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)

Squamous, large cell, and adenocarcinoma, collectively termed non-small cell lung cancer (NSCLC), are diagnosed in approximately 75% of patients with lung cancer in the United States. The treatment of these three tumor cell types is approached in virtually identical fashion because, in contrast to small cell carcinoma of the lung, NSCLC more frequently presents with localized disease at the time of diagnosis and is thus more often amenable to surgical resection but less frequently responds to chemotherapy and irradiation. Cigarette smoking is etiologically related to the development of NSCLC in the great majority of cases. Genetic mutations in dominant oncogenes such as K-ras, loss of genetic material on chromosomes 3p, 11p, and 17p, and deletions or mutations in tumor suppressor genes such as rb and p53 have been documented in NSCLC tumors and tumor cell lines. NSCLC is diagnosed because of symptoms related to the primary tumor or regional or distant metastases, as an incidental finding on chest radiograph, or rarely because of a paraneoplastic syndrome such as hypercalcemia or hypertrophic pulmonary osteoarthropathy. Screening smokers with periodic chest radiographs and sputum cytologic examination has not been shown to reduce mortality. The diagnosis of NSCLC is usually established by fiberoptic bronchoscopy or percutaneous fine-needle aspiration, by biopsy of a regional or distant metastatic site, or at the time of thoracotomy. Pathologically, NSCLC arises in a setting of bronchial mucosal metaplasia and dysplasia that progressively increase over time. Squamous carcinoma more often presents as a central endobronchial lesion, while large cell and adenocarcinoma have a tendency to arise in the lung periphery and invade the pleura. Once the diagnosis is made, the extent of tumor dissemination is determined. Since most NSCLC patients who survive 5 years or longer have undergone surgical resection of their cancers, the focus of the staging process is to determine whether the patient is a candidate for thoracotomy with curative intent. The dominant prognostic factors in NSCLC are extent of tumor dissemination, ambulatory or performance status, and degree of weight loss. Stages I and II NSCLC, which are confined within the pleural reflection, are managed by surgical resection whenever possible, with approximate 5-year survival of 45% and 25%, respectively. Patients with stage IIIa cancers, in which the primary tumor has extended through the pleura or metastasized to ipsilateral or subcarinal lymph nodes, can occasionally be surgically resected but are often managed with definitive thoracic irradiation and have 5-year survival of approximately 15%.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Non-small cell lung cancer. Part I: Biology, diagnosis, and staging. 164 34

Squamous, large cell, and adenocarcinoma, collectively termed non-small cell lung cancer (NSCLC), are diagnosed in approximately 75% of patients with lung cancer in the United States. The treatment of these three tumor cell types is approached in virtually identical fashion because, in contrast to small cell carcinoma of the lung, NSCLC more frequently presents with localized disease at the time of diagnosis and is thus more often amenable to surgical resection but less frequently responds to chemotherapy and irradiation. Cigarette smoking is etiologically related to the development of NSCLC in the great majority of cases. Genetic mutations in dominant oncogenes such as K-ras, loss of genetic material on chromosomes 3p, 11p, and 17p, and deletions or mutations in tumor suppressor genes such as rb and p53 have been documented in NSCLC tumors and tumor cell lines. NSCLC is diagnosed because of symptoms related to the primary tumor or regional or distant metastases, as an incidental finding on chest radiograph, or rarely because of a paraneoplastic syndrome such as hypercalcemia or hypertrophic pulmonary osteoarthropathy. Screening smokers with periodic chest radiographs and sputum cytologic examination has not been shown to reduce mortality. The diagnosis of NSCLC is usually established by fiberoptic bronchoscopy or percutaneous fine-needle aspiration, by biopsy of a regional or distant metastatic site, or at the time of thoracotomy. Pathologically, NSCLC arises in a setting of bronchial mucosal metaplasia and dysplasia that progressively increase over time. Squamous carcinoma more often presents as a central endobronchial lesion, while large cell and adenocarcinoma have a tendency to arise in the lung periphery and invade the pleura. Once the diagnosis is made, the extent of tumor dissemination is determined. Since most NSCLC patients who survive 5 years or longer have undergone surgical resection of their cancers, the focus of the staging process is to determine whether the patient is a candidate for thoracotomy with curative intent. The dominant prognostic factors in NSCLC are extent of tumor dissemination, ambulatory or performance status, and degree of weight loss. Stages I and II NSCLC, which are confined within the pleural reflection, are managed by surgical resection whenever possible, with approximate 5-year survival of 45% and 25%, respectively. Patients with stage IIIa cancers, in which the primary tumor has extended through the pleura or metastasized to ipsilateral or subcarinal lymph nodes, can occasionally be surgically resected but are often managed with definitive thoracic irradiation and have 5-year survival of approximately 15%.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Non-small cell lung cancer. Part II: Treatment. 171 39

