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)

Interactions of CD70, a tumor necrosis factor-related cell surface ligand and its receptor, CD27, are thought to play an important role for T-, B-, and natural killer-cell activation. However, ligation of CD27 can also induce apoptosis. Human glioblastoma is paradigmatic for cancer-associated immunosuppression. We identified CD70 as a radioinducible gene in U87 MG glioma cells. A screening of a panel of human glioma cell lines revealed that 11 of 12 cell lines expressed CD70 mRNA and protein. Two human neuroblastoma cell lines did not express CD70. CD70 mRNA expression was enhanced by irradiation in 8 of 12 glioma cell lines in a p53-independent manner. No alteration in CD70 expression was observed after glioma cell exposure to cytotoxic drugs such as lomustine. CD70 protein was also detected by immunocytochemistry in 5 of 12 glioblastomas and 3 of 4 anaplastic astrocytomas in vivo. CD27 expression was not detected in any glioma cell line, and there was no evidence for autocrine or backward signaling of the CD70 system in human glioma cells. Unexpectedly, CD70 expressed on glioma cells did not increase the immunogenicity of glioma cells in vitro. In contrast, CD70-positive glioma cells induced apoptosis in peripheral blood mononuclear cells (PBMCs) in a CD70-dependent manner. Neutralization of CD70 expressed on glioma cells prevented apoptosis and enhanced the release of tumor necrosis factor-alpha in cocultures of glioma cells and PBMCs. The effects of CD70-expressing glioma cells on PBMCs were mimicked by agonistic CD27 antibodies. Conversely, the shedding of CD27 by PBMCs was identified as a possible escape mechanism from glioma cell-induced CD70-dependent apoptosis. Thus, induction of B-cell and T-cell apoptosis via interactions of CD70 expressed on glioma cells and CD27 expressed on B and T cells may be a novel way for the immune escape of malignant gliomas.
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PMID:Identification of CD70-mediated apoptosis of immune effector cells as a novel immune escape pathway of human glioblastoma. 1198 Jun 54

Tissue-specific gene expression is mediated largely by transcription factors, and a master regulatory gene is thus a potential marker of cellular lineage. Using normal fetal through adult pulmonary tissues and 64 consecutive lung adenocarcinomas, we examined the expression of thyroid transcription factor (TTF-1), which plays a crucial role in normal lung function and morphogenesis. TTF-1 was expressed consistently throughout the life stages and uniformly in the terminal respiratory unit, which is comprised of peripheral airway cells and small-sized bronchioles. Furthermore, the expression was maintained in 72% of adenocarcinomas that exhibited high correlation with surfactant apoprotein (p <0.001) and morphologic resemblance to terminal respiratory unit cells (p <0.001). The staining pattern was also uniform in the adenocarcinomas despite histologic and microenvironmental diversity in individual tumors and their metastatic foci. This consistency and uniformity, therefore, suggested that TTF-1 expression could be used as a lineage marker of terminal respiratory unit. We also identified interesting distinctions between TTF-1-positive and -negative adenocarcinomas based on their clinicopathologic features and expression of various cancer-associated genes. TTF-1-positive adenocarcinomas had statistically significant prevalence of female (p <0.01), nonsmoker (p <0.05), negative p53 staining (p <0.01), less frequent RB loss (p <0.05), and preserved expression of p27 (p <0.01). The results supported the TTF-1 lineage marker and suggested that molecular pathogenesis may in part be characterized by cellular lineage.
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PMID:TTF-1 expression in pulmonary adenocarcinomas. 1202 81

Recently our laboratory identified a cytoplasmic RNA-binding protein p62 which binds to and regulates the expression of IGF II mRNA. p62 was initially shown to be recognized by auto-antibodies in hepatocellular carcinoma (HCC) but now anti-p62 has been described in diverse malignancies. p62 is uniformly expressed in fetal liver and prominently in 33% of HCC nodules, but not detectable in adult liver or normal tissue adjacent to HCC nodules. In this study, a 90 kDa protein (p90), auto-antibodies to which were found associated with anti-p62 responses in the same HCC patient group, was identified by cDNA expression cloning. Indirect immunofluorescence showed that, like p62, p90 localized to the cytoplasm in cultured cells and mouse fetal, but not adult liver. Among 11 human gastric cancer tissues examined, p90 was overexpressed in six (55%). Together with other cancer associated auto-antibodies such as anti-p53, anti-p62, anti-Koc, and anti-CENP-F, auto-antibodies to p90 represent a new marker for tumors such as HCC and gastric cancer. Our data support the working hypothesis that auto-antibody production in cancer may be directly linked to aberrant auto-antigen expression.
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PMID:Cloning and characterization of a novel 90 kDa 'companion' auto-antigen of p62 overexpressed in cancer. 1211 81

Part 2 of this review discusses DNA damage in biliary epithelial cells in the development of cholangiocarcinoma, alterations in cell kinetics of biliary epithelial cells, biliary epithelial mitoinhibition, and apoptosis that includes the role of Bcl-2, transforming growth factor-beta, telomerase activities and deregulation of Ras and p53, cancer-associated antigens in cholangiocarcinoma, precancerous lesions, stroma formation and angiogenesis, cancer invasion, cell-cell and cell-matrix interactions, and the mechanism of evasion from immune surveillance. These discussions are followed briefly by treatments such as photodynamic therapy, and surgical approaches comparing resection and liver transplantation.
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PMID:Cholangiocarcinoma: recent progress. Part 2: molecular pathology and treatment. 1220 64

