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)

Cancer development is a multistage process that results from the step-wise acquisition of somatic alterations in diverse genes. Recent studies indicate that caveolin-1 expression correlates with the level of oncogenic transformation in NIH3T3 cells, suggesting that caveolin in caveolae may regulate normal cell proliferation. In order to better understand potential functions of caveolin-1 in cancer development, we have studied expression levels of caveolin-1 in human breast cancer cells, and have found that caveolin expression is significantly reduced in human breast cancer cells compared with their normal mammary epithelial counterparts. When the caveolin cDNA linked to the CMV promoter is transfected into human mammary cancer cells having no detectable endogenous caveolin, overexpression of caveolin-1 resulted in substantial growth inhibition, as seen by the 50% decrease in growth rate and by approximately 15-fold reduction in colony formation in soft agar. In addition, characterization of caveolin-1 expression during cell cycle progression indicates that expression of alpha-caveolin-1 is regulated during cell cycle. Furthermore p53-deficient cells showed a loss in caveolin expression. In summary, the overall expression patterns, its ability to inhibit tumor growth in culture, its regulation during the cell cycle, and the loss of expression in p53-deficient cells all are consistent with an important growth regulating function for caveolin-1 in normal human mammary cells, that needs to be repressed in oncogenic transformation and tumor cell growth.
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PMID:Tumor cell growth inhibition by caveolin re-expression in human breast cancer cells. 952 38

Although cytokine gene transfer for cancer treatment can stimulate immune recognition and tumor regression in animal models, there is still a need for improvements to these strategies. In this study, we examined the efficacy of a combination gene therapy using adenovirus (Ad) 5 vectors expressing human interleukin-2 and the wild-type (wt) human p53 gene under control of the human cytomegalovirus immediate early promoter (AdIL-2 and Adp53wt, respectively). Infected murine cell lines and primary mouse tumor cells secreted high levels of IL-2 and over expressed the p53 protein for at least 9 days. After infection of cells with Adp53wt, DNA synthesis was significantly inhibited and apoptosis was induced within 3-5 days. Both vectors were tested in a transgenic mouse mammary adenocarcinoma model for antitumor response. Following a single intratumoral injection of mice bearing PyMT induced tumors, the combination of Adp53wt (1 x 10(9) pfu) plus a relatively low dose of AdIL-2 (1.5 x 10(8) pfu) caused regressions in 65% of the treated tumors without toxicity. Fifty percent of the treated mice remained tumor free and were immune to rechallenge with fresh tumor cells. In contrast, injection of either vector alone at this does resulted in only a delay in tumor growth. Only mice co-injected with Adp53wt and AdIL-2 showed specific antitumor cytolytic T lymphocyte (CTL) activity, indicating that the immune response involved in tumor regression was promoted by the combination therapy. These results suggest that cancer treatment strategies involving combined delivery of immunomodulatory and antiproliferative genes may be highly effective.
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PMID:Combination therapy with interleukin-2 and wild-type p53 expressed by adenoviral vectors potentiates tumor regression in a murine model of breast cancer. 955 18

The expression of the 8-oxo-7,8-dihydrodeoxyguanosine triphosphatase (8-oxo-dGTPase) gene in human breast tumors was evaluated at the level of the single cell to better understand how breast tumor cells regulate expression in response to oxidative stress. Compared to normal breast ductal cells, the level of 8-oxo-dGTPase expression in the breast tumor cells increased from non-detectable levels in normal breast to expression in 30-85% of the tumor cells in individual tumors. There was no significant association between 8-oxo-dGTPase expression and tumor grade and metastatic malignancy. The upregulation of 8-oxo-dGTPase was not directly linked to the expression of cyclins D1 and D3, estrogen receptor, p53, Ki-67 and c-erbB-2, which are genes involved in cell cycle regulation and tumor growth. The elevated expression of 8-oxo-dGTPase in human breast ductal carcinoma cells appears to be a general characteristic of breast tumors and may provide the tumor cell with a cellular defense mechanism to prevent the incorporation of 8-hydroxy-deoxyguanosine during DNA replication.
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PMID:Enhanced expression of the 8-oxo-7,8-dihydrodeoxyguanosine triphosphatase gene in human breast tumor cells. 956 6

