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)

Cell cycle progression is controlled by cyclin-dependent kinases (CDKs) at the transition of both G1 to S and G2 to M phases. The activities of CDKs are negatively regulated by CDK inhibitors. Deregulation of CDK activity at the G1-S transition allows an aberrant progression of the cell cycle in tumor cells. Recent developments on cell cycle control have revealed a signal transducing pathway of tumor suppressor genes, p53 and pRb, concerning CDK and CDK inhibitors. CDK inhibitor p21 is a target of p53. p53 binds a promoter of the p21 gene and activates the transcription of p21. Consequently, cell cycle progression is blocked at the G1 phase through the suppression of CDK activity. pRb is a substrate of CDK. pRb functions to suppress cell cycle progression at the G1 phase associated with the E2F transcription factor. Phosphorylated pRb by CDK releases an active E2F, which promotes the expression of genes whose products may play a crucial role in controlling G1-S progression. These findings have deepened our understanding on the molecular mechanisms of tumor growth suppression.
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PMID:[The cell cycle and the tumor suppressor genes]. 869 37

Investigation of extensively sampled nontumor gastric mucosa from 205 early gastric cancers showed Helicobacter pylori colonization in 85% of cases, including 100% of diffuse and 78% (83% in 97 cases with Swiss rolls) of glandular or mixed cancers. Intestinal metaplasia, including its type III variant, was prominent in the mucosa associated with glandular and mixed (but not diffuse) early cancers. Both glandular (usually called "intestinal") and diffuse-type cancers showed admixtures of intestinal and gastric tumor cell phenotypes. Both p53 gene mutations and p53 protein immunostaining were essentially restricted to glandular or mixed cancers and associated dysplastic lesions. Their appearance in the advanced stage of diffuse cancer was partly due to a change of the histologic pattern from glandular to diffuse during progression of some tumors. Loss of laminin, beta I integrin, or zonula adherens junctions was a common finding in both early and advanced diffuse cancer. It is concluded that two main pathways operate in gastric carcinogenesis, both starting from H. pylori gastritis and both leading to phenotypically variable, often mixed gastric/intestinal tumor growth. However, only one of the two pathways involves intestinal metaplasia, its type III variant, p53 gene alteration, and dysplasia to end in glandular cancer. In the other pathway, diffuse cancer apparently arises directly from hyperplastic, sometimes atypical necks of mostly nonmetaplastic gastric glands, through primary involvement of genes affecting cell-cell and cell-matrix junctional proteins.
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PMID:Intestinal and diffuse gastric cancers arise in a different background of Helicobacter pylori gastritis through different gene involvement. 869 48

Mutation of the p53 gene is found in about one third of astrocytic brain tumors, and expansion of tumor cell clones containing mutant p53 has been implicated in astrocytic tumor progression. However, admixture of normal cells in astrocytic tumor specimens limits the power of traditional studies of tumor cell clonality. To address this problem we have employed a yeast p53 functional assay that scores the content of mutant p53 alleles in tumors and cell lines quantitatively. We have analyzed 17 cases where matching tumor material and derived cell lines were available. The yeast assay gave > 20% red (i.e., mutant p53-containing) yeast colonies in 7 out of 17 cases. One case had no mutations in the primary tumor but gave 76% red colonies in a recurrence, clearly demonstrating tumor overgrowth by a mutant clone. During early passages of cultured tumor cells, mutant p53 content increased rapidly with passage due to outgrowth of mutant clones from a heterogeneous starting population. In addition, de novo p53 mutations appeared during culture in 2 cases. This indicates that there is stronger selective pressure for mutation during the establishment of cell lines in vitro than during tumor growth in vivo. Our results demonstrate the utility of the p53 functional assay for studies of clonality and support the hypothesis of clonal progression of brain tumors in vivo.
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PMID:Clonality and stability of the p53 gene in human astrocytic tumor cells: quantitative analysis of p53 gene mutations by yeast functional assay. 870 23

