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It is not all about BRCA: Cullin-Ring ubiquitin Ligases in ovarian cancer.

ABSTRACT: Mutations in the BRCA1 and BRCA2 genes predispose individuals to the development of breast and ovarian cancers. As a result, biochemical functions of BRCA1 and BRCA2 proteins are being characterised in great detail. These studies have prompted the use of PARP inhibitors to treat BRCA1 and BRCA2-deficient ovarian cancers. This example of synthetic lethality represents a conceptual progress made recently in the approach to cancer treatment and is being currently tested in multiple clinical trials. Other than BRCA1 and BRCA2, many other factors might influence the survival of ovarian cancer patients. Currently, ovarian cancer remains the fifth most common cancer in the United Kingdom among women. Recent evidence suggests benefit in the modulation of the ubiquitin-proteasome system for the treatment of ovarian cancer. In this manuscript, we review the role of Cullin-Ring ubiquitin Ligases (CRLs) in the pathogenesis of ovarian cancer and their potential therapeutic exploitation. CRLs comprise a large family of proteins that, like kinases, might represent ideal candidates for targeted therapy and provide a large repertoire for the development of new anti-cancer compounds.

SUBMITTER: Carlucci A

PROVIDER: S-EPMC4453745 | biostudies-other | 2015 Jan

REPOSITORIES: biostudies-other

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Project description:UnlabelledThe rotavirus nonstructural protein NSP1 acts as an antagonist of the host antiviral response by inducing degradation of key proteins required to activate interferon (IFN) production. Protein degradation induced by NSP1 is dependent on the proteasome, and the presence of a RING domain near the N terminus has led to the hypothesis that NSP1 is an E3 ubiquitin ligase. To examine this hypothesis, pulldown assays were performed, followed by mass spectrometry to identify components of the host ubiquitination machinery that associate with NSP1. Multiple components of cullin RING ligases (CRLs), which are essential multisubunit ubiquitination complexes, were identified in association with NSP1. The mass spectrometry was validated in both transfected and infected cells to show that the NSP1 proteins from different strains of rotavirus associated with key components of CRL complexes, most notably the cullin scaffolding proteins Cul3 and Cul1. In vitro binding assays using purified proteins confirmed that NSP1 specifically interacted with Cul3 and that the N-terminal region of Cul3 was responsible for binding to NSP1. To test if NSP1 used CRL3 to induce degradation of the target protein IRF3 or ?-TrCP, Cul3 levels were knocked down using a small interfering RNA (siRNA) approach. Unexpectedly, loss of Cul3 did not rescue IRF3 or ?-TrCP from degradation in infected cells. The results indicate that, rather than actively using CRL complexes to induce degradation of target proteins required for IFN production, NSP1 may use cullin-containing complexes to prevent another cellular activity.ImportanceThe ubiquitin-proteasome pathway plays an important regulatory role in numerous cellular functions, and many viruses have evolved mechanisms to exploit or manipulate this pathway to enhance replication and spread. Rotavirus, a major cause of severe gastroenteritis in young children that causes approximately 420,000 deaths worldwide each year, utilizes the ubiquitin-proteasome system to subvert the host innate immune response by inducing the degradation of key components required for the production of interferon (IFN). Here, we show that NSP1 proteins from different rotavirus strains associate with the scaffolding proteins Cul1 and Cul3 of CRL ubiquitin ligase complexes. Nonetheless, knockdown of Cul1 and Cul3 suggests that NSP1 induces the degradation of some target proteins independently of its association with CRL complexes, stressing a need to further investigate the mechanistic details of how NSP1 subverts the host IFN response.

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It is not all about BRCA: Cullin-Ring ubiquitin Ligases in ovarian cancer.

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