Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

In human cancers, telomeres are commonly maintained by elevated levels of the ribonucleoprotein enzyme telomerase, which contains an intrinsic templating RNA moiety (human telomerase RNA; hTER) and the core protein (human telomerase reverse transcriptase). We developed a lentiviral system for efficient overexpression of mutant-template human telomerase RNA (MT-hTer) to add mutant DNA to telomeres in cancer cells. We show that such MT-hTer overexpression rapidly inhibits cell growth and induces apoptosis in telomerase-positive precancerous or cancer cells but not in telomerase-negative cells. These rapid effects occurred independent of wild-type p53 and telomere length. Tumor growth and progression were significantly decreased in xenografts of human tumor cells overexpressing MT-hTers. Expression of a hairpin short-interfering RNA that specifically targeted the endogenous wild-type hTER template region, but spared the MT-hTers, also caused p53-independent cell growth inhibition and apoptosis, and when coexpressed with MT-hTer, synergistically killed cancer cells. Hence, anti-wild-type-hTER short-interfering RNA and MT-hTers may act through distinct pathways and, particularly in combination, represent a promising approach to anticancer therapies.
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PMID:Rapid inhibition of cancer cell growth induced by lentiviral delivery and expression of mutant-template telomerase RNA and anti-telomerase short-interfering RNA. 1525 53

Constitutively photomorphogenic 1 (COP1), a RING finger ubiquitin ligase with substrates including c-Jun and p53, was recently found to be overexpressed in a number of breast and ovarian tumor samples. In addition to its E3 activity, COP1 was also shown to be able to inhibit activator protein 1 (AP-1) transcription. Through an affinity purification method, we have identified major vault protein (MVP) as a novel interacting partner for COP1 in mammalian cells. MVP, also known as lung resistance protein, is the main component of a ribonucleoprotein organelle called vault, and has been implicated in multiple drug resistance in many cancer cell lines and primary tumor samples. The interaction between COP1 and MVP is detectable at the endogenous level and occurs mostly in the cytoplasm. Similar to COP1, MVP inhibits c-Jun accumulation and AP-1 transcription activity. MVP knockout or knockdown cells contain elevated amount of c-Jun and increased AP-1 transcription activity. UV irradiation enhances MVP tyrosine phosphorylation, causes dissociation of COP1 from MVP, and alleviates the inhibitory activity of MVP on AP-1 transcription. Taken together, we propose that MVP, most likely through its interaction with COP1, suppresses c-Jun-mediated AP-1 transcription under unstressed conditions, thereby preventing cells from undergoing stress response.
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PMID:Major vault protein, in concert with constitutively photomorphogenic 1, negatively regulates c-Jun-mediated activator protein 1 transcription in mammalian cells. 1599 60

Paraffin wax-embedded ocular globes of cats with post-traumatic ocular sarcomas were examined for the presence of TERT, the active subunit of telomerase. The latter is a ribonucleoprotein complex essential for immortalization and expressed by most malignant tumours, germ line cells, lens epithelial cells, and some stem cells. Due to the frequent loss of cell cycle control with the increased expression of telomerase activity, post-traumatic ocular sarcomas were also examined for loss of p16 expression and alterations in p53, the findings being related to mitotic score, tumour grade, and proliferating cell nuclear antigen. These sarcomas expressed telomerase at a high frequency (62.5%); in addition, the majority showed alterations in cell cycle control, as evaluated by lack of p16 immunolabelling (66.7%). Alterations in p53 were the sole mechanism by which cell cycle control was dysregulated in only two tumours expressing TERT (13%). These findings suggest that p16, and not p53, represents the primary mechanism by which post-traumatic ocular sarcomas that express telomerase activity escape cell cycle control.
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PMID:Telomerase activity with concurrent loss of cell cycle regulation in feline post-traumatic ocular sarcomas. 1615 37

