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  • Original Article
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COP1D, an alternatively spliced constitutive photomorphogenic-1 (COP1) product, stabilizes UV stress-induced c-Jun through inhibition of full-length COP1

Oncogene volume 27, pages 2401–2411 (2008)Cite this article

Abstract

COP1 is an evolutionarily conserved RING-finger ubiquitin ligase acting within a Cullin-RING ligase (CRL) complex that promotes polyubiquitination of c-Jun and p53. Stability of the above substrates is affected by post-translational changes priming the proteins for polyubiquitination and proteasome-dependent degradation. However, degradation of both substrates is controlled indirectly by signaling pathways affecting the E3 ligases involved in their polyubiquitination. Here, we report the identification of COP1D, a ubiquitously expressed splice variant of COP1 lacking a portion of a coiled-coil region involved in intermolecular associations. While being unable to associate with other components of the CRL complex, COP1D exerts a dominant-negative function over the full-length protein, due to its ability to heterodimerize with COP1 and sequester it from the enzymatically active complex. Ectopic expression of COP1D antagonizes the function of COP1, while its selective downregulation by RNA interference promotes more efficient degradation of c-Jun and p53 by the full-length protein. The COP1/COP1D mRNA ratio is modulated by UV stress and a decreased COP1/COP1D ratio correlates with elevated c-Jun, but not p53 protein levels in invasive ductal breast cancer. Thus, dynamic changes of the COP1/COP1D ratio provide an additional level of regulation of the half-life of the substrates of this E3 ligase under homeostatic or pathological conditions.

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Acknowledgements

We thank S Putignano and B Clissi for technical help, L Cremonesi for assistance in designing the RT–PCR strategy, C Doglioni and S Grassi for providing breast cancer samples. This work was supported in part by grants from AIRC, FIRB and MIUR (PRIN projects) to RP and from National Institutes of Health Grant R01 HL43331 and the Raymond and Beverly Sackler Foundation to JRB. This study was carried out in the framework of the Italian MUIR Center of Excellence in Physiopathology of Cell Differentiation.

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  1. M G Savio and G Rotondo: These authors contributed equally to this work.

Authors and Affiliations

  1. Unit of Leukocyte Biology, Vita-Salute San Raffaele University School of Medicine, DIBIT-Scientific Institute San Raffaele, Milano, Italy

    M G Savio, G Rotondo, S Maglie, G Rossetti & R Pardi

  2. Raymond and Beverly Sackler Foundation Cardiovascular Laboratory, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA

    J R Bender

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  1. M G Savio
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  3. S Maglie
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  4. G Rossetti
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Correspondence to R Pardi.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Savio, M., Rotondo, G., Maglie, S. et al. COP1D, an alternatively spliced constitutive photomorphogenic-1 (COP1) product, stabilizes UV stress-induced c-Jun through inhibition of full-length COP1. Oncogene 27, 2401–2411 (2008). https://doi.org/10.1038/sj.onc.1210892

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