Twenty women with ovarian small cell carcinoma of the hypercalcemic type were studied. Mean patient age was 24 years, 11 had hypercalcemia, and the 2-year actuarial survival was 18%; there was only one long-term survivor. Twelve of 15 tumors tested (80%) exhibited p53 protein accumulation by immunohistochemistry, supporting the presence of p53 gene mutations in these tumors. p53 gene mutations may have an important role in the evolution of small cell ovarian carcinomas.
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PMID:Small cell carcinoma of the ovary of the hypercalcemic type: p53 protein accumulation and clinicopathologic features. 759 Apr 88

A rare case of ovarian small cell carcinoma is reported. Laboratory examination of a 46-year-old woman with a lower abdominal tumor showed marked hypercalcemia. Her condition deteriorated progressively, and she died one month after admission. A right ovarian tumor, 8 cm in diameter, metastases to multiple organs, and intraperitoneal bleeding were confirmed by autopsy. Microscopically, the small tumor cell had rounded nuclei with small distinct nucleoli and a scanty cytoplasm. Small cell carcinoma was diagnosed from these histological features and the clinical course associated with hypercalcemia. Immunohistochemical studies showed positive staining of neuron specific enolase (NSE) and keratin. Genetic analysis using DNA extracted from paraffin sections of metastatic lesions revealed mutation of K-ras codon 12. Loss of heterozygosity of the p53 and adenomatous polyposis coli (APC) genes was not informative. Previous reports have shown that ras gene mutations occur in 30% of epithelial ovarian tumors and significantly more frequently in mucinous than in other types of ovarian tumors. These results suggest that small cell carcinoma is of epithelial origin and may have a genetic alteration similar to that of mucinous tumors.
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PMID:Ovarian small cell carcinoma with K-ras mutation: a case report with genetic analysis. 854 15

Parathyroid hormone-related protein (PTHrP) is a normal secretory product of a variety of squamous epithelia, including epidermal keratinocytes. Only a subset of squamous carcinomas, however, express the gene at levels sufficient to cause humoral hypercalcemia. In the present study, comparison of PTHrP expression levels with p53 functional status in a series of squamous carcinoma lines has revealed an association between expression of specific mutant isoforms of p53 and very low levels of PTHrP mRNA. Evaluation of p53 isoforms with mutations in codons 248 and 273 showed them to be capable of repressing PTHrP gene expression in a high-expressing, p53-negative squamous line by approximately 50%. Conversely, inactivation of an endogenous mutant p53 with E1B proteins resulted in an increase in PTHrP expression in a low-expressing cell line. Subsequent analysis of promoter-specific PTHrP transcripts in a p53-negative squamous line transfected with mutant p53 isoforms suggested that down-regulation occurred primarily at the two TATA-based promoters. Direct testing of a murine PTHrP reporter construct in transient transfection assays confirmed the capacity of the 248 and 273 mutants to repress this TATA-based promoter, although only about half as effectively as wild-type p53.
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PMID:Parathyroid hormone-related protein gene expression in human squamous carcinoma cells is repressed by mutant isoforms of p53. 875 79