Recently, the importance of tumor angiogenesis in the process of tumor growth, progression and metastasis in solid tumors has been widely accepted. The prognostic value of angiogenesis has been demonstrated in a variety of solid tumors including breast cancer. In this report, we reviewed recent studies investigating on the value of intratumoral microvessel density (MVD), assessed by a sermiquantitative immunohistochemical assay with using factor-VIII related antibody or anti CD-31 antibody, as a prognostic indicator in primary breast cancer patients. Studies using factor-VIII related antibody showed that the average MVD ranged from 67.3 to 84.0 counts per mm2 area. When used by anti CD-31 monoclonal antibody, the average MVD were 120.3 approximately 135 counts per mm2 area in the range. More than 8 clinical investigations have showed that MVD was a potent prognostic indicator for relapse free survival and/or overall survival in both node-negative and -positive patients. Two reports concluded no prognostic value of MVD, however the average MVD of these two studies significantly differed from other reports. Thus, at present, angiogenesis grade seems to provide an independent prognostic value when the MVD was properly assessed. With respect to the relationship with conventional prognostic indicators, several reports showed the tendency that increased MVD was correlated with younger age and increase of tumor size below 3 cm diameter, however, some reports failed to demonstrate the tendency, suggesting that these correlations are still in controversial. Biological markers including ER, p53 and c-erB2 showed no correlation with the MVD in many studies including our investigation. Only a significant correlation we found was that MVD was increased in tumors with the expression of vascular endothelial growth factor and platelet-derived endothelial cell growth factor, which are noted to be potent endothelial growth factor. Since the evaluation of tumor angiogenesis as a prognostic indicator is now widely investigated in a prospective study, MVD might be introduced to the category of the criteria for determining the schedule of postoperative adjuvant therapy of breast cancer.
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PMID:[The importance of tumor angiogenesis as a prognostic indicator in primary breast cancer]. 870 39

Human malignancies are often characterized by mutations of the p53 tumor suppressor gene. In a large proportion of cases, the mutation results in production of an altered protein that can bind and inactivate the wild-type gene product. This "dominant-negative" activity of mutant p53 molecules may limit the utility of p53 gene therapy of cancer. Using replication-deficient recombinant adenoviruses (rAd-p53) as a p53 gene delivery system, we evaluated the effects of p53 reintroduction on a series of 45 human cell lines containing wild-type, mutated, or no p53 protein. Results indicate a p53-specific, dose-dependent, and promoter-specific growth inhibition of a majority of p53-altered cell lines that correlates with the degree of adenovirus transgene expression. Similar effects were not observed on cells containing wild-type p53. rAd-p53 inhibited the growth of cells expressing various mutant p53 proteins including those characterized as "dominant negative mutants", and the antiproliferative effects were not abrogated by high levels of endogenous mutated p53 protein. In vivo, rAd-p53 also suppressed tumor growth and increased survival of nude mice bearing tumors that express mutant p53. These results support a role for p53 gene therapy of cancer, including malignancies harboring mutations in this tumor suppressor gene.
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PMID:Adenovirus-mediated p53 gene transfer inhibits growth of human tumor cells expressing mutant p53 protein. 872 11

A retroviral vector containing the wild-type p53 gene under control of a beta-actin promoter was produced to mediate transfer of wild-type p53 into human non-small cell lung cancers by direct injection. Nine patients whose conventional treatments failed were entered into the study. No clinically significant vector-related toxic effects were noted up to five months after treatment. In situ hybridization and DNA polymerase chain reaction showed vector-p53 sequences in posttreatment biopsies. Apoptosis (programmed cell death) was more frequent in posttreatment biopsies than in pretreatment biopsies. Tumor regression was noted in three patients, and tumor growth stabilized in three other patients.
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PMID:Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer. 878 51

In a mouse model of multistage tumorigenesis of islet beta-cells, apoptosis was activated concomitant with T-antigen oncogene-induced cell proliferation, further increased in the angiogenic stage, and markedly reduced in solid tumors. Crosses to p53-null mice confirmed this stage-specific variation as a p53-independent apoptotic process. Several apoptosis regulators were expressed, of which bcl-xL was up-regulated in tumors. When overexpressed throughout the pathway, bcl-xL protected most oncogene-expressing cells from apoptosis, enhancing progression from angiogenic progenitor to tumor without affecting earlier transitions. Further, two classes of solid tumor are described, distinguished by size and apoptotic incidence, implicating apoptosis regulation in expansive tumor growth. Thus, down-modulation of apoptosis selectively contributes to late steps in a tumorigenesis pathway.
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PMID:The rise and fall of apoptosis during multistage tumorigenesis: down-modulation contributes to tumor progression from angiogenic progenitors. 880 6

