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Spotlight on the role of COP1 in tumorigenesis

Nature Reviews Cancer volume 12, pages 455–464 (2012)Cite this article

Subjects

Key Points

  • COP1 is a well-conserved E3 ubiquitin ligase that is involved in the ubiquitylation of various protein substrates to trigger their proteasomal degradation.

  • Several putative targets of mouse and human COP1 have been identified, including COP1 itself, p53, JUN and ETS variant (ETV) family members, indicating that depending on context it may act as an oncogene or as a tumour suppressor.

  • Both overexpression and loss of function of COP1 have been described in a variety of human tumours. In mice, the complete loss of COP1 function results in embryonic lethality, whereas studies of a partial loss of COP1 function have provided the first in vivo evidence for its tumour suppressor function.

  • Most identified COP1 targets are transcription factors that are implicated in cancer, although other targets imply that COP1 might also function in lipid and glucose metabolism. The main cellular functions of COP1 are probably mediated through the ubiquitylation and degradation of its substrates.

  • Unlike previously described E3 ligases, such as FBW7 and ITCH, COP1 can target unphosphorylated JUN for degradation. Thus, distinct pools of JUN may be targeted for degradation by different E3 ligases.

  • Given its role in the regulation of JUN and of the ETV family members, which are all known prostate cancer oncoproteins, COP1 might have a particularly important role in prostate cancer.

  • Despite early biochemical evidence that COP1 targets p53, recent in vivo data suggest that this interaction is unlikely to have an important role or to even occur in vivo.

  • The absence of confirmatory evidence for a role for COP1 in the regulation of p53 stability and activity argues against the use of COP1-inhibitory drugs for cancer therapy.

Abstract

COP1 is an E3 ubiquitin ligase that is involved in the ubiquitylation of various protein substrates to trigger their proteasomal degradation. Although originally identified in a light signalling pathway in plants, biochemical studies have identified putative targets of mammalian COP1 with relevant roles in tumorigenesis, including the oncoproteins JUN and ETV family members, as well as the p53 tumour suppressor. Recent genetic studies have shown that COP1 deficiency leads to spontaneous tumour formation in mice, and have identified mutations in COP1 and its substrates in various human cancers. These findings add to our growing appreciation of the roles for E3 ligases in cancer.

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Figure 1: Schematic representation of COP1 structural domains and the human COP1 locus.
Figure 2: COP1 promotes ubiquitylation and proteasome-mediated degradation by distinct mechanisms.
Figure 3: JUN stability is co-ordinately regulated by the E3 ligases FBW7, ITCH and COP1.
Figure 4: Mechanisms of evasion from COP1-mediated degradation in cancers.

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Acknowledgements

The author thanks M. Skipper for help in preparing this manuscript. This research was partly supported by VIB, the Belgian Federation for Cancer and AICR.

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  1. Laboratory for Molecular Cancer Biology, VIB-KULeuven, O&N I Herestraat 49 - bus 602, Leuven, B-3000, Belgium

    Jean-Christophe Marine

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Glossary

26S proteasome

The ATP-dependent proteolytic complex that is responsible for ubiquitin-dependent protein degradation.

RING domain

A protein structural domain of zinc finger proteins, which contains a (Cys)3-His-(Cys)4 amino acid motif that binds two zinc cations. It contains 40 to 60 amino acids. Many proteins containing a RING domain are involved in the ubiquitylation pathway.

WD40 repeats

Also known as the WD repeats and β-transducin repeats. Short structural motifs of approximately 40 amino acids, with tryptophan and aspartic acid often found at their ends; several such repeats combine to form the WD domain.

Hydrops fetalis

A condition in which abnormal amounts of fluid accumulate in two or more body areas of a fetus or newborn.

Pleiotropic

A phenomenon whereby one gene influences multiple phenotypic traits.

Histiocytic sarcoma

A tumour derived from histiocytes, cells that are part of the mononuclear phagocyte system.

Testicular teratoma

A type of gonadal tumour derived from germ cells that occurs in the testes.

Degrons

Sequences of amino acids in a protein that is necessary and sufficient to confer its degradation by the ubiquitin–proteasome system.

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Marine, JC. Spotlight on the role of COP1 in tumorigenesis. Nat Rev Cancer 12, 455–464 (2012). https://doi.org/10.1038/nrc3271

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