Our previous studies demonstrated that the promyelocytic leukemia gene, PML which involved in the 15;17 translocation in acute promyelocytic leukemia (APL) is a growth and transformation suppressor. In this study, recombinant PML adenovirus, Ad-PML was constructed and used to infect human breast cancer cells in vitro and in vivo, the anti-oncogenic function of PML and its mechanism of growth suppressing effect in breast cancer cells were examined. We showed that Ad-PML effectively infected the MCF-7 and SK-BR-3 cells. A high level of PML protein was expressed within 24 h post-infection and a detectable level remained at day 16. Ad-PML significantly suppressed the growth rate, clonogenicity, and tumorigenicity of breast cancer cells. Intratumoral injections of MCF-7-induced tumors by high titer Ad-PML suppressed tumor growth in nude mice by about 80%. The injection sites expressed high level of PML and associated with a massive apoptotic cell death. To elucidate the molecular mechanism of PML's growth suppressing function, we examined the effect of Ad-PML on cell cycle distribution in MCF-7 and SK-BR-3 cells. We found that Ad-PML infection caused a cell cycle arrest at the G1 phase. We further showed that G1 arrest of MCF-7 cells is associated with a significant decrease in cyclin D1 and CDK2. An increased expression of p53, p21 and cyclin E was found. The Rb protein became predominantly hypophosphorylated 48 h post-infection. These findings indicate that PML exerts its growth suppressing effects by modulating several key G1 regulatory proteins. Our study provides important insight into the mechanism of tumor suppressing function of PML and suggests a potential application of Ad-PML in human cancer gene therapy.
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PMID:Recombinant PML adenovirus suppresses growth and tumorigenicity of human breast cancer cells by inducing G1 cell cycle arrest and apoptosis. 958 81

Experiments have been performed to clarify whether LHRH agonists might decrease growth of hormone-unresponsive prostate cancer in vivo. Male nude mice were injected s.c. with the human androgen-independent prostate tumor DU 145 cells; osmotic minipumps releasing the LHRH agonist Zoladex (LHRH-A) for 14 days were simultaneously implanted under the skin. Treatment with LHRH-A induced a significant decrease in tumor growth up to the end of the treatment. In subsequent experiment, minipumps releasing LHRH-A were implanted in nude mice either 7 or 14 days after cell inoculation. When the treatment was started 7 days after inoculation of the cells, tumor growth was significantly decreased up to 28 days; thereafter, tumor volume remained lower than in controls, although not significantly. When LHRH-A was administered beginning 14 days after cell inoculation, tumor growth was not significantly affected at any time interval considered. LHRH-A did not appear to induce apoptosis in DU 145 cells, at least on the basis of the apoptotic index and immunohistochemical staining of the p53 protein. On the other hand, treatment with LHRH-A was accompanied by a significant decrease of the concentration of epidermal growth factor receptors in DU 145 prostate cancer specimens. Our results show that the LHRH agonist used significantly inhibits the growth of DU 145 androgen-independent prostate tumor xenografts in nude mice.
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PMID:Growth-inhibitory effects of luteinizing hormone-releasing hormone (LHRH) agonists on xenografts of the DU 145 human androgen-independent prostate cancer cell line in nude mice. 959 Jan 26

A novel gene, p73, encoding a protein with significant homology to p53, was recently identified at 1p36. To investigate penetrance of p73 in prostatic carcinogenesis, mutation, allelotyping, and transcription analyses of p73 were performed in prostatic carcinoma. No types of mutation causing amino acid substitutions or frameshifts were found in 106 cases examined. Loss of heterozygosity in the gene was found in 2 of 38 cases (5.3%). Various expression levels of p73 alpha variant were observed in tumor compared with those in normal tissue. These data suggest that the p73 gene is not playing an essential role, but expression of p73 may associate with tumor growth in prostatic carcinogenesis.
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PMID:Mutation, allelotyping, and transcription analyses of the p73 gene in prostatic carcinoma. 960 45

