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

We immunohistochemically compared benign myoepithelial tumors (adenomyoepitheliomas [AMEs]) and metaplastic matrix-producing (MMP-CA) and spindle cell (MSC-CA) carcinomas of the breast to identify helpful diagnostic markers. Normal myoepithelial cells (MECs) consistently expressed cytokeratin, alpha-smooth muscle actin (SMA), myosin, S-100, CD10, and maspin. They were variably positive for vimentin and negative for epithelial membrane antigen (EMA), steroid receptors, p53, and HER-2/neu. MECs in AMEs less frequently expressed CD10 (4/8 [50%]) and myosin (6/8 [75%]) but frequently acquired characteristics of luminal cells, such as expression of EMA (5/8 [63%]) and steroid receptors (5/8 [63%]). No abnormal p53 or HER-2/neu expression was seen in AMEs. MMP-CA and MSC-CA were similar to AMEs in cytokeratin, vimentin, S-100, maspin, and HER-2/neu expression. MMP-CAs expressed less alpha-SMA (2/8 [25%]) and myosin (2/7 [29%]) and lacked estrogen receptor (0/9 [0%]). MSC-CAs were consistently CD10+ (4/4 [100%]) yet failed to express myosin (0/3 [0%]). p53 overexpression was seen frequently in MMP-CAs (4/8 [50%]) and MSC-CAs (1/3 [33%]). Benign myoepithelial mammary tumors differ immunophenotypically from normal MECs; a panel of immunohistochemical markers may be required to establish their myoepithelial origin. A similarly altered myoepithelial phenotype also is characteristic of metaplastic mammary carcinomas. The abnormal expression of oncogenes or antioncogenes, such as p53, may be more useful for distinguishing between those entities than the expression of the classic myoepithelial markers.
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PMID:Benign myoepithelial tumors of the breast have immunophenotypic characteristics similar to metaplastic matrix-producing and spindle cell carcinomas. 1293 44

The serine protease inhibitor maspin has been reported to inhibit invasiveness and motility of tumor cells. Additionally, a p53-dependent regulatory pathway of maspin in human cancer has been indicated. In a pre-study we were able to detect maspin protein in papillary thyroid carcinomas (PTC), whereas normal (tumor-free) thyroid tissue, follicular adenomas, follicular carcinomas, poorly differentiated carcinomas and undifferentiated carcinomas of the thyroid were maspin-negative. The first aim of our study was to determine the prognostic value of maspin protein expression for the recurrence-free and overall survival of PTC patients undergoing radical thyroidectomy and postoperative irradiation. Secondly, maspin expression was correlated to p53 protein expression in order to gain additional information on a possible regulatory influence of the wild-type p53 protein on maspin. An immunohistochemical approach study was performed on 68 tumor specimens. Maspin protein expression was detectable in 48 of 68 patients (71%; M+). After a median follow-up of 81 (26-117) months the median recurrence-free survival was 60 (28-117) months for M+ and 42 (11-108) months for M- (p=0.03). After 110 months 83% of patients had recurrence-free disease in M+, whereas in M- only 40% of patients were recurrence-free. The median long-term survival was 81 (42-108) months for M+ and 55 (21-99) months for M- (p=0.03). After 5 years, M+ and M- patients had a total survival of 98 and 80%, and after 9 years 90 and 60%, respectively. Mutant-type p53 expression was detectable in 17 of 68 PTC (25%). Mt p53 was positive in 1 of 47 M+ (2%) compared with 16 of 20 M- (80%, p<0.01). This study indicates that maspin protein possibly functions as a clinically relevant inhibitor of tumor progression, preventing local invasiveness and further systemic progression of papillary thyroid carcinomas. Our data hint of a p53-dependent regulatory pathway of the maspin protein in human cancer.
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PMID:Maspin in thyroid cancer: its relationship with p53 and clinical outcome. 1453 96

Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme with tumor suppressor activity; however, the molecular mechanisms of MnSOD antitumor effects remain unclear. We hypothesized that MnSOD activity in cancer cells might cause downstream changes in the expression of other tumor suppressor genes. To determine whether maspin, a tumor suppressor gene that inhibits breast cancer cell invasion and metastasis, might be a target of MnSOD, we forced MnSOD expression in several human breast and prostate cancer cell lines by adenovirus-mediated gene transfer and measured maspin mRNA expression. Forced expression of MnSOD caused maspin mRNA to accumulate in a dose-dependent manner in both human breast and prostate cancer cells. Normal p53 was not necessary to mediate the effect of MnSOD because MnSOD up-regulated maspin in cells that harbor wild-type p53 and in cells that harbor mutant p53. Moreover, the effects of MnSOD on maspin were not due to demethylation of the maspin promoter. Analyses of maspin promoter activity, transcriptional run-on, and mRNA stability showed that maspin mRNA stability was the major mechanism for maspin up-regulation by MnSOD. Our findings identify a mechanism underlying MnSOD antitumor effects and provide evidence to support MnSOD as a genetic therapy in the treatment of human breast and prostate cancers.
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PMID:MnSOD up-regulates maspin tumor suppressor gene expression in human breast and prostate cancer cells. 1458 Mar 25

Human papillomavirus (HPV) 16 is involved in causing cervical cancer. The E6 and E7 proteins of HPV 16 immortalize human keratinocytes and this is due, at least in part, to inactivation of the tumor suppressor proteins p53 and pRB. These tumor suppressor proteins also regulate the expression of pro- and antiangiogenic factors by cells. For this reason, experiments were conducted to determine whether the expression of E6 and E7 in primary keratinocytes alters the phenotype of these cells such that they express diminished levels of antiangiogenic factors and/or increased levels of proangiogenic factors. To avoid variances in experimental observations, pools of human foreskin keratinocytes from multiple sources were infected with recombinant retrovirus expressing HPV 16 E6 and E7 or control retrovirus. Gene array analysis, RT-PCR, ELISAs and Western blotting showed that in cells expressing HPV 16 E6 and E7, expression levels of two potent angiogenesis inhibitors, thrombospondin-1 and maspin, were lower compared to controls. Additionally, major angiogenesis inducers, interleukin-8 and vascular endothelial growth factor (VEGF), were increased relative to controls. VEGF can be produced as multiple splice variants, all of which are required for the formation of patent blood vessels. The expression of HPV 16 E6 and E7 in keratinocytes augmented expression of VEGF 121, 145, 165 and 189. These observations show that HPV 16 E6 and E7 alter the phenotype of primary keratinocytes, diminishing expression of inhibitors and increasing expression of inducers of angiogenesis. This altered phenotype may permit keratinocytes infected by HPV 16 to play a role in the progression of cancer by permitting tumors to acquire a blood supply permissive of growth and spread.
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PMID:Expression of human papillomavirus type 16 E6 and E7 oncoproteins in primary foreskin keratinocytes is sufficient to alter the expression of angiogenic factors. 1496 15

Maspin inhibits metastasis of some cancer cells, and clinical studies have identified correlations between maspin loss and poor prognosis in several cancer types. Maspin was found to be significantly overexpressed in lung cancer samples as compared with matched normal lung tissues. However, the regulatory mechanism of maspin expression remains unclear. We show here that differential expression of maspin in carcinoma-derived lung cancer cells is regulated at the transcriptional level. We found that p63 is a critical factor for the transcription of maspin, which is lost in highly invasive cancer cells such as NCI-H157, NCI-322, and NCI-358. No correlation was found between maspin expression and the previously associated transcription factors, p53, Ets1, and Pdef. Instead, maspin expression was strictly dependent on the presence of p63 in lung cancer tissues (P < 0.001) and in the tested cell lines. Transient expression of p63 transactivated the maspin promoter with remarkable fold changes in cells expressing the TAp63, suggesting that TAp63 might be a novel stimulator of the maspin promoter in lung cancer. We have also demonstrated the binding of p63 protein to a previously identified p53-binding site on the maspin promoter by gel shift and chromatin immunoprecipitation assays. In tumor tissues, maspin expression was associated with lymph node involvement (P = 0.035) and tumor stage (P = 0.063) in all tested cases, except squamous carcinoma. In terms of function, ectopic expression of maspin inhibited cell invasion in squamous carcinoma as well as adenocarcinoma. Taken together, these results define maspin as a new molecular target of p63 that eventually inhibits the invasion of lung cancer.
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PMID:Maspin expression is transactivated by p63 and is critical for the modulation of lung cancer progression. 1546 79