PTH-related peptide (PTHrP) is the major factor responsible for humoral hypercalcemia of malignancy. This paraneoplastic syndrome has been described in association with a number of malignancies, but rarely with carcinoma of the colon. Moreover, little is known about the molecular mechanisms that underlie PTHrP overexpression in tumors. Here we report a patient who presented with hypercalcemia 6 months after resection of a neuroendocrine colonic carcinoma (tumor I). At the time of admission, intact PTH was decreased, circulating PTHrP levels were elevated, and there was tumor recurrence (tumor II). Immunohistochemical staining of paraffin-embedded sections from tumor I did not stain for PTHrP, whereas cells from tumor II stained intensely positive. Southern blot analysis and differential PCR of genomic DNAs from tumor specimens and the patient's leukocytes demonstrated amplification of the PTHrP gene in tumor II. Moreover, staining for p53 protein was evident in tumor II, but not in tumor I, consistent with the presence of a mutant form of p53 and associated loss of tumor suppressor function in the recurrent tumor. PTHrP gene amplification was also detected in one of five other tumors associated with humoral hypercalcemia of malignancy. These findings suggest that a potential mechanism contributing to PTHrP overexpression in malignancies is gene amplification, which could arise from increased genomic instability associated with the progressive stages of neoplasia.
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PMID:Amplification of the parathyroid hormone-related peptide gene in a colonic carcinoma. 876 40

Parathyroid carcinoma is a rare, reported to be less than 1% of patients with primary hyperparathyroidism. Recently, cell cycle regulators such as the retinoblastoma gene and p53 have been implicated in the pathogenesis of parathyroid carcinoma. Yet definite diagnosis remains difficult not only clinically but also pathologically. However, the clinical presentation, biochemical and hormonal findings, and appearance at the operation may possibly raise suspicion regarding the diagnosis. A radical en bloc resection at the primary operation is most important. Even after a successful initial operation parathyroid carcinoma carries an increased risk of recurrence. There is wide diversity in the interval between the initial operation and the manifestation of metastasis. Histopathology and DNA ploidy are valuable predictors of the clinical outcome. Because the severe hypercalcemia it engenders has catastrophic consequences, proper management of the recurrent hypercalcemia is also mandatory. The lung is the most common site of distant metastasis. Selected patients with pulmonary metastasis of parathyroid carcinoma can obtain significant benefit from aggressive surgical resection even when they have multiple or recurrent lesions. When hypercalcemia is refractory to surgical resection, medical treatment with bisphosphonate has a beneficial effect.
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PMID:Functioning parathyroid carcinoma: clinicopathologic features and rational treatment. 908 69

A clinicopathologic study was conducted to assess the implication of HTLV-I infection, Strongyloides stercoralis (Ss) infection, and P53 overexpression in the development, response to treatment, and evolution of non-Hodgkin's lymphoma (NHL) in Martinique, French West Indies. Two groups of patients, with 22 and 41 participants with B-cell and T-cell lymphoma, respectively, were analyzed. HTLV-I antibodies were detected in 24 (59%) patients with T-cell lymphoma of whom 19 (46%) fulfilled diagnostic criteria of adult T-cell leukemia/lymphoma (ATLL). By comparison with other T-cell lymphomas, patients with ATLL were significantly younger (52 versus 63 years; p = .03), had a significantly higher incidence of hypercalcemia (60% versus 0%; p = .0001), a trend for higher incidence of digestive tract localization (21% versus 4%; p = .1) and significantly shorter median survival (6 versus 17 months; p = .03). Similar results were observed when all 24 HTLV-I-infected patients with T-cell lymphoma were compared with the 17 seronegative patients. Strongyloidiasis was diagnosed in 11 of 34 patients tested for Ss infection. All 4 Ss-infected (Ss-positive) ATLL patients treated with combination chemotherapy achieved complete remission (CR) versus only 2 of 7 Ss-negative ATLL patients (p = .04). In addition, survival of Ss-positive patients with ATLL was better than that of the uninfected patients: 27 versus 5 months, p = .04, respectively). P53 expression was assessed by immunohistochemistry on lymph node biopsies from 37 patients including 18 B-cell lymphomas, 14 ATLL, and 5 other T-cell lymphomas. P53 overexpression (P53-positive) was observed in 6 samples that corresponded in all 6 patients with ATLL. All P53-positive ATLL patients had stage IV disease with elevated lactate dehydrogenase (LDH) levels. By comparison with other ATLL patients studied for p53 expression, P53-positive ATLL were characterized by a lower response rate to combination chemotherapy (CR: 0 of 6 versus 4 of 6; p = .04) and a shorter survival (2 versus 9 months, p = .04). Our results suggest that ATLL represents almost 50% of T-cell lymphomas in Martinique; Ss infection during ATLL seems to be linked with a high response rate to chemotherapy and prolonged survival; and P53 overexpression is observed in almost 50% of aggressive ATLL from Martinique and, even in advanced clinical subtypes, is associated with resistance to chemotherapy and short-term survival.
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PMID:Implication of HTLV-I infection, strongyloidiasis, and P53 overexpression in the development, response to treatment, and evolution of non-Hodgkin's lymphomas in an endemic area (Martinique, French West Indies). 1009 85

