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)

Two immortalized human airway epithelial cell lines were established by the ectopic expression of human telomerase reverse transcriptase (hTERT). These cell lines have been continuously cultured for >200 population doublings (PDs). They are characterized by an overexpression of hTERT mRNA, elongated telomere length and higher telomerase activity. Early passage of these cells (<20 PDs) expressed the p16 protein at a level comparable to their parental cells. In later passages (>150 PDs), p16 protein was decreased but recovered to the early passage level upon treatment with a methylation inhibitor, 5-Aza-CdR. Chromosome analysis showed a near-diploid karyotype albeit with a gain or loss of certain chromosomes and a few stable translocations in both cell lines. No p53 gene alterations were found in these cell lines. They remained anchorage dependent in growth and were non-tumorigenic in nude mice. These two cell lines are the first reported immortalized human airway epithelial cell lines by hTERT expression without incorporation of virus or other genes, which may serve as a useful model system for studies on bronchial carcinogenesis.
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PMID:Immortalization of human small airway epithelial cells by ectopic expression of telomerase. 1567 31

In this work, we described the proliferation of human non-small-cell-lung-cancer (NSCLC) cells H1437 harboring p53 alleles (proline-267) can be inhibited by low-dosage topoisomerase II inhibitor etoposide (VP-16) in vitro and in vivo. The cytotoxicity was demonstrated by prolonged cell arrest at G2-M checkpoint exhibiting senescence-like phenotype followed by apoptotic cell death that appeared on the sixth day of VP-16 treatment. The experimental in vivo evidence of growth suppression was also demonstrated in xenograft tumors. The appearance of senescence-like state during extended G2-M phase arrest was indicated by slow proliferation and loss of growth sensitivity in culture accompanied with cellular morphological changes, time-dependent regulation of beta-galactosidase staining as well as distinct reduction of telomerase activity upon protracted VP-16 exposure. Further molecular determinants leading to G2-M cell arrest was also characterized by the concerted up-regulation of cyclin-dependent kinase inhibitors, p16(INK4a) and p21(Waf1/Cipi), beginning 2 days later following drug exposure at both translational and transcriptional levels, while human telomerase reverse transcriptase (hTERT) activities reduced progressively. The clinically important therapeutic agent VP-16-mediated prolonged cell arrest at G2-M phase prior to apoptotic death offered a different perspective in restraining human cancer cells at low drug dosage, thereby serving as an effective telomerase inhibitor as well as an apoptosis effector. The overall results demonstrated that apoptosis can be regulated differently in human NSCLC cells with disrupted p53. Further effort in elucidating G2-M arrest before leading to apoptosis promises to provide an alternative insight in reversing tumorigenic phenotype of human cancers.
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PMID:Etoposide (VP-16) elicits apoptosis following prolonged G2-M cell arrest in p53-mutated human non-small cell lung cancer cells. 1589 59

Replacement of the p53 tumor suppressor gene is a rational approach to the management of malignant gliomas because p53 is frequently mutated or inactivated in these cancers. Major weaknesses of this approach are that malignant gliomas are mixtures of cells with wild-type and mutant p53, and that tumor cells exhibiting wildtype p53 are resistant to p53 gene transfer. An effective alternative is needed to overcome these difficulties. p53-upregulated modulator of apoptosis (PUMA) was identified as a p53-inducible proapoptotic molecule. Our purpose was to elucidate a role for PUMA in p53 gene therapy and to investigate whether PUMA is an efficient substitute for p53 in cancer therapy. We demonstrated that PUMA was upregulated in mutant p53 malignant glioma cells (U373-MG and T98G) undergoing apoptosis but was not upregulated in apoptosis-resistant wild-type p53 malignant glioma cells (U87-MG and D54) after adenoviral transfer of p53. Overexpression of PUMA resulted in massive apoptosis associated with mitochondrial damage and caspase-3 activation in all tumor cells tested. Use of the human telomerase reverse transcriptase (hTERT) promoter system induced apoptosis only in malignant glioma cells with telomerase activity, while sparing normal cells lacking telomerase. The ability of PUMA to induce apoptosis was greater than that of caspase-6 or caspase-8 transfer, using the same system. Moreover, exogenous expression of PUMA under the hTERT promoter system significantly suppressed the growth of subcutaneous U87-MG tumors in nude mice and did not induce apoptosis in surrounding nontumor tissues. These results indicate that PUMA, which is regulated under a tumor-specific expression system such as the hTERT promoter, may be better than p53 as a therapeutic tool for malignant gliomas.
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PMID:Therapeutic efficacy of PUMA for malignant glioma cells regardless of p53 status. 1596 Jun

Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase holoenzyme as well as the rate-limiting component of the telomerase enzyme complex. However, the role of the hTERT in apoptosis induced by histone deacetylase inhibitor has only been marginally addressed. For the first time, our study demonstrated that trichostatin A (TSA) briefly activated the proliferation of cervical cancer cell lines, HeLa and SiHa, within 12 h, but then inhibited cell growth after that time point. In response to TSA, hTERT expression, telomerase activity, and telomere length also underwent similar changes during the same time frame. Furthermore, the data in our study showed that cells transfected with dominant negative hTERT were more likely to undergo apoptosis induced by TSA than cells transfected with wild-type hTERT. The cyclin/cdk inhibitor p21waf1 was down-regulated by hTERT without changing the expression of p53. Results from this study suggest that the hTERT might be a primary target of TSA and the anti-apoptosis effect of hTERT might be carried out through a p21waf1-dependent and p53-independent pathway.
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PMID:Role of hTERT in apoptosis of cervical cancer induced by histone deacetylase inhibitor. 1605 Nov 88

Thioredoxin reductase (TrxR) in conjunction with thioredoxin (Trx) is a ubiquitous intracellular oxidoreductase system with antioxidant and redox regulatory roles. In some human tumors, the thioredoxin system is found overexpressed. We have used an antisense approach to investigate whether inhibition of TrxR overexpression can suppress the growth of human hepatocellular carcinoma SMMC-7721 cells. TrxR cDNA fragment was inserted in the antisense direction into pcDNA3.1/myc-His and SMMC-7721 cells were stably transfected with the plasmid construct. The results showed that TrxR antisense RNA could significantly reduce TrxR mRNA level and activity, and suppress the growth of SMMC-7721 cells. Cell-cycle analysis showed G2/M phase arrest in SMMC-7721 cells transfected with TrxR antisense plasmid. TrxR antisense RNA could significantly increase p53 mRNA level and decrease Bcl-2 mRNA level by reverse transcriptase-polymerase chain reaction (RT-PCR). Furthermore a significant decrease in human telomerase reverse transcriptase (hTERT) mRNA level was found in SMMC-7721 cells transfected with TrxR antisense plasmid. Flow cytometry and telomere fluorescence in situ hybridization (Flow FISH) showed that TrxR antisense RNA could significantly reduce the telomere fluorescence in SMMC-7721 cells. The results suggested that TrxR antisene RNA inhibited the growth of SMMC-7721 cells through an accumulation of cell cycle at G2/M phase, an increase in p53 mRNA level and a reduction in telomere fluorescence and Bcl-2, hTERT mRNA levels.
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PMID:Inhibitory effects of thioredoxin reductase antisense RNA on the growth of human hepatocellular carcinoma cells. 1608 46

Cancer cells transcriptionally activate many genes that are important for uncontrolled proliferation and cell death. Deregulated transcriptional machinery in tumor cells usually consists of increased expression/activity of transcription factors. Ideally, cancer-specific killing can be achieved by delivering a therapeutic gene under the control of the DNA elements that can be activated by transcription factors that are overexpressed and/or constitutively activated in cancer cells. Additionally, tumor-specific translation of tumor-killing genes has been also exploited in cancer gene therapy. Based on these rationales, cancer-specific expression of a therapeutic gene has emerged as a potentially successful approach for cancer gene therapy. To achieve tumor-specific expression, cancer-specific vectors are generally composed of promoters, enhancers, and/or 5'-UTR that are responsive to tumor-specific transcription factors. A number of cancer-specific promoters have been reported, such as those of probasin, human telomerase reverse transcriptase, survivin, ceruloplasmin, HER-2, osteocalcin, and carcinoembryonic antigen. Evidences suggest that the enhancer element targeted by beta-catenin can be useful to target colon cancer cells. The 5'-UTR of the basic fibroblast growth factor-2 has been reported to provide tumor specificity. Moreover, a variety of therapeutic genes demonstrated direct antitumor effects such as those encoding proapoptotic proteins p53, E1A, p202, PEA3, BAX, Bik, and prodrug metabolizing enzymes, namely thymidine kinase and cytosine deaminase. As cancerous cells of different origins vary significantly in their genetic, transcriptional/translational, and cellular profiles, the success of a cancer gene therapy will not be promised unless it is carefully designed based on the biology of a specific tumor type. Thus, tremendous research efforts have been focused on the development of non-viral vectors that selectively target various tumors resulting in minimal toxicity in the normal tissues. Significant progresses were also made in the exploitation of various novel apoptotic, cytotoxic genes as therapeutic tools that suppress the growth of different tumors. Together, these recent advances provide rationales for future clinical testing of transcriptionally targeted non-viral vectors in cancer patients.
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PMID:Cancer-specific gene therapy. 1609 14

Telomerase is Ribonucleoprotein complex in eukaryocyte, which is composed of telomerase reverse transcriptase(TERT) and telomerase RNA. Telomerase is a special DNA polymerase which can extend the terminal of DNA and maintain the length of telomere. TERT have reverse transcriptase activity. Telomerase activity do not examine in most somatic cell and primary cell, but most tumor cell have strong telomerase activity. It was think that the telomerase has strong relation with tumor occurrences. In this article,the author instruct the correlation of G-strand and P53 in tumor occurrences.
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PMID:[The advance of tumor development mechanism applying mTR-/- mouse model]. 1611 48

