Cop1 constitutively regulates c-Jun protein stability and functions as a tumor suppressor in mice

Domenico Migliorini ¹, Sven Bogaerts , Dieter Defever

⁰Laboratory for Molecular Cancer Biology, Department of Molecular and Developmental Genetics, VIB-K.U.Leuven, Leuven, Belgium.

The Journal of Clinical Investigation +

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March 16, 2011

View abstract on PubMed

Summary

Constitutive photomorphogenesis protein 1 (Cop1) acts as a tumor suppressor by inhibiting the oncogenic activity of c-Jun. Cop1 deficiency promotes cancer development and is linked to c-Jun upregulation in human cancers.

Area Of Science

Oncology
Molecular Biology
Genetics

Background

Conflicting roles for E3 ubiquitin ligase Cop1 in tumorigenesis, with c-Jun and p53 as proposed targets.
Lack of in vivo studies investigating Cop1's role in cancer etiology.

Purpose Of The Study

To investigate the in vivo role of Cop1 in cancer development.
To elucidate the mechanism by which Cop1 influences tumorigenesis, focusing on its interaction with c-Jun and p53.

Main Methods

Generation of an allelic series of Cop1 hypomorphic mice.
Analysis of spontaneous and radiation-induced malignancy in Cop1 mutant mice.
Investigation of c-Jun as a physiological target of Cop1 in vivo.
Assessment of COP1 gene deletions in human cancers.

Main Results

Cop1 hypomorphic mice exhibited high-frequency spontaneous malignancy and susceptibility to radiation-induced lymphomagenesis.
Cop1 directly targets c-Jun, maintaining it at low levels in vivo and regulating c-Jun/AP-1 transcriptional activity.
Cop1 deficiency promoted c-Jun-dependent cell proliferation.
Focal deletions of COP1 were frequent in various human cancers, correlating with c-Jun upregulation.

Conclusions

Cop1 functions as a tumor suppressor by antagonizing c-Jun oncogenic activity.
COP1 loss is a mechanism for c-Jun upregulation in human cancer.
Evidence suggests Cop1 does not genetically interact with p53, cautioning against Cop1-inhibitory drugs in cancer therapy.

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