiquitin and ubiquitin-like proteins in cancer pathogenesis

Nature Reviews Cancer volume 6, pages 776–788 (2006)Cite this article

Key Points

  • Ubiquitin is an 8 kDa polypeptide that can be covalently attached to other proteins through a process called ubiquitylation (also known as ubiquitination). Similar to phoshporylation, ubiquitylation is an inducible and reversible process that changes the properties of the modified substrate; for example, its subcellular localization, stability or enzymatic activity.

  • The attachment of ubiquitin to substrates requires the sequential action of three enzymes: ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin ligase (E3). This process can be reversed by de-ubiquitylating enzymes (DUBs) that remove ubiquitin from substrates.

  • Several ubiquitin-like modifiers (Ubls) have been identified, such as SUMO, NEDD8, ISG15 and FAT10. They possess a distinct primary sequence but share characteristic features with ubiquitin, including the 3-dimensional fold and the mode of their conjugation to substrates.

  • Protein domains that bind to ubiquitin (UBDs) or Ubls have crucial roles in the recognition of modified proteins and the translation of the encoded information into the proper cellular response. Most UBD-containing proteins undergo monoubiquitylation themselves, which causes their auto-inhibition by intramolecular UBD–ubiquitin interactions.

  • Alterations to the ubiquitin and Ubl systems are associated with various pathologies, such as inflammatory diseases and cancer. Moreover, many disease-related pathways are not only regulated by a single ubiquitin or Ubl, but by a sophisticated cross-talk of different types of modifications.

  • Examples of such ubiquitin or Ubl interplays in oncogenic pathways include p53, nuclear factor κB and DNA repair pathways, which are regulated by monoubiquitylation, polyubiquitylation, sumoylation and neddylation.

  • Bortezomib is the first compound that targets the ubiquitin-system to be approved for clinical use in human cancers. It inhibits the active site of one of the proteasome subunits and shuts down the proteasomal protein-degradation system.

  • New, more specific anticancer drugs that target the ubiquitin-system are being developed, including selective inhibitors of E3 enzymes like MDM2. Moreover, DUBs and the binding interface of ubiquitylated proteins and UBDs have emerged as promising drug targets.

Abstract

Ubiquitin and ubiquitin-like proteins (Ubls) are signalling messengers that control many cellular functions, such as cell proliferation, apoptosis, the cell cycle and DNA repair. It is becoming apparent that the deregulation of ubiquitin pathways results in the development of human diseases, including many types of tumours. Here we summarize the common principles and specific features of ubiquitin and Ubls in the regulation of cancer-relevant pathways, and discuss new strategies to target ubiquitin signalling in drug discovery.

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Figure 1: Different modification states of p53 and MDM2.
Figure 2: Ubiquitin and Ubl modifications in the NFκB pathway.
Figure 3: CYLD interferes at different steps of the NFκB pathway depending on the stimulus received by the cell and the cell type.

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Acknowledgements

We apologize to investigators whose important contributions were not included in this review due to space limitations. We would like to thank D. Vucic and members of the Dikic laboratory for critical reading of the manuscript. C.M.H. is fellow of the Hessian ministry of arts and sciences. I.D. gratefully acknowledges support from the Deutsche Forschungsgemeinschaft, the German–Israeli Foundation and the Boehringer Ingelheim Foundation.

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Authors and Affiliations

  1. Institute of Biochemistry II, Goethe University School of Medicine, University Hospital, Building 75, Theodour-Stern-Kai 7, Frankfurt, D-60590, Germany

    Daniela Hoeller & Christina-Maria Hecker

  2. Mediterranean Institute for Life Sciences, Mestrovicevo Setaliste bb, Split, 21 000, Croatia

    Ivan Dikic

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  1. Daniela Hoeller
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  2. Christina-Maria Hecker
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  3. Ivan Dikic
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Correspondence to Ivan Dikic.

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DATABASES

National Cancer Institute

basal-cell carcinomas

colourectal cancer

kidney cancer

leukaemia

liver cancer

melanoma

non-Hodgkin lymphoma

non-small cell-lung cancer

squamous-cell carcinomas

FURTHER INFORMATION

Ivan Dikic's homepage

Glossary

Ubl

Ubiquitin-like proteins are small proteins that have significant sequence and structural similarity to ubiquitin and are conjugated in a similar way.

Small ubiquitin-related modifier

SUMO belongs to the family of ubiquitin-like proteins. Three ubiquitously expressed paralogues are known. SUMO2 and SUMO3 are highly similar to each other (95%), whereas SUMO1 shows about 50% sequence similarity with SUMO2.

NEDD8

This protein belongs to the family of ubiquitin-like proteins and modifies specific ubiquitin E3 ligases to influence their catalytic ubiquitylation activity.

Interferon-stimulated gene 15

This protein consists of two ubiquitin-like folds, and is conjugated to substrates after interferon 1 stimulation. ISG15 is important in the regulation of the immune response.

FAT10

A ubiquitin-like protein that constists of two ubiquitin-like folds and is conjugated to substrates after interferon-γ and tumour-necrosis factor-α induction. Its expression has been shown to cause apoptosis.

26S proteasome

A large 2.5 MDa multisubunit protein that is the main proteolytic system in eukaryotic cells. It degrades polyubiquitylated proteins.

UBDs

Ubiquitin binding domains bind to ubiquitin and have crucial roles in the recognition of modified proteins and the translation of encoded information into the proper cellular response.

SKP1–CUL1–F-box ligase complexes

An E3 ligase protein complex that consists of three invariable components: RBX1 (RING-finger protein), CUL1 (scaffold protein) and SKP1 (adaptor protein), and one variable component, the F-box protein.

Nuclear factor κB

A transcription factor that consists of either a homo- or a heterodimer of proteins such as NFκB1, RelA, NFκB2 and RelB.

Ataxia telangiectasia mutated

ATM is a crucial signal-transducing kinase for mediating certain forms of DNA damage such as double-strand breaks. The activation of many proteins has been shown to be ATM-dependent. These include CHK1 and CHK2 kinases, BRCA1, NBS1, and p53, among others.

UBM and UBZ

Ubiquitin-binding motif (UBM) and ubiquitin-binding zinc finger (UBZ) were recently discovered to be involved in the TLS response. UBMs do not bind to the hydrophobic Ile44 patch of ubiquitin.

Y-family polymerases

These are translesion synthesis (TLS) polymerases of low fidelity, such as Polι, Polη, Polκ and REV1, which are involved in the error-prone DNA-repair pathway.

Wnt

The family of secreted cysteine-rich glycoproteins that act as short-range ligands to locally activate receptor-mediated pathways.

KAI1

A member of the tetraspanin family that is capable of inhibiting the progression of tumour metastasis without affecting primary tumorigenicity.

All trans retinoic acid

A form of vitamin A used as a drug for the treatment of acute promyelocytic leukaemia.

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Hoeller, D., Hecker, CM. & Dikic, I. Ubiquitin and ubiquitin-like proteins in cancer pathogenesis. Nat Rev Cancer 6, 776–788 (2006). https://doi.org/10.1038/nrc1994

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