We reviewed 11 cases of primary thymic neuroendocrine carcinomas with combined features ranging from well-differentiated to poorly differentiated neuroendocrine carcinoma. For 3 asymptomatic patients, tumors were discovered during routine examination. Presentation in the other patients was as follows: Cushing syndrome, 2 patients; chest pain, 3 patients; superior vena cava syndrome, 1 patient; and hypercalcemia and hypophosphatemia, 1 patient. No clinical data were available for the 11th patient. All tumors were located in the anterior mediastinum and treated by surgical excision. The lesions were large and well-circumscribed with areas of hemorrhage and necrosis. They were characterized by areas showing a proliferation of monotonous, round tumor cells adopting a prominent organoid pattern admixed with areas showing sheets of atypical cells with hyperchromatic nuclei, frequent mitoses, and extensive areas of hemorrhage and necrosis. Immunohistochemical studies performed in 6 cases showed strong CAM 5.2 low-molecular-weight cytokeratin positivity in all cases, chromogranin and synaptophysin positivity in 4, Leu-7 in 3, and focal positivity for p53 in 2. Follow-up information for 9 cases showed that all patients died of their tumors between 1 and 4 years after diagnosis. The present cases highlight the heterogeneity of neuroendocrine neoplasms and reinforce the notion that these tumors form part of a continuous spectrum of differentiation.
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PMID:Thymic neuroendocrine carcinomas with combined features ranging from well-differentiated (carcinoid) to small cell carcinoma. A clinicopathologic and immunohistochemical study of 11 cases. 1070 13

We have evaluated the status of p53 expression in three squamous carcinoma cell lines that express high levels of PTHrP mRNA and protein and also cause hypercalcemia when grown in nude mice. All three of these lines possess a single p53 allele, each of which harbors a missense point mutation that gives rise to it mutant p53 protein with a denatured conformation. Using site-directed mutagenesis, we created a p53 expression construct bearing a missense mutation at codon 158, identical to that expressed by one of the cell lines. This construct and p53 constructs expressing representative denatured conformation mutants were then used to develop stably transfected lines, which expressed increased levels of PTHrP mRNA. Promoter-specific RNase protection indicated that this increase was due primarily to transcripts originating from the two TATA promoters, and not the GC-rich initiator element within the PTHrP gene. Cotransfection of mutant p53 expression vectors with a series of reporter constructs under the control of the human PTHrP promoter region showed that mutant p53 isoforms activated constructs containing multiple promoter elements and flanking sequences, but failed to activate constructs with individual promoters in isolation. These findings suggest that the activation of PTHrP gene expression by mutant p53 isoforms displaying a denatured conformation is dependent on interactions with sequences in the PTHrP gene regulatory region beyond the basal TATA promoters.
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PMID:Activation of PTHrP gene expression in squamous carcinoma cell lines by mutant isoforms of the tumor suppressor p53. 1113 26


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