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)

Pituitary carcinomas are only defined by their metastatic growth, which may be intracranial or systemic. To establish further morphological and immunohistochemical differences between pituitary carcinomas and adenomas, 19 ACTH-secreting adenomas (10 non invasive and 9 invasive) and 2 ACTH-secreting carcinomas with their metastases were studied for expression of the intermediate filaments keratin and vimentin and the tumor-associated antigens Ki67, proliferating cell nuclear antigen (PCNA), epidermal growth factor (EGF), cathepsin D, p53, and carcinoembryonic antigen (CEA). Immunohistochemistry was performed using avidin-biotin techniques on formalin-fixed, paraffin-embedded tissue. With the exception of one noninvasive pituitary adenoma, one carcinoma, and the metastases, all tumors contained keratin; none contained vimentin. All tumors stained negative for CEA and p53. Eleven (58.5%) adenomas and both pituitary carcinomas contained Ki67-positive nuclei; 14 (74%) adenomas and one carcinoma revealed PCNA. No correlation was found between the two markers. Seven (38%) adenomas showed a labeling index <1 % for cathepsin D, whereas none of the carcinomas or metastases did so. EGF was found in 7 (38%) adenomas and in both carcinomas. A tendency to a higher rate of EGF positivity in the invasive adenomas was observed. The metastases showed a higher labeling index, and far more intense staining results for Ki67, PCNA, and EGF than the primary tumor. The metastases also had a higher proliferation rate and growth factor content than the carcinoma itself.
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PMID:Proliferation Markers and EGF in ACTH-Secreting Adenomas and Carcinomas of the Pituitary. 1211 89

Blockade of the mitochondrial permeability transition pore (mPTP) by cyclosporin A (CsA) inhibits apoptosis in various cell types. However, use of CsA in humans is associated with damage to the arterial endothelium. We evaluated whether inhibition of the apoptotic machinery by CsA promotes other forms of cell death in arterial endothelial cells (EC). Exposure of human umbilical artery EC (HUAEC) to clinically relevant concentrations of CsA for up to 24 h was associated with a significant increase in necrotic features. We detected inhibition of apoptosis and a significant increase in necrosis in HUAEC exposed concomitantly to CsA and mitomycin C, a proapoptotic DNA damaging agent. We found that CsA-induced cell death is independent of caspase activation, p53 induction, and calcineurin inhibition. However, bongkrekic acid, another mPTP blocker, also increased necrosis in HUAEC. Dihydroethidium and acridine orange staining revealed increased intracellular production of reactive oxygen species (ROS) followed by lysosomal damage in HUAEC exposed to CsA. Hydroxyl radical and superoxide scavengers and inhibition of cathepsin D activity significantly attenuated CsA-induced EC death. These results suggest that inhibition of the apoptotic machinery by CsA in arterial EC favors development of a necrotic form of cell death regulated by ROS and secondary lysosomal damage.
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PMID:Blockade of the apoptotic machinery by cyclosporin A redirects cell death toward necrosis in arterial endothelial cells: regulation by reactive oxygen species and cathepsin D. 1251 15

The aim of this prospective study was to evaluate biological markers, their correlation with response and outcome, and the change in these markers under the influence of preoperative chemotherapy (PCT) in patients with a large primary breast cancer. One hundred and thirty-five women were treated with PCT, followed by locoregional therapy and adjuvant treatment. Estrogen receptor (ER), progesterone receptor (PgR), HER-2, p53, and cathepsin D were determined by immunohistochemistry (IHC) before and after PCT. The overall response (OR) was 70% and the pathologic complete response (pCR) was 13%. Forty-four percent of the patients could be offered breast-conserving surgery (BCS). At a median follow-up of 50 mo the overall survival is 82% and the disease-free survival is 70%. No local recurrence (LR) has developed following BCS. Invasive ductal carcinoma (IDC) was more frequently ER-negative and HER-2-positive than invasive lobular carcinoma (ILC). P53-negative and ER-negative patients seemed to be more chemosensitive compared to p53-positive patients (74% vs 53%) and ER-positive patients (75% vs 65%), but this difference did not reach statistical significance. A trend toward higher complete pathologic remission rate was seen for ER-negative patients (p = 0.0609). PgR, HER-2, and cathepsin D were not related to response. The pattern of biological markers did not change with PCT, making repeated determination useless.
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PMID:The role of biological markers as predictors of response to preoperative chemotherapy in large primary breast cancer. 1451 71

