Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ovarian surface epithelial cells have been implicated in the genesis of common ovarian cancers. The integrity of DNA of ovarian surface epithelial cells contiguous with the ovulatory stigma becomes compromised during the rupture process; most cells degenerate by apoptosis, however some, bearing sublethal lesions, persist along the margins of ovulated follicles. Clonal expansion of a genetically-damaged surface epithelial cell (i.e. with unrepaired DNA, but not committed to death) can presumably give rise to ovarian carcinoma. It was hypothesized that estradiol and progesterone regulate ovarian surface epithelial cell-cycle dynamics associated with folliculo-luteal transitions and ovulatory wound repair/remodeling. Progesterone up-regulated the tumor suppressor p53 and inhibited baseline and estradiol-stimulated proliferation of cultured sheep ovarian surface epithelial cells. Anti/mitotic responses to steroid hormones were transcriptionally- and receptor-dependent. Rates of apoptosis (DNA fragmentation) were unaffected by progesterone. High concentrations of estradiol, via a nongenomic (perhaps antioxidant) mechanism, suppressed basal and H(2)O(2)-induced apoptosis. We suggest that, progesterone serves to inhibit proliferation of ovarian surface epithelial cells throughout the luteal phase--providing the time (growth arrest) required to correct any metabolic disturbances to DNA that are perpetrated as an inevitable by-product of the ovulatory process. With luteolysis and dominance of an estrogenic preovulatory follicle the ovarian surface epithelium is then regenerated. Thus, it is conceivable that perturbations to the steroid hormonal milieu of ovarian cycles could be a predisposing factor for cancerous transformation of an ovarian surface epithelial cell.
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PMID:Steroid hormonal regulation of proliferative, p53 tumor suppressor, and apoptotic responses of sheep ovarian surface epithelial cells. 1185 Jan 22

Progesterone has been used in the treatment of patients with recurrent or metastatic progesterone receptor-positive endometrial carcinoma and breast cancer. In vitro study using a breast cancer cell line, T47D, demonstrated an increase in p53 gene expression and induction of apoptosis by the administration of progesterone. Therefore, we investigated the effect of progesterone administration on the proliferation and apoptosis in a mesothelioma cell line, 211H. The expression of the progesterone receptor gene was detected in this cell line by a nested RT-PCR method. The proliferation of the cell line was suppressed after a 10-day incubation with 30 microM progesterone. In progesterone-treated 211H cells, apoptotic cells were detected by TUNEL assay and nuclear DNA fragmentation analysis. These results clearly demonstrated that progesterone administration suppressed the cell proliferation and induced apoptosis in malignant mesothelioma cells.
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PMID:Progesterone induces apoptosis in malignant mesothelioma cells. 1191 Dec 61

The aim of this study was to assess the correlation of survival with clinical, surgical, histopathological, and biochemical parameters in patients with ovarian cancer. Age, surgical and histopathological data, the concentrations of estrogen and progesterone receptors, Her-2 neu, p53, U-PA, PAI-1, and Cathepsin D, DNA-and S-phase indexes of 111 ovarian cancer patients have been analyzed and correlated to survival. Progesterone receptors were correlated with prolonged survival. FIGO staging at the time of diagnosis is an independent prognostic factor for the patient's survival. Endometrioid and serous ovarian cancers have a better prognosis than mucinous and clear cell ovarian cancers. Survival of optimally debulked patients was substantially longer than that of not optimally debulked patients. This study shows, that an accurate clinical and surgical staging with an according histopathological assessment combined with optimal cytoreduction is of importance for the prognosis of ovarian cancer patients.
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PMID:Analysis of potential prognostic factors in 111 patients with ovarian cancer. 1501 65