The terminal ends of eukaryotic chromosomes, termed telomeres, progressively shorten during each round of cell division eventually leading cells into senescence. Tumor cells typically overcome this barrier to unlimited proliferation by activation of the human telomerase reverse transcriptase (hTERT) gene. In contrast, in most human somatic cells hTERT expression is tightly repressed by multiple tumor suppressors. Here, we studied the regulation of hTERT by the p53 family member p73. We show that forced expression of p73 or activation of endogenous p73 by E2F1 results in the downregulation of telomerase activity. Vice versa, siRNA-mediated knockdown of p73 induces hTERT expression. Responsiveness to p73 is conferred by Sp1 binding sites within the hTERT core promoter. In tumor cells, p73 isoforms lacking the transactivation domain (DeltaNp73) are frequently overexpressed and believed to function as oncogenes. We show that DeltaNp73 antagonizes the repressive effect of the proapoptotic p53 family members on hTERT expression and, in addition, induces hTERT expression in telomerase-negative cells by interfering with E2F-RB-mediated repression of the hTERT core promoter. These data provide evidence that the p73 gene functions as an important regulator of telomerase activity with implications for embryonic development, cellular differentiation and tumorigenesis.
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PMID:Regulation of telomerase activity by the p53 family member p73. 1620 39

Activation of telomerase is linked to tumorigenesis and has been observed in a variety of human tumors. Previous reports demonstrated that p53 represses human telomerase reverse transcriptase (hTERT), a key component for telomerase activity. The p73 protein displays a tumor suppressor activity similar to p53. In the present study, we examined the effect of transactivation competent p73 isoforms on hTERT expression in p53-negative human H1299 cells. Overexpression of C-terminal p73 isoforms (alpha, beta, gamma, delta) resulted in a clear down-regulation of hTERT promoter activity. The strongest inhibitory effect, comparable with p53, was observed for p73beta. Moreover, suppression of hTERT expression was also mediated by endogenous p73 after activation of E2F1 in H1299ER-E2F1 cells. Mutations in the Sp1 transcription factor-binding sites of the proximal core promoter region significantly abolished p73-induced repression, suggesting that the effect is mediated by Sp1. Finally, we demonstrate that p73 directly interacts with Sp1, suggesting that formation of a p73-Sp1 complex is the underlying mechanism for p73-triggered inhibition of hTERT expression. Our findings provide additional evidence that p73 mimics p53 in many aspects in cells lacking functional p53, thereby contributing to tumor surveillance.
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PMID:C-terminal p73 isoforms repress transcriptional activity of the human telomerase reverse transcriptase (hTERT) promoter. 1623 37

Ionizing radiation has been reported to promote accelerated or premature senescence in both normal and tumour cell lines. The current studies were designed to characterize the accelerated senescence response to radiation in the breast tumour cell in terms of its dependence on functional p53 and its relationship to telomerase activity, telomere lengths, expression of human telomerase reverse transcriptase (hTERT, the catalytic subunit of telomerase) and human telomerase RNA (hTR, the RNA subunit of telomerase), as well as the induction of cytogenetic aberrations. Studies were performed in p53 wild-type MCF-7 cells, MCF-7/E6 cells with attenuated p53 function, MDA-MB231 cells with mutant p53 and MCF-7/hTERT cells with constitutive expression of hTERT. Telomerase activity was measured by the telomeric repeat amplification protocol (TRAP assay), telomere lengths by the terminal restriction fragment (TRF) assay, hTR and hTERT expression by reverse transcriptase-polymerase chain reaction (RT-PCR), senescence by beta-galactosidase staining, and apoptosis by TdT-mediated d-UTP-X nick-end labelling (TUNEL assay). Widespread and extensive expression of beta-galactosidase, a marker of cellular senescence, was evident in MCF-7 breast tumour cells following exposure to 10 Gy of ionizing radiation. Radiation did not suppress expression of either hTERT or hTR, alter telomerase activity or induce telomere shortening. Senescence arrest was also observed in irradiated MCF-7/hTERT cells, which have elongated telomeres due to the ectopic expression of the catalytic component of telomerase. In contrast to MCF-7 cells, irradiated MDA-MB231 breast tumour cells and MCF-7/E6 cells failed to senesce and instead demonstrated a delayed apoptotic cell death. Irradiation produced chromosome end associated abnormalities, including end-to-end fusions (an indicator of telomere dysfunction) in MCF-7 cells, MCF-7/hTERT cells, as well as in MCF-7/E6 cells. When cells were maintained in culture following irradiation, proliferative recovery was evident exclusively after senescence while the cell lines which responded to radiation by apoptosis continued to decline in cell number. Accelerated senescence in response to ionizing radiation is p53 dependent and associated with telomer dysfunction but is unrelated to changes in telomerase activity or telomere lengths, expression of hTERT and hTR. In the absence of functional p53, cells are unable to arrest for an extended period, resulting in apoptotic cell death while accelerated senescence in cells expressing p53 is succeeded by proliferative recovery.
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PMID:p53-Dependent accelerated senescence induced by ionizing radiation in breast tumour cells. 1630 15


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