The E3 ubiquitin ligase EDD is an adverse prognostic factor for serous epithelial ovarian cancer and modulates cisplatin resistance in vitro

O’Brien, Philippa M.; Davies, Michael J.; Scurry, James; Smith, A N; Barton, Caroline; Henderson, Michelle J.; Saunders, Darren N.; Gloss, Brian; Patterson, Kate I.; Clancy, Jennifer L.; Heinzelmann‐Schwarz, Viola; Murali, Rajmohan; Scolyer, Richard A.; Zeng, Yiping; Williams, Elizabeth D.; Scurr, Lyndee L.; deFazio, Anna; Quinn, David I.; Watts, Colin; Hacker, Neville F.; Henshall, Susan M.; Sutherland, Robert L.

doi:10.1038/sj.bjc.6604281

Cited by 61 publications

(56 citation statements)

References 41 publications

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“…Evidence suggesting an involvement of EDD1 in human cancer includes the finding from several studies demonstrating that the degree by which EDD1 interacts with CIB, TOPBP1, and CHK2 is regulated by the DNA damage response (22,24,25). Moreover, EDD1 expression has been shown to functionally correlate with the responsiveness of patients with ovarian cancer to DNA-damaging cytotoxic therapies (26). Several reports have also demonstrated that EDD1 is overexpressed in a high percentage of cancers, consistent with a pattern that correlates with an increased copy number of the EDD1 locus (27,28).…”

Section: Discussionmentioning

confidence: 99%

A whole-genome RNAi screen identifies an 8q22 gene cluster that inhibits death receptor-mediated apoptosis

Dompe

Rivers

Li³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Deregulation of apoptosis is a common occurrence in cancer, for which emerging oncology therapeutic agents designed to engage this pathway are undergoing clinical trials. With the aim of uncovering strategies to activate apoptosis in cancer cells, we used a pooled shRNA screen to interrogate death receptor signaling. This screening approach identified 16 genes that modulate the sensitivity to ligand induced apoptosis, with several genes exhibiting frequent overexpression and/or copy number gain in cancer. Interestingly, two of the top hits, EDD1 and GRHL2, are found 50 kb apart on chromosome 8q22, a region that is frequently amplified in many cancers. By using a series of silencing and overexpression studies, we show that EDD1 and GRHL2 suppress death-receptor expression, and that EDD1 expression is elevated in breast, pancreas, and lung cancer cell lines resistant to death receptor-mediated apoptosis. Supporting the relevance of EDD1 and GRHL2 as therapeutic candidates to engage apoptosis in cancer cells, silencing the expression of either gene sensitizes 8q22-amplified breast cancer cell lines to death receptor induced apoptosis. Our findings highlight a mechanism by which cancer cells may evade apoptosis, and therefore provide insight in the search for new targets and functional biomarkers for this pathway.

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Section: Discussionmentioning

confidence: 99%

A whole-genome RNAi screen identifies an 8q22 gene cluster that inhibits death receptor-mediated apoptosis

Dompe

Rivers

Li³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…EDD is frequently amplified and overexpressed in many types of cancer, including ovarian cancer, breast cancer, hepatocellular carcinoma, squamous cell carcinoma of the tongue, and metastatic melanoma (20). Furthermore, high nuclear EDD expression in serous ovarian carcinoma is associated with adverse prognosis, and depletion of EDD inhibits the growth of cisplatin-resistant ovarian cancer cells and partially restores their platinum sensitivity (43). It would be interesting to investigate whether the association of EDD overexpression with poor clinical outcome in cancer patients is related to its activity in suppressing p53 activation.…”