Expression of the hormone-related proteins hsp27, pS2, and also of cathepsin D (CD) and metallothionein (MT) was studied by immunohistochemistry and analyzed against clinical data in breast cancer. Archived material of paraffin-embedded breast carcinoma tissues from a cohort of 134 patients with primary invasive breast cancer was used. Hsp27 and pS2 (>10% of tumor cells stained) were found to be expressed in 63.6% and 37.6% of cases, respectively, and were correlated negatively with grading (P=0.006 and 0.01) and positively with estrogen receptors (ER) (P=0.04 and 0.04). pS2 expression was correlated with lymph node status (P=0.02), tumor size (P=0.01), progesterone receptor (PR) content (P=0.02), hsp27 (P=0.015) and bcl-2 protein (P=0.001). An inverse relationship between pS2 expression and the expression of p53 protein (P=0.005) and proliferation-associated index MIB1 (P<0.0001) was noted. Stromal cathepsin D was positively correlated with tumor grade (P=0.01), PCNA (P=0.007), MIB1 (P=0.001) and p53 (P=0.01), and negatively with ER (P=0.04) and bcl-2 (P<0.0001). MT was correlated positively with stromal CD (P=0.007) and inversely with PgR (P=0.04). Univariate analysis showed CD expression to be a positive prognostic factor for survival (P=0.035), with borderline significance, while MT was more strongly positive (P=0.01). However, none of the proteins studied was found to be related to disease outcome in univariate analysis. Our data show that hsp27, pS2 and stromal CD expression may reflect tumor differentiation and the functional status of ER in breast cancer, but stromal CD and tumor MT expression were the only factors found that may be of limited prognostic value.
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PMID:Clinicopathological study of the expression of hsp27, pS2, cathepsin D and metallothionein in primary invasive breast cancer. 1465 40

Cathepsin D protein patterns were analyzed in 59 colorectal tumors by Western blotting, glycosylation and immunohistochemical assays. Measurement of protein content by laser densitometry of tumor/normal pairs on Western blots revealed loss of cathepsin D protein in more than 50% of colorectal tumors. Independent loading controls and statistical estimates of reproducibility on duplicate assays confirmed frequent decreases in cathepsin D. For cases having a tumor/normal ratio (T/N) <1, the average T/N was 0.50+/-0.19, equivalent to the loss of one cathepsin D allele. However, 2-fold increases in cathepsin D protein levels were also observed in approximately 1/3 of tumors, supporting the concept that colorectal cancers develop via divergent molecular pathways and that cathepsin D may function differently in different cancers. Although normal cathepsin D expression was detected in some earlier stage tumors, protein levels became increasingly bimodal with progression such that cathepsin D levels were increased in 1/3 but decreased in 2/3 of stage III and IV cancers. Other laboratories have reported both significant loss and gain of chromosome 11 (site of the cathepsin D gene) in different colorectal tumors, providing a possible mechanism for our observations on cathepsin D. However, differential regulation of cathepsin D expression by mutant versus wild-type p53 may also contribute to variable cathepsin D levels in colorectal cancers. Immunohistochemical studies demonstrated a shift from a predominantly punctate distribution of cathepsin D protein in normal mucosa to a more diffuse cytoplasmic distribution in tumor tissues. Mutant forms of cathepsin D were not detected in tumors either as changes in electrophoretic mobility or altered glycosylation but minor changes in protein sequence could not be ruled out. Loss of cathepsin D protein may provide an advantage to colorectal tumors related to a loss of cathepsin D function in proapototic or antiangiogenic pathways while increased cathepsin D may promote cancer cell proliferation or invasion.
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PMID:Cathepsin D protein levels in colorectal tumors: divergent expression patterns suggest complex regulation and function. 1476 31