This study demonstrated, for the first time, the following events related to p19(ARF) involvement in mammary gland development: 1) Progesterone appears to regulate p19(ARF) in normal mammary gland during pregnancy. 2) p19(ARF) expression levels increased sixfold during pregnancy, and the protein level plateaus during lactation. 3) During involution, p19(ARF) protein level remained at high levels at 2 and 8 days of involution and then, declined sharply at day 15. Absence of p19(ARF) in mammary epithelial cells leads to two major changes, 1) a delay in the early phase of involution concomitant with downregulation of p21(Cip1) and decrease in apoptosis, and 2) p19(ARF) null cells are immortal in vivo measured by serial transplantion, which is partly attributed to complete absence of p21(Cip1) compared with WT cells. Although, p19(ARF) is dispensable in mammary alveologenesis, as evidenced by normal differentiation in the mammary gland of pregnant p19(ARF) null mice, the upregulation of p19(ARF) by progesterone in the WT cells and the weakness of p21(Cip1) in mammary epithelial cells lacking p19(ARF) strongly suggest that the functional role(s) of p19(ARF) in mammary gland development is critical to sustain normal cell proliferation rate during pregnancy and normal apoptosis in involution possibly through the p53-dependent pathway.
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PMID:p19ARF determines the balance between normal cell proliferation rate and apoptosis during mammary gland development. 1510 43

VEGF, a potent angiogenic growth factor, is up-regulated in many tumors including human breast tumors and stimulates growth of vascular networks that support tumor growth and metastasis. We previously reported that natural and synthetic progestins (P) increased VEGF mRNA and protein levels in progesterone receptor (PR) containing T47-D human breast cancer cells in a PR dependent manner, but not in PR positive ZR-75 and MCF-7, or in PR negative MDA-MB-231 cells. This indicated that factors beside PR are involved in progesterone-dependent VEGF regulation. We, therefore, tested additional tumor cell lines reported to contain PR for progestin-dependent VEGF induction. Out of nine PR-positive breast tumor cell lines, progestins induced VEGF in three cell lines that lack wild-type p53 (T47-D, BT-474, and HCC-1428) but not in cell lines that contained the wild-type p53 protein. The T47-D and BT-474 cells express mutant p53, while the p53 protein is absent HCC-1428 cells. The anti-progestin RU-486 blocked progestin-dependent induction of VEGF in T47-D and BT-474 cells but not in HCC-1428 cells. However, RU-486 partially blocked medroxyprogesterone acetate-dependent induction of VEGF in HCC-1428 cells. Estrogen receptor (ER) and PR agonists and antagonists also induce VEGF in HCC-1428 cells and this effect was partially blocked by anti-estrogen ICI-182, 780. Progestin-dependent VEGF induction was completely inhibited by PRIMA-1-activated p53 in all cell-types, but progestin-dependent transcription of a progesterone-regulated minimal promoter was only partially inhibited. PRIMA-1 induced activation of p53 in tumor cell lines was confirmed with a p53-responsive p21 reporter plasmid and by detecting increased levels of p21 proteins in cell lysates. PRIMA-1 induced p53 protein in the HCC-1428 cells while levels of mutant p53 protein in T47-D and BT-474 remained unaltered. Progestin-dependent induction of VEGF was also inhibited by stable transfection of wild-type p53 in T47-D cells. These results are consistent with the hypothesis that wild-type p53 blocks progestin-dependent induction of VEGF in breast cancer cells and this may be a novel anti-angiogenic mechanism for controlling the growth of progestin-dependent tumors.
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PMID:p53-dependent inhibition of progestin-induced VEGF expression in human breast cancer cells. 1586 Feb 60

Women with mutations in the breast cancer susceptibility gene BRCA1 are predisposed to breast and ovarian cancers. Why the BRCA1 protein suppresses tumor development specifically in ovarian hormone-sensitive tissues remains unclear. We demonstrate that mammary glands of nulliparous Brca1/p53-deficient mice accumulate lateral branches and undergo extensive alveologenesis, a phenotype that occurs only during pregnancy in wild-type mice. Progesterone receptors, but not estrogen receptors, are overexpressed in the mutant mammary epithelial cells because of a defect in their degradation by the proteasome pathway. Treatment of Brca1/p53-deficient mice with the progesterone antagonist mifepristone (RU 486) prevented mammary tumorigenesis. These findings reveal a tissue-specific function for the BRCA1 protein and raise the possibility that antiprogesterone treatment may be useful for breast cancer prevention in individuals with BRCA1 mutations.
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PMID:Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist. 1713 73