Section: Discussionmentioning

confidence: 99%

EDD Inhibits ATM-mediated Phosphorylation of p53

Ling

Lin

2011

Journal of Biological Chemistry

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The EDD (E3 identified by differential display) gene, first identified as a progestin-induced gene in T-47D breast cancer cells, encodes an E3 ubiquitin ligase with a HECT domain. It was reported that EDD is involved in the G 2 /M progression through ubiquitination of phospho-katanin p60. Previous study has also shown that EDD can act as a transcription cofactor independently of its E3 ligase activity. In this study, we uncover a new role for EDD during cell cycle progression in an E3 ligase-independent manner. We demonstrate that EDD can physically interact with p53 and that this interaction blocks the phosphorylation of p53 by ataxia telangiectasia mutated (ATM). Silencing of EDD induces phosphorylation of p53 at Ser 15 and activates p53 target genes in fibroblasts and some transformed cells without activation of DNA damage response. The G 1 /S arrest induced by EDD depletion depends on p53. On the other hand, overexpression of EDD inhibits p53-Ser 15 phosphorylation and suppresses the induction of p53 target genes during DNA damage, and this effect does not require its E3 ligase activity. Thus, through binding to p53, EDD actively inhibits p53 phosphorylation by ATM and plays a role in ensuring smooth G 1 /S progression.The tumor suppressor p53, one of the most important proteins in preventing human cancer, is a critical factor controlling cell cycle progression, particularly during the G 1 /S transition. Mutations of the p53 gene occur in at least half of all human cancers. Phosphorylation of p53 stabilizes p53 and hence induces both cell cycle arrest and apoptosis. Regulation of p53 phosphorylation is very complicated. There are three main kinases that are thought to be responsible for p53 phosphorylation at Ser 15 residue under genotoxic stresses: ataxia telangiectasia mutated (ATM), 3 ataxia telangiectasia and Rad3-related (ATR), and DNA-PK (DNA-dependent protein kinase) (1-3). ATM is a major player in phosphorylating p53 at Ser 15 in response to ionizing radiation, and ATR plays a central role in response to UV light. The group of proteins phosphorylated by DNA-PK, including p53, is mainly involved in the non-homologous end joining DNA double strand break repair. However, all these three kinases can phosphorylate p53 at Ser 15 , and there is a lot of cross-talk between these three pathways. Besides Ser 15 , ATM can also stimulate Chk2 to phosphorylate p53 at Ser 20 , a site that is critical for the stability of p53. In addition to phosphorylation, other post-translational modifications such as acetylation, methylation, ubiquitination, and sumoylation regulate p53 as well (4). The status of these post-translational modifications determines whether p53 is active or not. Even in the cycling cells, there exist spontaneous pulses of p53, but without sustained active modifications, these p53 fail to induce p21 or cell cycle arrest (5). Therefore, p53 is controlled actively by both inhibitors and activators in a delicate manner so that cellular proliferation can proceed in unstressed condition, but upon encount...

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“…Indeed, the gene for UBR5 (EDD), one of N-recognins (Fig. 1A), is often amplified in ovarian carcinoma, and it is an adverse prognostic factor in this disease (40).…”

Section: Discussionmentioning

confidence: 99%

The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments

Piatkov

Brower

Varshavsky

2012

Proc. Natl. Acad. Sci. U.S.A.

126

195

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In the course of apoptosis, activated caspases cleave ∼500 to ∼1,000 different proteins in a mammalian cell. The dynamics of apoptosis involve a number of previously identified, caspase-generated proapoptotic protein fragments, defined as those that increase the probability of apoptosis. In contrast to activated caspases, which can be counteracted by inhibitor of apoptosis proteins, there is little understanding of antiapoptotic responses to proapoptotic protein fragments. One possibility is the regulation of proapoptotic fragments through their selective degradation. The previously identified proapoptotic fragments Cys-RIPK1, Cys-TRAF1, Asp-BRCA1, Leu-LIMK1, Tyr-NEDD9, Arg-BID, Asp-BCL XL , Arg-BIM EL , Asp-EPHA4, and Tyr-MET bear destabilizing N-terminal residues. Tellingly, the destabilizing nature (but not necessarily the actual identity) of N-terminal residues of proapoptotic fragments was invariably conserved in evolution. Here, we show that these proapoptotic fragments are short-lived substrates of the Arg/N-end rule pathway. Metabolic stabilization of at least one such fragment, Cys-RIPK1, greatly augmented the activation of the apoptosis-inducing effector caspase-3. In agreement with this understanding, even a partial ablation of the Arg/N-end rule pathway in two specific N-end rule mutants is shown to sensitize cells to apoptosis. We also found that caspases can inactivate components of the Arg/N-end rule pathway, suggesting a mutual suppression between this pathway and proapoptotic signaling. Together, these results identify a mechanistically specific and functionally broad antiapoptotic role of the Arg/N-end rule pathway. In conjunction with other apoptosis-suppressing circuits, the Arg/N-end rule pathway contributes to thresholds that prevent a transient or otherwise weak proapoptotic signal from reaching the point of commitment to apoptosis.

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The E3 ubiquitin ligase EDD is an adverse prognostic factor for serous epithelial ovarian cancer and modulates cisplatin resistance in vitro

Cited by 61 publications

References 41 publications

A whole-genome RNAi screen identifies an 8q22 gene cluster that inhibits death receptor-mediated apoptosis

A whole-genome RNAi screen identifies an 8q22 gene cluster that inhibits death receptor-mediated apoptosis

EDD Inhibits ATM-mediated Phosphorylation of p53

The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments

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