Disease relevance of EDD1

• Progestin-induced caveolin-1 expression mediates breast cancer cell proliferation [1].
• 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 [2].
• 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 [2].
• History of premenstrual syndrome, type of progestin, and dose of progestin have thus far been shown to influence the progestin-induced adverse mood symptoms during HRT [3].
• In haplotype analysis, the HYD haplotype was associated with increased risk of stomach cancer when compared with HYA, the most common haplotype (OR = 1.9, 95% CI 1.1-3.2; p = 0.021) [4].

Psychiatry related information on EDD1

• Plasma concentrations of BUP were time dependent, as were withdrawal symptoms, carbon dioxide sensitivity and extent of HYD blockade [5].

High impact information on EDD1

• Preliminary evidence for the biological significance of this PR signaling pathway through regulatory SH3 domains was shown with respect to an influence on progestin-induced growth arrest of breast epithelial cells and induction of Xenopus oocyte maturation [6].
• Brachial artery diameter was measured at rest, during increased flow (causing endothelium-dependent dilation, EDD) and after sublingual glyceryl trinitrate (causing endothelium-independent dilation) [7].
• Dietary supplementation with L-arginine significantly improves EDD in hypercholesterolemic young adults, and this may impact favorably on the atherogenic process [7].
• Expression of the progestin-induced fatty acid synthetase in benign mastopathies and breast cancer as measured by RNA in situ hybridization [8].
• Sequence profile searches and comparative protein structure modeling identified a small ORF from the Arabidopsis thaliana genome that encodes a structurally similar but distantly related PABP/HYD domain [9].

Chemical compound and disease context of EDD1

• Use of the differential display technique to isolate progestin-regulated genes in T-47D human breast cancer cells led to identification of a novel gene, EDD [10].
• Estrogen, androgen, glucocorticoid, and progesterone receptors in progestin-induced regression of human breast cancer [11].
• Endothelium-dependent and -independent vasodilatations (EDD and EID, respectively) were assessed by establishing of the responses to reactive hyperemia and by using sublingual nitroglycerine, respectively [12].

Biological context of EDD1

• These results demonstrated that hHYD coordinated TopBP1 in the DNA damage response [13].
• The human homologue of the regulator of cell proliferation hyperplastic discs in Drosophila, designated hHYD, is a HECT-domain ubiquitin ligase [13].
• Lactacystin and calpain inhibitor I, specific inhibitors of the 26S proteasome, blocked progestin-induced down-regulation, and ubiquitinated conjugates of PR accumulated in cells [14].
• Frequent allelic imbalance at the EDD chromosomal locus in human cancers suggests a role in tumorigenesis [15].
• EDD also binds progesterone receptor (PR) and potentiates progestin-mediated gene transactivation [15].

Anatomical context of EDD1

• Decidualization is the progestin-induced differentiation of estrogen-primed endometrial stromal cells (ESCs), which is crucial for implantation and maintenance of pregnancy [16].
• Recently we reported that progestin-induced GH excess originates from foci of hyperplastic ductular epithelium of the mammary gland in the dog [17].
• Proliferation of endothelial and tumor epithelial cells by progestin-induced vascular endothelial growth factor from human breast cancer cells: paracrine and autocrine effects [18].
• Progestin-induced fibroadenomatous changes in the mammary gland of cats are also associated with locally enhanced GH expression [19].
• Mitral valve EPSS and EPSS/EDD can now be used in pediatric echocardiography as a simple, practical and accurate means of separating normal from abnormal LV function [20].

Associations of EDD1 with chemical compounds

• EDD was significantly lower in hyperhomocysteinemic subjects (6.5+/-1.7%) than in subjects with low homocysteine levels (10.8+/-1.7%) (P<.001) [21].
• More importantly, the progestin-induced growth stimulation was blocked by the antiestrogens 4-hydroxytamoxifen and ICI 164,384 but not the antiprogestin 17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)-17 alpha-(1-propynyl)-estra-4, 9-dien-3-one (RU486) [22].
• The interference was not mutual, as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent activator of the AhR, did not inhibit progestin-induced promoter activity [23].
• EDD is necessary for the efficient activating phosphorylation of CHK2 in response to DNA damage following exposure to ionizing radiation or the radiomimetic, phleomycin [24].
• An im injection of 5000 IU hCG was given 2-4 d after spontaneous or progestin-induced menstrual bleeding, and blood samples for LH, FSH, inhibin B, 17-hydroxyprogesterone, androstenedione (A), testosterone (T), and estradiol assays were collected at 0, 24, 48, and 96 h [25].

Physical interactions of EDD1

• A yeast two-hybrid screen showed that DNA topoisomerase IIbeta-binding protein 1 (TopBP1) interacted with hHYD [13].
• Endogenous hHYD bound the BRCA1 C-terminus domains of TopBP1 that are highlighted in DNA damage checkpoint proteins and cell cycle regulators [13].

Enzymatic interactions of EDD1

• To further validate the method, we present data that confirm that ERK2 phosphorylates EDD in vitro and in vivo [26].

Regulatory relationships of EDD1

• In this study, we investigate the role of GPR30 in regulating cell proliferation and mediating progestin-induced growth inhibition [27].
• In human mammary tumor T47D cells that contain both progesterone and epidermal growth factor (EGF) receptors, the progestin-induced transactivation at various hormone regulated promoters is enhanced by EGF [28].

Other interactions of EDD1

• The data presented here demonstrate a role for EDD in PR signaling but also suggest a link to cancer through DNA damage response pathways [15].
• We show that progestin-induced S-phase entry and upregulation of selected target genes, including cyclin D1, are MAPK-dependent events [29].
• This activity is comparable with that of the coactivator SRC-1, but, in contrast, the interaction between EDD and PR does not appear to involve an LXXLL receptor-binding motif [15].
• We have previously shown that the G protein-coupled receptor (GPR)30 is critical for progestin-induced growth inhibition [30].
• We have previously shown that G protein-coupled receptor 30 (GPR30) is a progestin target gene whose expression correlates with progestin-induced growth inhibition in breast cancer cells [27].

Analytical, diagnostic and therapeutic context of EDD1

• Multivariate analysis confirmed homocysteine level as the strongest predictor for impaired EDD, independent of age, sex, body mass index, or blood pressure, folate, vitamin B12, and cholesterol levels [21].
• METHODS: Availability of muOR (measured with positron emission tomography and [(11)C]-carfentanil), plasma BUP concentration, opioid withdrawal symptoms, and blockade of hydromorphone (HYD; heroin-like agonist) effects were measured at 4, 28, 52, and 76 hours after omitting the 16 mg/d dose of BUP in a study reported elsewhere [5].
• Measurements of left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), stroke dimension (SD = LVEDD-LVESD), fractional shortening (FS = SD/EDD) and posterior wall thickness (PWT) were obtained from continuous 2-D targeted on M-mode echocardiography [31].
• In normal subjects, EPSS was 2.5 +/- 1.7 mm and "normalized" EPSS, that is, the ratio of EPSS to end-diastolic dimension (EPSS/EDD), was 0.08 +/- 0.06 (mean +/- standard deviation); there was no correlation between either of these indexes and age, body surface area, height or weight [20].
• Materials and methods Blood was drawn on the third and sixth days after progestin-induced withdrawal bleeding in 20 young non-diabetic women with PCOS and once between the third and sixth days of the menstrual cycle in 21 age-matched lean healthy control women during a 75-g oral glucose tolerance test (oGTT) [32].

References