Telomerase is a complex ribonucleoprotein enzyme that exhibits elevated activity in the majority of cases of human leukemia. We have previously shown that retroviral expression of the catalytic subunit of telomerase, human telomerase reverse transcriptase (hTERT), in human cord blood CD34+ cells leads to an enhanced survival of mature hematopoietic cells. The mechanism for this pro-survival effect is not known. Here, we show that telomerase may play a role in leukemogenesis as a survival factor, independent of its role in maintaining telomere length. Retroviral expression of hTERT in the cytokine-dependent, human hematopoietic progenitor cell line, TF-1, resulted in the survival of cells following the withdrawal of cytokine, with protection from apoptosis, but did not promote unlimited replicative potential. This hTERT-mediated effect on cell survival does not involve Bcl-2 family members, results in accumulation of cells in G1 and appears to operate via autocrine expression of IL-3 and activation of the p53/p21 pathway. Survival in the absence of cytokine stimulation was also observed following retroviral expression of hTERT in normal cord blood CD34+ cells. This study demonstrates a novel pro-survival role for hTERT and may have important implications for the role of hTERT in the pathogenesis of leukemia and drug resistance.
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PMID:Human telomerase reverse transcriptase protects hematopoietic progenitor TF-1 cells from death and quiescence induced by cytokine withdrawal. 1667 17

Heterogeneous ribonucleoprotein K (hnRNP K) is a member of the hnRNP family which has several different cellular roles including transcription, mRNA shuttling, RNA editing and translation. Several reports implicate hnRNP K having a role in tumorigenesis, for instance hnRNP K increases transcription of the oncogene c-myc and hnRNP K expression is regulated by the p53/MDM 2 pathway. In this study comparing normal colon to colorectal cancer by proteomics, hnRNP K was identified as being overexpressed in this type of cancer. Immunohistochemistry with a monoclonal antibody to hnRNP K (which we developed) on colorectal cancer tissue microarray, confirmed that hnRNP K was overexpressed in colorectal cancer (P<0.001) and also showed that hnRNP K had an aberrant subcellular localisation in cancer cells. In normal colon hnRNP K was exclusively nuclear whereas in colorectal cancer the protein localised both in the cytoplasm and the nucleus. There were significant increases in both nuclear (P=0.007) and cytoplasmic (P=0.001) expression of hnRNP K in Dukes C tumours compared with early stage tumours. In Dukes C patient's good survival was associated with increased hnRNP K nuclear expression (P=0.0093). To elaborate on the recent observation that hnRNP K is regulated by p53, the expression profiles of these two proteins were also analysed. There was no correlation between hnRNP K and p53 expression, however, patients who presented tumours that were positive for hnRNP K and p53 had a poorer survival outcome (P=0.045).
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PMID:Heterogeneous nuclear ribonucleoprotein K is over expressed, aberrantly localised and is associated with poor prognosis in colorectal cancer. 1766 25

Telomeres are specialized structures at eukaryotic chromosomes ends, which role is to prevent them from degradation, end to-end fusion and rearrangement. However, they shorten after each cellular division because of an incomplete DNA replication, acting in normal somatic cells as a mitotic clock for permanent proliferation arrest or senescence entry. Short telomeres are perceived as damaged DNA leading to p53/ATM pathway activation. In tumoral cells, a ribonucleoprotein complex termed telomerase enables telomere elongation. This complex, composed of 2 main components, the telomerase RNA component or hTR, the RNA template for telomere synthesis, and telomerase reverse transcriptase, the catalytic subunit, is reactivated in the majority of cancers, including those of the lung. In this review, we briefly present the main results on telomerase expression in various histological types of lung carcinoma and in bronchial carcinogenesis along with telomere attrition. Inhibition of one of the main components of the enzyme or limitation of telomere access by telomerase represent novel targets for cancer therapies and chemoprevention in high risk patients of lung cancer.
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PMID:Telomerase expression in lung preneoplasia and neoplasia. 1731 Dec 57

Telomeres are ribonucleoprotein structures that protect the end of linear chromosomes from recognition as DNA double-stranded breaks and activation of a DNA damage response. Telomere-associated proteins also regulate telomerase, the protein responsible for maintaining telomere length. Loss of telomere function results from either alteration in the capping function at telomeres, or from progressive loss of telomeric repeats necessary to maintain proper telomeric structure. Dysfunctional telomeres activate p53 to initiate cellular senescence or apoptosis to suppress tumorigenesis. However, in the absence of p53, telomere dysfunction is an important mechanism to generate chromosomal instability commonly found in human carcinomas. Telomerase is expressed in the majority of human cancers, making it an attractive therapeutic target. Emerging anti-telomerase therapies that are currently in clinical trials might prove useful against some forms of human cancers.
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PMID:Role of telomeres and telomerase in genomic instability, senescence and cancer. 1776 95