The p53 protein activates cellular death programs through multiple pathways. Because the high frequency of p53 mutations in human tumors is believed to contribute to resistance to commonly used chemotherapeutic agents, it is important to identify drugs that induce p53-independent cell death and to define the mechanisms of action of such drugs. Here we screened a drug library (the National Cancer Institute mechanistic set; 879 compounds with diverse mechanisms of actions) and identified 175 compounds that induced caspase cleavage of cytokeratin-18 in cultured HCT116 colon cancer cells at <5 microM. Interestingly, whereas most compounds elicited a stronger apoptotic response in cells with functional p53, significant apoptosis was observed also in p53-null cells. A subset of 15 compounds showing weak or no dependence on p53 for induction of apoptosis was examined in detail. Of these compounds, 11 were capable of activating caspase-3 in enucleated cells. Seven such compounds with nonnuclear targets were found to induce lysosomal membrane permeabilization (LMP). Translocation of the lysosomal proteases cathepsin B and cathepsin D into the cytosol was observed after treatment with these drugs, and apoptosis was inhibited by pepstatin A, an inhibitor of cathepsin D. Apoptosis depended on Bax, suggesting that LMP induced a mitochondrial apoptotic pathway. We conclude that a large number of potential anticancer drugs induce p53-independent apoptosis and that LMP is a mediator of many such responses.
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PMID:Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis. 1561 92

In an exploratory study, 11 common polymorphisms were examined for contributing to longevity including: apolipoprotein E (apoE), methylenetetrahydrofolate reductase (MTHFR), cathepsin D (CAD), superoxide dismutase 2 (SOD2), angiotensinogen (AGT) and insulin-like growth factor 2 (IGF2), Leiden factor 7, p53 oncogene, dopamine D4 receptor (DRD4) and the serotonin transporter (SERT). Genotype and allele frequencies of these genes were compared in 224 older (75 years) Jewish Jerusalem residents of Ashkenazi ethnicity to a group of 441 younger subjects (22 years). Nominally significant results provide suggestive evidence in the Ashkenazi group that apoE, MHTFR, SOD2, IGF2 ApaI, and factor VII are risk factors for a single outcome, survival to 75. Overall, the more genetically homogenous Ashkenazi ethnic group showed evidence for association in five genes examined suggesting that future studies in this population would gainfully focus on this ethnic group.
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PMID:Candidate genes associated with ageing and life expectancy in the Jerusalem longitudinal study. 1562 Dec 15

The estrogen receptor (ER)-beta isoform has been recently identified to be distinct from ERalpha isoform and regulates separate sets of genes, and can exert opposite signaling functions depending on the ligand and response elements. Previous studies of ERbeta have been at the mRNA level and few by immunohistochemistry, and the results are inconsistent. In this study the authors compared expression of ERbeta with those of other prognostic biomarkers by immunohistochemistry on tissue microarray slides, and with morphologic parameters on 147 cases of primary breast cancer. Immunoreactivity of more than 10% of cancer cells was considered to be positive. Associations between categoric variables were analyzed using the chi test, and a P value less than 0.05 was considered to be significant. ERbeta was expressed in benign epithelium and stromal cells, and breast cancer cells in 59% of different histologic types of breast cancer. ERbeta was coexpressed with ERalpha in 45% of cases. There was a statistically significant association between expression of ERbeta and Her-2/neu (P<0.000), cathepsin D (P<0.02), p53 (P<0.03), and PS2 (P<0.002). Ki-67 was almost exclusively expressed in ERbeta-positive cells. No statistically significant association was seen between ERbeta expression and histologic grade, DNA ploidy, or S-phase.
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PMID:Estrogen receptor beta in breast cancer: associations between ERbeta, hormonal receptors, and other prognostic biomarkers. 1572 89