Ovarian cancer is a disease difficult to detect in early stages due to nonspecific symptoms and has a rapid progression with frequent relapses after radical surgical procedure. For these reasons, ovarian cancer generally represents the fourth cause of death through cancer in females, while in our country it is surpassed only by cervix cancer. The reduced survival is associated with the absence of symptoms, especially in early stages. Therefore, the diagnosis is delayed, when the metastases are already present and the prognosis is poor. While the etiology of the ovarian cancer is less understood, the histopathological studies and experiments regarding ovarian cancer development suggest that the majority of the tumors refined to the surface epithelium, a cuboidal layer that lays the ovary. It is still unclear if the molecular changes in this layer generate a neoplastic precursor that can be used for establishing an early diagnosis. None of the changes of the involved genes (p53, k-Ras, Her-2/neu, c-Myc, etc.) does seem to follow certain steps. We analyzed histological and immunohistochemical a group of 60 female patients admitted during January 2004 and January 2005 in Surgery Clinic of "Sfantul Ioan" Emergency Hospital, Bucharest. Our study reveals that a high percent (68.33%) of females had a correct diagnosis at admission, only five patients (8.33%) being diagnosed with other diseases. In 86.66% of cases, total hysterectomy with bilateral anexectomy has been made, in two cases (3.33%) tumor resection was the only needed therapy and in 19 cases (31.66%) peritoneal implants were found. More than 75% were serous tumors, 20% mucinous carcinoma and 5% borderline ovarian tumors. We found three cases of borderline tumors (5%) that histopathological proved to be serous tumors. The analysis of hormone receptors showed estrogen receptors in 32 cases (71.1%) of serous ovarian adenocarcinoma, in seven cases (58.33%) of mucinous adenocarcinoma, all three cases (100%) of borderline tumors and in four cases (21.05%) of the 19 with peritoneal implants. Progesterone receptors were found in 27 cases (60%) of serous carcinoma, five cases (41.66%) of mucinous carcinoma, one case (33.33%) of borderline tumors and five cases (26.31%) with peritoneal metastases. Immunohistochemical study of CerbB-2 showed positively only in 37 cases (82.22%) of serous carcinomas, five cases (41.66%) of mucinous carcinomas, one case (33.33%) of borderline tumor and eight cases (42.10%) with peritoneal metastases. All tumor types presented positives for CA125 (91.1% in serous tumors, 83.33% in mucinous tumors, 33.33% in borderline tumors and 73.68% in tumors with peritoneal implants. The investigated proliferative factors p53 and Ki-67 demonstrated correlation with tumor aggressiveness. Lack of positivity in borderline tumors and strong positivity in serous and mucinous carcinomas shows correlations with literature. This study outlines that an immunohistochemical analysis of certain antibodies cannot offer useful data regarding the prognosis or the screening for ovarian cancer.
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PMID:Clinical factors and biomarkers in ovarian tumors development. 1875 37

Biomarkers of breast cancer are necessary for prognosis and prediction to chemotherapy. Prognostic biomarkers provide information regarding outcome irrespective of therapy, while predictive biomarkers provide information regarding response to therapy. Candidate prognostic biomarkers for breast cancers are growth factor receptors, steroid receptors, Ki-67, cyclins, urokinase plasminogen activator, p53, p21, pro- and anti-apoptotic factors, BRCA1 and BRCA2. But currently, the predictive markers are Estrogen and Progesterone receptors responding to endocrine therapy, and HER-2 responding to herceptin. But there are numerous breast cancer cases, where tamoxifen is ineffective even after estrogen receptor positivity. This lead to search of new prognostic and predictive markers and the number of potential markers is constantly increasing due to proteomics and genomics studies. However, most biomarkers individually have poor sensitivity or specificity, or other clinical value. It can be resolved by studying various biomarkers simultaneously, which will help in better prognosis and increasing sensitivity for chemotherapeutic agents. This review is focusing on growth factor receptors, apoptosis markers, signaling cascades, and their correlation with other associated biomarkers in breast cancers. As our knowledge regarding molecular biomarkers for breast cancer increases, prognostic indices will be developed that combine the predictive power of individual molecular biomarkers with specific clinical and pathologic factors. Rigorous comparison of these existing as well as emerging markers with current treatment selection is likely to see an escalation in an era of personalized medicines to ensure the breast cancer patients receive optimal treatment. This will also solve the treatment modalities and complications related to chemotherapeutic regimens.
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PMID:Growth factor receptors and apoptosis regulators: signaling pathways, prognosis, chemosensitivity and treatment outcomes of breast cancer. 2155 49