Maintenance of intestinal mucosal epithelial integrity requires polyamines that modulate the expression of various genes involved in cell proliferation and apoptosis. Recently, polyamines were shown to regulate the subcellular localization of the RNA-binding protein HuR, which stabilizes its target transcripts such as nucleophosmin and p53 mRNAs. The activating transcription factor-2 (ATF-2) mRNA encodes a member of the ATF/CRE-binding protein family of transcription factors and was computationally predicted to be a target of HuR. Here, we show that polyamines negatively regulate ATF-2 expression posttranscriptionally and that polyamine depletion stabilizes ATF-2 mRNA by enhancing the interaction of the 3'-untranslated region (UTR) of ATF-2 with cytoplasmic HuR. Decreasing cellular polyamines by inhibiting ornithine decarboxylase (ODC) with alpha-difluoromethylornithine increased the levels of ATF-2 mRNA and protein, whereas increasing polyamines by ectopic ODC overexpression repressed ATF-2 expression. Polyamine depletion did not alter transcription via the ATF-2 gene promoter but increased the stability of ATF-2 mRNA. Increased cytoplasmic HuR in polyamine-deficient cells formed ribonucleoprotein complexes with the endogenous ATF-2 mRNA and specifically bound to 3'-UTR of ATF-2 mRNA on multiple nonoverlapping 3'-UTR segments. Adenovirus-mediated HuR overexpression elevated ATF-2 mRNA and protein levels, whereas HuR silencing rendered the ATF-2 mRNA unstable and prevented increases in ATF-2 mRNA and protein. Furthermore, inhibition of ATF-2 expression prevented the increased resistance of polyamine-deficient cells to apoptosis induced by treatment with tumor necrosis factor-alpha and cycloheximide. These results indicate that polyamines modulate the stability of ATF-2 mRNA by altering cytoplasmic HuR levels and that polyamine-modulated ATF-2 expression plays a critical role in regulating epithelial apoptosis.
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PMID:Polyamines regulate the stability of activating transcription factor-2 mRNA through RNA-binding protein HuR in intestinal epithelial cells. 1780 13

Tumor suppressor p53 is a well-characterized transcription factor that binds DNA. More enigmatic are the RNA-binding properties of p53 and their physiological relevance. We used three sensitive co-immunoprecipitation methods in an attempt to detect RNAs that tightly associate with p53 in cultured human cells. Although recombinant p53 protein binds RNA in a sequence-nonspecific mode, we do not detect specific in vivo RNA binding by p53. These results suggest that RNA binding is prevented by post-translational p53 modifications. A ribonucleoprotein (not p53) is purified by multiple IgG monoclonal antibodies (including anti-p53 antibodies) from both p53 +/+ and p53 null cells. Caution is therefore required in interpreting RNA co-immunoprecipitation experiments. Though not formally excluded, these results do not support models in which p53 binds specific RNA partners in vivo.
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PMID:Analysis of p53-RNA interactions in cultured human cells. 1786 21

Oxygen molecule modulates tumour response to radiotherapy. Higher radiation doses are required under hypoxic conditions to induce cell death. Hypoxia may inhibit the non-homologous end-joining DNA repair through down regulating Ku70/80 expression. Hypoxia induces drug resistance in clinical tumours, although the mechanism is not clearly elucidated. Vaults are ribonucleoprotein particles with a hollow barrel-like structure composed of three proteins: major vault protein (MVP), vault poly(ADP-ribose) polymerase, and telomerase associated protein-1 and small untranslated RNA. Over-expression of MVP has been associated with chemotherapy resistance. Also, it has been related to poor outcome in patients treated with radiotherapy alone. The aim of the present study was to assess the relation of Major Vault Protein expression and tumor hypoxia in clinical cervical tumors. MVP, p53 and angiogenesis, together with tumor oxygenation, were determined in forty-three consecutive patients suffering from localized cervix carcinoma. High MVP expression was related to severe hypoxia compared to low MVP expressing tumors (p = 0.022). Tumors over-expressing MVP also showed increased angiogenesis (p = 0.003). Besides it, in this study we show for the first time that severe tumor hypoxia is associated with high MVP expression in clinical cervical tumors. Up-regulation of MVP by hypoxia is of critical relevance as chemotherapy is currently a standard treatment for those patients. From our results it could be suggested that hypoxia not only induces increased genetic instability, oncogenic properties and metastatization, but through the correlation observed with MVP expression, another pathway of chemo and radiation resistance could be developed.
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PMID:Severe hypoxia induces chemo-resistance in clinical cervical tumors through MVP over-expression. 1966 Jan


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