Maspin, a serine protease inhibitor related to the serpin family, was originally identified in normal mammary epithelium. Reduced expression of maspin is related with development, invasion and metastasis of certain human cancers. In the present study, the expression of maspin was examined in gastric mucosa, adenoma and carcinoma by immunohistochemistry and RT-PCR. In non-neoplastic mucosa, maspin was expressed in cytoplasm and cell membrane of foveolar epithelia, fundic glandular cells and pyloric glandular cells. Maspin expression was lost in 71% (71/100) of gastric carcinomas, and in 19% (4/21) of adenomas, respectively. Loss of maspin expression was significantly associated with poorly differentiated histology, advanced stage and deep invasion (P<0.001). There was an inverse correlation between maspin expression and abnormal p53 accumulation. Maspin mRNA expression was lost in all of 8 gastric carcinoma cell lines that was retrieved after treatment with demethylation agent 5-aza-2'-deoxycytidine in 5 of 8 cell lines. These results suggest that loss of maspin expression partly due to DNA methylation may participate in tumor development and progression of gastric carcinoma in relation with p53 pathway. Loss of maspin expression may serve as a biological marker of high-grade malignancy.
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PMID:Loss of maspin expression is associated with development and progression of gastric carcinoma with p53 abnormality. 1549 82

Maspin is a Class II tumor suppressor protein and plays a role in tumor growth by inhibiting cellular invasion and motility. It is a member of the serpin family of protease inhibitors and has been shown to reduce angiogenesis. Maspin gene expression can be upregulated by the tumor suppressor p53. We tested 7 p53-related proteins of the p63 and p73 families for their ability to induce maspin expression. The p63 splice form TAp63gamma can substitute for p53 in activating the maspin promoter. TAp63gamma activates the promoter through the same consensus site as p53. In the DLD-1 colorectal adenocarcinoma cell line, harboring a tet-off regulated transgene, induction of TAp63gamma leads to an upregulation of maspin mRNA from the chromosomal gene. With a short lag phase also maspin protein levels are elevated after induced TAp63gamma expression. To assess a potential function of p63-dependent maspin upregulation in tumors we followed expression of p53, p63 and maspin by immunohistochemistry in hepatocellular carcinomas. Two types of tumors with wild-type or mutant p53 were assayed. Interestingly, the majority of tumors expressing only a mutated and inactive p53 protein nonetheless stain positive for maspin, whereas these tumors were positive for p63 protein expression. In summary, we show that TAp63gamma can substitute for p53 in transcriptional activation of the maspin tumor suppressor gene. TAp63gamma employs the same DNA recognition site for this activation as p53. We observe expression patterns of p53, p63 and maspin proteins in tumor tissue that may indicate also a function of maspin induction by p63 in tumors.
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PMID:TAp63gamma can substitute for p53 in inducing expression of the maspin tumor suppressor. 3191 78

Maspin is a unique serpin with the ability to suppress certain types of malignant tumors. It is one of the few p53-targeted genes involved in tumor invasion and metastasis. With this in mind, we attempted to study the molecular mechanism behind this tumor suppression. Maspin-expressing mammary tumors are more susceptible to apoptosis in both implanted mammary tumors in vivo, a three-dimensional spheroid culture system, as well as in monolayer cell culture under lowered growth factors. Subcellular fractionation shows that a fraction of maspin (in both TM40D-Mp and mutant maspinDeltaN cells) translocates to the mitochondria. This translocation of maspin to the mitochondria is linked to the opening of the permeability transition pore, which in turn causes the loss of transmembrane potential, thus initiating apoptotic degradation. This translocation is absent in the other mutant, maspinDeltaRSL. It fails to cause any loss of membrane potential and also shows decreased caspase 3 levels, proving that translocation to the mitochondria is a key event for this increase in apoptosis by maspin. Suppression of maspin overexpression by RNA interference desensitizes cells to apoptosis. Our data indicate that maspin inhibits tumor progression through the mitochondrial apoptosis pathway. These findings will be useful for maspin-based therapeutic interventions against breast cancer.
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PMID:Maspin mediates increased tumor cell apoptosis upon induction of the mitochondrial permeability transition. 1571 31