Settings. Despite the limited diagnostic utility of AgNORs (argyrophilic nucleolar organiser region-associated proteins) for individual breast lesions, AgNOR analysis bears a significant potential for characterizing cell proliferative activity of breast lesions. Methodology. The present study investigated the relationship between mean AgNORs count and immunohistochemical expression of ER, PR, HER2/neu, and p53 in breast carcinoma in serial paraffin sections from 137 breast carcinomas. Twenty control cases of benign breast lesions were included. Results. Mean AgNOR counts correlated significantly inversely with hormone estrogen receptors (ER), Progesterone receptors (PR), and p53 immunohistochemical expression, denoting P values of 0.05, 0.01, and 0.001, respectively. No significant correlation was found between mean AgNOR counts and HER2/neu, P = 0.9. Mean AgNOR count was significantly higher in grade II tumor cells. We conclude that mean AgNOR counts correlate with ER, PR, and P53 tumor markers in breast carcinomas. Conclusion. We recommend the use of mean AgNOR count for accurate reporting of breast carcinomas, as well as prediction of ER, PR, and P53 in routine paraffin sections.
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PMID:Association between AgNORs and Immunohistochemical Expression of ER, PR, HER2/neu, and p53 in Breast Carcinoma. 2213 66

Islet leukocytic infiltration (insulitis) is first obvious at around 4 weeks of age in the NOD mouse--a model for human type 1 diabetes (T1D). The molecular events that lead to insulitis and initiate autoimmune diabetes are poorly understood. Since TID is caused by numerous genes, we hypothesized that multiple molecular pathways are altered and interact to initiate this disease. We evaluated the molecular phenotype (mRNA and protein expression) and molecular networks of ex vivo unfractionated spleen leukocytes from 2 and 4 week-old NOD mice in comparison to two control strains. Analysis of the global gene expression profiles and hierarchical clustering revealed that the majority (~90%) of the differentially expressed genes in NOD mice were repressed. Furthermore, analysis using a modern suite of multiple bioinformatics approaches identified abnormal molecular pathways that can be divided broadly into 2 categories: metabolic pathways, which were predominant at 2 weeks, and immune response pathways, which were predominant at 4 weeks. Network analysis by Ingenuity pathway analysis identified key genes/molecules that may play a role in regulating these pathways. These included five that were common to both ages (TNF, HNF4A, IL15, Progesterone, and YWHAZ), and others that were unique to 2 weeks (e.g. MYC/MYCN, TGFB1, and IL2) and to 4 weeks (e.g. IFNG, beta-estradiol, p53, NFKB, AKT, PRKCA, IL12, and HLA-C). Based on the literature, genes that may play a role in regulating metabolic pathways at 2 weeks include Myc and HNF4A, and at 4 weeks, beta-estradiol, p53, Akt, HNF4A and AR. Our data suggest that abnormalities in regulation of metabolic pathways in the immune cells of young NOD mice lead to abnormalities in the immune response pathways and as such may play a role in the initiation of autoimmune diabetes. Thus, targeting metabolism may provide novel approaches to preventing and/or treating autoimmune diabetes.
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PMID:Molecular phenotyping of immune cells from young NOD mice reveals abnormal metabolic pathways in the early induction phase of autoimmune diabetes. 2307 69


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