Tumor size, axillary nodal status, histologic grading and the hormonal receptor status are the established prognostic factors for breast carcinoma. Concurrent to these factors the clinical validation of the new innovative tumor characteristics from molecular biology is difficult to achieve. Clinicians are more and more interested in indicators of response to particular treatments (predictive factors) and less in prognostic factors relevant for the natural course. The hormonal receptor status is the best known predictive factor with regard to the response to hormonal treatment. Among the innovative parameters the tumor suppressor gene p53 and the oncogene Her2/neu show a good correlation to sensitivity to cytostatic treatment. The detection of more and more molecular mechanisms of tumor growth and tumor spread raise hopes that innovative treatment approaches will lead to an antineoplastic effect. The molecular tumor parameters then may play the role of predictive factors for a specific treatment. For the present the established tumor factors should be used as the base for a treatment plan and the available already known predictive factors should be taken into consideration.
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PMID:[Relative indicators for disease outcome in breast carcinoma]. 960 45

An 18-year old male was admitted to our hospital complaining of back pain. His chest computed tomography showed a tumor in the posterior mediastinum. Open biopsy was performed, and a diagnosis of peripheral neuroepithelioma was made. No genetic abnormalities were detected in the DNA obtained from the biopsy specimen. He received chemotherapy and radiation several times. These treatment regimens were effective, but he relapsed 14 months later and died of respiratory failure due to tumor growth. Autopsy examination revealed a large tumor which occupied almost the entire right thoracic cavity, but there was no evidence of metastasis to other organs. Chromosomal translocation t(14;17) (q24;p12.2) and point mutation of exon 5 of the p53 gene were detected.
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PMID:An autopsy case of peripheral neuroepithelioma in posterior mediastinum with p53 point mutation. 961 73

Recent studies have indicated that angiogenesis may be regulated, in part, by p53 tumor suppressor gene function. We hypothesized that wild-type p53 replacement would down-regulate vascular endothelial growth factor (VEGF) expression and inhibit angiogenesis. KM12L4 and SW620, human colon cancer cell lines with p53 mutations, were transduced with a replication-defective adenoviral vector containing the wild-type p53 gene (Ad5/CMV/p53). Reverse transcription-PCR confirmed the presence of p53 in Ad5/CMV/p53-transduced cells. Transduction of colon cancer cells with wild-type p53 decreased VEGF RNA expression compared with that of controls. The decrease in VEGF expression in SW620 cells was dose dependent, with a 49% decrease observed at a multiplicity of infection of 50, and a 71% decrease observed at a multiplicity of infection of 100. Similar effects were seen in KM12L4 cells. VEGF supernatant protein levels were significantly reduced compared with those in nontransduced controls 48 h after the introduction of wild-type p53. Ad5/CMV/p53 inhibited tumor cell-induced angiogenesis in vivo. Restoration of wild-type p53 expression may decrease tumor growth by inhibiting the angiogenic response. These findings may explain, in part, the bystander effect seen with p53 tumor suppressor gene therapy.
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PMID:Adenovirus-mediated wild-type p53 gene transfer down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human colon cancer. 962 60

Gene replacement therapy is potentially a very powerful tool, targeting specific molecular mediators of cancer development and progression. p21WAF1 (p21) is a cyclin-dependent kinase inhibitor that is induced by p53 upon DNA damage or p53 overexpression, resulting in cell cycle arrest at the G1 checkpoint and inhibition of further cell proliferation. Using a replication-deficient recombinant adenovirus (AdV) ((rAd)-p21) as a p21 gene delivery system, we have evaluated the effect of p21 introduction in lung cancer cells in vitro as well as in vivo. In in vitro experiments, two human non-small cell lung cancer (NSCLC) cell lines, NCI-H460 and NCI-H322, showed dose-dependent p21 induction and concomitant cell growth inhibition following rAd/p21 infection. Flow cytometric analysis of the cell cycle revealed a significant increase in the percentage of NCI-H460 cells in G0/G1 following rAd/p21 infection compared with untreated cells, suggesting that p21-induced growth inhibition was due to G0/G1 arrest. We also tested the therapeutic efficacy of rAd/p21 in an in vivo human NSCLC model in SCID mice. Tumor-bearing mice were established by subcutaneous injections of NCI-H460 cells and treated by repeated intratumoral injections of rAd/p21. Intratumoral delivery of rAd/p21 significantly suppressed tumor growth and prolonged survival in rAd/p21-treated mice. Our in vitro and in vivo results provide strong preliminary evidence for the growth inhibition of NSCLC by rAd/p21. Collectively, these results justify further studies to evaluate the efficacy of rAd/p21 for gene therapy in human lung cancer.
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PMID:Inhibition of tumor cell growth by p21WAF1 adenoviral gene transfer in lung cancer. 962 2


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