Quantitative DNA perturbations of p53 in endometriosis: analysis of American and Icelandic cases

Gylfason, Jon Torfi; Dang, Dianne; Pétursdóttir, Vigdís; Benediktsdóttir, Kristrún R.; Geirsson, Reynir Tómas; Poindexter, Alfred N.; Mitchell-Leef, Dorothy; Buster, John E.; Carson, Sandra Ann; Simpson, Joe Leigh; Bischoff, Farideh Z.

doi:10.1016/j.fertnstert.2005.05.031

Cited by 7 publications

(4 citation statements)

References 43 publications

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“…68 Gylfason et al investigated p53 copy numbers in eutopic endometrial and endometriotic tissue and observed a link between somatic p53 locus alterations and the pathogenesis of late- or severe-stage endometriosis. 69 Ovarian endometriosis can progress to epithelial cytological atypia and malignant transformation. 70 Thus, our integrative analysis suggests that p53 regulatory program might be implicated in the pathology of endometriosis and implies a possible link between endometriosis and ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

Integrative Analysis Reveals Regulatory Programs in Endometriosis

et al. 2015

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Endometriosis is a common gynecological disease found in approximately 10% of reproductive-age women. Gene expression analysis has been performed to explore alterations in gene expression associated with endometriosis; however, the underlying transcription factors (TFs) governing such expression changes have not been investigated in a systematic way. In this study, we propose a method to integrate gene expression with TF binding data and protein-protein interactions to construct an integrated regulatory network (IRN) for endometriosis. The IRN has shown that the most regulated gene in endometriosis is RUNX1, which is targeted by 14 of 26 TFs also involved in endometriosis. Using 2 published cohorts, GSE7305 (Hover, n = 20) and GSE7307 (Roth, n = 36) from the Gene Expression Omnibus database, we identified a network of TFs, which bind to target genes that are differentially expressed in endometriosis. Enrichment analysis based on the hypergeometric distribution allowed us to predict the TFs involved in endometriosis (n = 40). This included known TFs such as androgen receptor (AR) and critical factors in the pathology of endometriosis, estrogen receptor α, and estrogen receptor β. We also identified several new ones from which we selected FOXA2 and TFAP2C, and their regulation was confirmed by quantitative real-time polymerase chain reaction and immunohistochemistry (IHC). Further, our analysis revealed that the function of AR and p53 in endometriosis is regulated by posttranscriptional changes and not by differential gene expression. Our integrative analysis provides new insights into the regulatory programs involved in endometriosis.

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Section: Discussionmentioning

confidence: 99%

Integrative Analysis Reveals Regulatory Programs in Endometriosis

et al. 2015

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“…Despite the fact that glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was considered as estrogen dependent, 15 we used it as a housekeeping gene (HKG). This decision was made because ( a ) it is an accepted HKG evaluating GPER expression, 16 ( b ) it has already been used in granulosa cell experiments 17 as well as in endometriosis studies, 18 –20 and ( c ) the current experimental plan involves comparison of granulosa and theca cells from the same ovary. The same estrogenic environment is expected to exert uniform effects to both the cell types under study.…”

Section: Methodsmentioning

confidence: 99%

The G-Protein-Coupled Estrogen Receptor (GPER) is Expressed in Normal Human Ovaries and is Upregulated in Ovarian Endometriosis and Pelvic Inflammatory Disease Involving the Ovary

et al. 2012

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Estrogens play a crucial role in maintaining ovarian function. Deregulation of estrogen signals is associated with fertility-impairing disorders. The aim of this study was to investigate whether the G-protein-coupled estrogen receptor (GPER) is present in the human ovary. Additionally, we analyzed the folliculogenesis and ovarian endometriosis in GPER expression. Seventy-nine patients (ovarian endometriosis, n = 26; ovarian pelvic inflammatory disease [PID], n = 10; normal ovaries/endometrium, n = 30/13) were analyzed by immunohistochemistry. Normal ovaries were also assessed by real-time polymerase chain reaction and double immunofluorescence. The most intense expression of GPER was noted in the ovarian surface epithelium. Theca cells and oocytes were also significantly positive. Expression of GPER was more frequent in mature follicles/oocytes than in primordial ones, implying that GPER could be a selector during folliculogenesis. Moreover, GPER was upregulated in ovarian endometriosis and PID. Overexpression of GPER in both inflammation and endometriosis affecting the ovary may prove useful in explaining/predicting the main endometriosis-related symptoms.

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“…Although p53 expression in endometriosis has been controversial [81][82][83] , our data suggest and are consistent with the finding that anti-p53 AAb is restricted to patients with mutated forms of p53. Different patterns of TP53 mutations have been reported in endometriosis, including missense mutations and loss of heterozygosity that can contribute to or trigger an immune reaction by causing self-immunization of nonwildtype p53 [26][27][28] . It is worth noting that immunogenic epitopes are mapped primarily to both the N-and C-terminals of the protein 84 , while TP53 mutations are concentrated in the central portion (exons 4 to 8) 85 where autoimmunity against p53 can be generated 86 .…”

Section: Endometriosis Is Epidemiologically Linked To Autoimmune Dise...mentioning

confidence: 99%

“…The tumour suppressor p53, encoded by the TP53 gene, is a DNA motif binding transcription factor that governs core cellular programs to ensure cell and tissue homeostasis, including arresting cell cycle progression and apoptotic response to cellular stress 25 . Different patterns of p53 mutations have been reported in endometriosis, including missense mutations, overexpression, deletion of the TP53 locus, and loss of heterozygosity, that can contribute to or trigger an immune reaction by causing self-immunization of non-wildtype p53 [26][27][28][29][30] . There is a strong correlation between the frequency of anti-p53 AAbs and the frequency of p53 mutations in certain types of cancer, suggesting that p53 mutations are associated with the generation of these AAbs 26 .…”

Section: Introductionmentioning

confidence: 99%