p53 has been shown to suppress tumor growth by regulating the cell cycle and by triggering apoptosis. Acquired somatic mutations of the p53 gene have been observed in a variety of human malignancies, and these result in a loss of its tumor suppressor function. To examine the occurrence of p53 abnormalities in bone and soft tissue sarcomas, 113 tumors were subjected to molecular analysis and mutations were confirmed in 16 tumors. The frequency of p53 alterations varied among the different subtypes of bone and soft tissue sarcomas, being observed predominantly in osteosarcomas (8/34 cases), rhabdomyosarcomas (2/3 cases), Ewing's sarcomas (1/5 cases), and liposarcomas (3/21 cases). In contrast, p53 gene mutations were detected at a lower frequency in malignant fibrous histiocytomas (2/34 cases) and not at all in nine chondrosarcomas and five leiomyosarcomas. Immunohistochemical staining of p53 protein was performed on 69 cases and compared to the DNA results. For 64 cases the results were concordant: 56 sarcomas were considered to have wild-type p53 by both techniques. As well, increased p53 protein expression was observed in eight of the nine tumors with p53 gene mutations. However, positive p53 staining was also seen in four sarcomas which had no detectable p53 mutations in exons 5 through 9. Because some sarcomas exhibit amplification and overexpression of MDM-2, which may interact with p53 and cause stabilization of wild-type p53 protein, we examined these tumors for MDM-2 amplification. None of the tumors with MDM-2 amplification exhibited p53 immunopositivity. Very weak p53 reactivity was detected in four malignant fibrous histiocytomas that had received either chemotherapy or radiotherapy. Of 16 metastatic lesions examined, only one contained a p53 mutation. In addition, for five cases in which both the original lesion and its metastases were analyzed, p53 alterations were not observed in the metastases if the tumor was wild-type at presentation. These data suggest that p53 alterations occur at different frequencies in various subtypes of sarcoma and, although detected in metastatic lesions, are not associated more frequently with progression.
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PMID:Molecular and immunohistochemical identification of p53 alterations in bone and soft tissue sarcomas. 882 48

Alterations in the p53 tumor-suppressor gene occur in 35-60% of human glioblastomas, and re-introduction of p53 can suppress neoplastic growth. To evaluate the potential for p53 gene therapy of glioblastoma, we have analyzed the response of human glioblastoma cell lines in vitro and in vivo to experimental therapy with replication-deficient recombinant adenoviruses encoding wild-type p53 (rAd-p53). Western blot analyses showed high-level expression of p53 protein after treatment with rAd-p53, and transgene expression was dependent on promoter strength. A p53-specific dose-dependent inhibition of in vitro cellular proliferation was observed in 5 of 6 cell lines, and growth inhibition corresponded to adenovirus-mediated gene transfer and expression. p53-specific cell death was quantitated by release of the lactate dehydrogenase enzyme. Fragmentation of DNA into nucleosomal oligomers and the occurrence of a hypodiploid cell population detected by flow cytometry provided evidence for apoptosis. Studies in nude mice demonstrated that ex vivo infection with rAd-p53 suppressed the tumorigenic potential of human glioblastoma cells. Furthermore, direct injection of rAd-p53 into established s.c. xenografts inhibited tumor growth. Our observations suggest that re-introduction of wild-type p53 may have potential clinical utility for gene therapy of glioblastoma.
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PMID:Adenovirus-mediated p53 gene transfer suppresses growth of human glioblastoma cells in vitro and in vivo. 882 52

Molecular alterations play a key role in the pathogenesis of gastrointestinal cancers. In the present paper we describe relevant molecular alterations in human pancreatic adenocarcinomas. Overexpression of growth factor receptors (EGF receptor, c-erbB2, c-erbB3, TGF beta receptor I-III), growth factors (EGF, TGF alpha, TGF beta-1-3, aFGF, bFGF), adhesion molecules (ICAM-1, ELAM-1) and gene mutations (p53, K-ras, DCC, APC) are present in a significant number of these tumors. These changes stimulate tumor growth and enhance the metastatic behavior of pancreatic cancer cells and thereby may contribute to shorter postoperative survival following tumor resection.
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PMID:Pancreatic cancer: the potential clinical relevance of alterations in growth factors and their receptors. 883 68


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