Endometrial adenocarcinoma is the most common malignant neoplasm of the female genital tract and, despite its relative frequency, the molecular events that contribute to the development and progression of the lesion remain poorly understood. The normal human endometrium is characterized by hormone-dependent variations during the menstrual cycle. This tightly controlled system is disturbed in endometrial hyperplasia and carcinomas and a series of changes initiate and promote progression towards the malignant phenotype. These changes can be subdivided into discrete steps, involving activation of oncogenes, inactivation of tumour suppressor genes, deregulation of cell cycle regulators or other proteins involved in tumour invasion and progression. Immunohistochemical expression of different biomarkers such as hormone receptor status (ER, PR), proliferation associated indices (PCNA, MIB1), oncogene (c-erbB-2), tumour suppressor gene products (pRb, p53 protein), cell cycle related proteins (cyclin D1, cyclin E, p21/WAF1), anti-apoptotic protein (bcl-2), adhesion molecule (CD44s), proteolytic enzyme (cathepsin D), heat shock protein (hsp27) and metallothionein (MT) has shown the contribution of these molecules to endometrial carcinogenesis in a hormone-dependent or independent manner as an early or late event. In addition, these biomarkers seem to be correlated with tumour differentiation or myometrial invasion, and therefore could be considered as indicators of the biological behaviour of endometrial carcinoma. Furthermore, the interrelationships of these molecular markers show that these genetic dysregulations could be implicated in the control of cell proliferation and differentiation, and thereby in the multistep process of endometrial carcinogenesis.
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PMID:Immunohistochemical tumour markers in endometrial carcinoma. 1612 80

Breast cancer is amongst the leading causes of death in women worldwide and the most common cancer amongst Iranian women. Unfortunately, the current clinical and histological criteria can only help 60 percent of women with breast cancer in diagnosis and long-term treatment. Therefore, genetic markers both at single gene and chromosomal level can play an important role in improving the diagnosis and prognosis of breast cancer patients. The aim of this retrospective study was to investigate the role of chromosome 1 and 8 copy number assessed by interphase fluorescence in situ hybridization (FISH), as prognostic parameters in 50 Iranian women, aged 35 to 64 years, with sporadic invasive ductal breast carcinoma. Chromosome 1 and 8 copy numbers were evaluated in relation to established clinicopathological parameters, the immunohistochemical markers ER, PR, P53 and cathepsin D, DNA index by flow cytometry, age and survival status of the patients. FISH using centromeric probes for chromosomes 1 and 8 was applied to interphase cell suspensions prepared from archived, Carnoyfixed tumor cells and selected paraffin-embedded tumor sections. Aneusomy for chromosomes 1 and 8 was present in all 50 patients to different levels. The total abnormality rate for chromosome 1 was 33.92 percent (4.24 percent monosomy and 29.68 percent polysomy), whereas for chromosome 8 this rate was 28.30 percent (6.48 percent monosomy and 21.82 percent polysomy). Statistically significant association (p<0.05) was demonstrated between monosomy 1 and patients' age below 50 years, and between monosomy 1 and poor survival, respectively. Disomy 8 was significantly associated with P53 expression. A borderline significant correlation was demonstrated between polysomy 8 and diploid DNA content, as well as between disomy 1 and disease-free status of the patients. Chromosome 1 and 8 copy numbers may be considered as useful prognostic markers in invasive ductal carcinoma of the breast.
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PMID:Prognostic value of chromosome 1 and 8 copy number in invasive ductal breast carcinoma among Iranian women: an interphase FISH analysis. 1619 69


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