Mammary serpin (Maspin) belongs to the serine protease inhibitor (serpin) superfamily and has been identified as a tumor suppressor. In addition, a p53-dependent regulatory pathway of maspin in human cancer has been indicated. The role of maspin in the tumorigenesis and progression of colorectal cancer is still unclear. Therefore, the first aim of the present study was to determine the prognostic value of maspin protein expression for the recurrence-free and overall survival of patients with colorectal carcinoma undergoing left- or right-sided colectomy. Secondly, maspin expression was correlated with p53 protein expression to gain additional information about a possible regulatory influence of the wild-type p53 protein on maspin; it was also correlated with further patient and tumor characteristics (age, sex, TNM, disease stage, tumor localization, and grading). An immunohistochemical study was performed on 280 carcinoma specimens using the tissue microarray technique. In addition, 80 colorectal adenomas and 60 tumor-free tissues were investigated. Maspin protein expression was detectable in 88-100% of the adenomas and non-tumorous tissues and in 193 out of 280 carcinoma patients (69%; maspin-positive). After a median follow-up of 102 months (23-140 months), the median recurrence-free survival was 80 months for maspin-positive cases (M +) and 42 months for maspin-negative cases (M-) (p = 0.02). The median long-term survival was 98 months for M + and 57 months for M- (p = 0.03). After 5 years, M + and M- patients had a total survival of 69% and 38%, and, after 10 years, 45% and 9%, respectively. Mutant type p53 expression was detectable in 178 colorectal carcinomas (64%). Mt p53 was positive in 91 out of 193 M + (47%) compared with 87 of 87 M- (100%, p<0.001). This study showed that loss of maspin protein correlates with p53 protein activity, with a higher likelihood for the development of tumor relapse, and with a decreased recurrence-free and overall survival in colorectal carcinomas. The determination of the immunohistochemical expression status of maspin might be a helpful independent prognosticator and an applicable tool for the development of therapeutic strategies for patients with this disease.
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PMID:Loss of maspin is a helpful prognosticator in colorectal cancer: a tissue microarray analysis. 1579 21

Maspin, a mammary homologue of Serine Protease Inhibitors, has been shown to inhibit tumor progression and metastasis. Recently, its biological functions have been linked to its subcellular localization. Specifically, a nuclear, opposed to a combined nuclear and cytoplasmic localization has been associated with increased survival in human malignancies, including non-small cell lung cancer (NSCLC). However, it is not known whether transformation affects maspin expression during lung carcinogenesis, and whether its subcellular localization correlates with the morphological features of NSCLC. To address these questions, we studied maspin expression in a model of transformation of bronchial epithelial cells and in resected NSCLC. We found that decreased maspin accompanied chemical transformation of normal immortalized bronchial epithelial cells BEAS 2B. Immunohistochemistry revealed maspin expression to be virtually universal in NSCLC, occurring in 72/77 Adenocarcinoma (ACa), and 46/46 squamous cell carcinoma (SqCCa). SqCCa showed almost exclusively a combined nuclear-cytosolic stain. In contrast, nuclear maspin, but not combined nuclear-cytoplasmic maspin significantly correlated with low histological grade, lower proliferative rate, absence of invasion, and negative p53 stain in ACa. These data support the hypothesis that nuclear localization of maspin may stratify subtypes of NSCLC with favorable clinical-pathological features.
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PMID:Maspin nuclear localization is linked to favorable morphological features in pulmonary adenocarcinoma. 1615 82


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