Genetic and Molecular Analysis of hyperplastic discs, a Gene Whose Product Is Required for Regulation of Cell Proliferation in Drosophila melanogaster Imaginal Discs and Germ Cells

Mansfield, Elizabeth; Hersperger, Evelyn; Biggs, Joseph R.; Shearn, Allen

doi:10.1006/dbio.1994.1271

Cited by 97 publications

(109 citation statements)

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“…The progestin-regulated HECT/E3 ubiquitin ligase EDD (E3 ligase identified by differential display; also called DD5, hHYD) is the human orthologue of the Drosophila melanogaster 'hyperplastic discs' tumour suppressor gene (Mansfield et al, 1994). Like hyd, EDD encodes a large protein of approximately 300 kDa that contains a number of potential functional domains, including a conserved carboxy terminus HECT domain with E3 ubiquitin protein ligase activity (Callaghan et al, 1998).…”

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confidence: 99%

“…Like hyd, EDD encodes a large protein of approximately 300 kDa that contains a number of potential functional domains, including a conserved carboxy terminus HECT domain with E3 ubiquitin protein ligase activity (Callaghan et al, 1998). Mutagenesis studies have revealed a critical role for hyd in the control of cell proliferation during Drosophila development (Mansfield et al, 1994), suggesting that hyd functions as a tumour suppressor gene. There is now substantial evidence that EDD is most likely involved in the regulation of mammalian cell proliferation and human tumorigenesis.…”

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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

et al. 2008

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Despite a high initial response rate to first-line platinum/paclitaxel chemotherapy, most women with epithelial ovarian cancer relapse with recurrent disease that becomes refractory to further cytotoxic treatment. We have previously shown that the E3 ubiquitin ligase, EDD, a regulator of DNA damage responses, is amplified and overexpressed in serous ovarian carcinoma. Given that DNA damage pathways are linked to platinum resistance, the aim of this study was to determine if EDD expression was associated with disease recurrence and platinum sensitivity in serous ovarian cancer. High nuclear EDD expression, as determined by immunohistochemistry in a cohort of 151 women with serous ovarian carcinoma, was associated with an approximately two-fold increased risk of disease recurrence and death in patients who initially responded to first-line chemotherapy, independently of disease stage and suboptimal debulking. Although EDD expression was not directly correlated with relative cisplatin sensitivity of ovarian cancer cell lines, sensitivity to cisplatin was partially restored in platinum-resistant A2780-cp70 ovarian cancer cells following siRNA-mediated knockdown of EDD expression. These results identify EDD as a new independent prognostic marker for outcome in serous ovarian cancer, and suggest that pathways involving EDD, including DNA damage responses, may represent new therapeutic targets for chemoresistant ovarian cancer.

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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

et al. 2008

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“…EDD1 was initially described from mutational screens in drosophila as hyperplastic discs (hyd), which, when disrupted, resulted in overgrowth of the imaginal discs (20)(21)(22). The mammalian orthologue E3 identified by Differential Display (EDD) was first discovered through the use of differential display to identify progestin-regulated genes in a breast cancer cell line (23).…”

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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“…Previously, we identified EDD (E3 isolated by Differential Display) (Callaghan et al, 1998), the human orthologue of the Drosophila melanogaster 'hyperplastic discs' gene (hyd) (Mansfield et al, 1994). Both genes encode large proteins of approximately 300 kDa that contain conserved carboxy terminus HECT domains, indicating they function as E3 ubiquitin protein ligases (Huibregtse et al, 1995;Schwarz et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…Both genes encode large proteins of approximately 300 kDa that contain conserved carboxy terminus HECT domains, indicating they function as E3 ubiquitin protein ligases (Huibregtse et al, 1995;Schwarz et al, 1998). Mutagenesis studies (Mansfield et al, 1994) define an apparent tumour suppressor role for hyd in Drosophila by demonstrating its critical requirement in control of cell proliferation during development. Some mutations result in imaginal disc hyperplasia and adult sterility due to germ cell defects, while the null hyd phenotype is lethality in the pupal or larval stages.…”

Section: Introductionmentioning

confidence: 99%

EDD, the human orthologue of the hyperplastic discs tumour suppressor gene, is amplified and overexpressed in cancer

et al. 2003

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EDD (E3 isolated by differential display), located at chromosome 8q22.3, is the human orthologue of the Drosophila melanogaster tumour suppressor gene 'hyperplastic discs' and encodes a HECT domain E3 ubiquitin protein-ligase. To investigate the possible involvement of EDD in human cancer, several cancers from diverse tissue sites were analysed for allelic gain or loss (allelic imbalance, AI) at the EDD locus using an EDD-specific microsatellite, CEDD, and other polymorphic microsatellites mapped in the vicinity of the 8q22.3 locus. Of 143 cancers studied, 38 had AI at CEDD (42% of 90 informative cases). In 14 of these cases, discrete regions of imbalance encompassing 8q22.3 were present, while the remainder had more extensive 8q aberrations. AI of CEDD was most frequent in ovarian cancer (22/47 informative cases, 47%), particularly in the serous subtype (16/22, 73%), but was rare in benign and borderline ovarian tumours. AI was also common in breast cancer (31%), hepatocellular carcinoma (46%), squamous cell carcinoma of the tongue (50%) and metastatic melanoma (18%). AI is likely to represent amplification of the EDD gene locus rather than loss of heterozygosity, as quantitative RT-PCR and immunohistochemistry showed that EDD mRNA and protein are frequently overexpressed in breast and ovarian cancers, while among breast cancer cell lines EDD overexpression and increased gene copy number were correlated. These results demonstrate that AI at the EDD locus is common in a diversity of carcinomas and that the EDD gene is frequently overexpressed in breast and ovarian cancer, implying a potential role in cancer progression.

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Genetic and Molecular Analysis of hyperplastic discs, a Gene Whose Product Is Required for Regulation of Cell Proliferation in Drosophila melanogaster Imaginal Discs and Germ Cells

Cited by 97 publications

References 0 publications

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

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

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

EDD, the human orthologue of the hyperplastic discs tumour suppressor gene, is amplified and overexpressed in cancer

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