Papillomaviruses possess small DNA genomes that encode five early (E) proteins. Transient DNA replication requires activities of the E1 and E2 proteins and a DNA segment containing their binding sites. The E6 and E7 proteins of cancer-associated human papillomavirus (HPV) transform cells in culture. Recent reports have shown that E6 and E7 are necessary for episomal maintenance of HPV in primary keratinocytes. The functions of E6 necessary for viral replication have not been determined, and to address this question we used a recently developed transfection system based on HPV31. To utilize a series of HPV16 E6 mutations, HPV31 E6 was replaced by its HPV16 counterpart. This chimeric genome was competent for both transient and stable replication in keratinocytes. Four HPV16 E6 mutations that do not stimulate p53 degradation were unable to support stable viral replication, suggesting this activity may be necessary for episomal maintenance. E7 has also been shown to be essential for episomal maintenance of the HPV31 genome. A point mutation in the Rb binding motif of HPV E7 has been reported to render HPV31 unable to stably replicate. Interestingly, HPV31 genomes harboring two of the three p53 degradation-defective E6 mutations combined with this E7 mutation were maintained as replicating episomes. These findings imply that the balance between E6 and E7 functions in infected cells is critical for episomal maintenance of high-risk HPV genomes. This model will be useful to dissect the activities of E6 and E7 necessary for viral DNA replication.
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PMID:Genetic analysis of high-risk e6 in episomal maintenance of human papillomavirus genomes in primary human keratinocytes. 1238 96

The high risk HPVs (such as HPV-16 and HPV-18) that are associated with specific anogenital cancers encode two oncoproteins E6 and E7, which are expressed in the HPV positive cancers. The E7 protein functions in cellular transformation, at least in part, through interactions with pRB and the other pRB related 'pocket proteins'. The major target of the E6 oncoprotein encoded by the genital tract, cancer associated human papillomaviruses is p53. Several lines of evidence suggest that E6 and E7 have additional targets important to the oncogenic potential of the virus. Work from a number of laboratories has focused on determining other activities of HPV relevant to carcinogenesis and identifying additional cellular targets of E6 and E7. This paper will review the state of the field at the time of the 19th International Papillomavirus Workshop in September 2001 with respect to the HPV encoded oncoproteins.
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PMID:Human papillomavirus immortalization and transformation functions. 1244 61

Certain types of human papillomaviruses have been etiologically associated with malignant lesions, most notably with cervical cancer. The major oncoproteins of these cancer-associated viruses are encoded by the viral E6 and E7 genes. Thorough characterization of these oncoproteins and their interaction with cellular proteins has shown that both E6 and E7 exploit the ubiquitin-proteasome system to degrade and, thus, to functionally inactivate negative cell-regulatory proteins including members of the p110(RB) family and p53. This act of piracy is assumed to contribute to both the efficient propagation of HPVs and HPV-induced carcinogenesis.
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PMID:Human papillomavirus-induced carcinogenesis and the ubiquitin-proteasome system. 1250 57

DNA repair of double strand breaks, interstrand DNA cross-links, and other types of DNA damage utilizes the processes of homologous recombination and non-homologous end joining to repair the damage. Aberrant homologous recombination is likely to be responsible for a significant fraction of chromosomal deletions, duplications, and translocations that are observed in cancer cells. To facilitate measurement of homologous recombination frequencies in normal cells, mutant cells, and cancer cells, we have developed a high titer retroviral vector containing tandem repeats of mutant versions of a GFP-Zeocin resistance fusion gene and an intact neomycin resistance marker. Recombination between the tandem repeats regenerates a functional GFP-Zeo(R) marker that can be easily scored. This retroviral vector was used to assess homologous recombination frequencies in human cancer cells and rodent fibroblasts with differing dosages of wild type or mutant p53. Absence of wild type p53 stimulated spontaneous and ionizing radiation-induced homologous recombination, confirming previous studies. Moreover, p53(+/-) mouse fibroblasts show elevated levels of homologous recombination compared to their p53(+/+) counterparts following retroviral vector infection, indicating that p53 is haploinsufficient for suppression of homologous recombination. Transfection of vector-containing p53 null Saos-2 cells with various human cancer-associated p53 mutants revealed that these altered p53 proteins retain some recombination suppression function despite being totally inactive for transcriptional transactivation. The retroviral vector utilized in these studies may be useful in performing recombination assays on a wide array of cell types, including those not readily transfected by normal vectors.
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PMID:Activities of wildtype and mutant p53 in suppression of homologous recombination as measured by a retroviral vector system. 1251 13

Cells expressing the neuronal stem cell marker Nestin are present in the human pancreas but the biological role of these cells has yet to be resolved. We report here the establishment with the catalytic subunit of human telomerase (hTERT) of a line of normal human cells representing this cell type. Primary human cells derived from the ducts of the pancreas were transduced with an hTERT cDNA. The infected cells became positive for telomerase, failed to senesce, and were still proliferating after more than 150 doublings. The immortalized cells were positive for the expression of Nestin (at both the mRNA and protein levels) and were found to be free of cancer-associated changes: diploid and expressing wild type p16(INK4a), p53, and K-Ras. An established line of normal human cells representing this cell type should be of great value to help define the biological properties of this novel cell type.
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PMID:Immortalization with telomerase of the Nestin-positive cells of the human pancreas. 1258 17

In codon 72 of the p53 antioncogene there are two alleles, arginine and proline; the arg/arg genotype has recently been identified as a risk factor for developing of cervicouterine cancer (CuCa) associated to human papillomavirus (HVP) infection. The aim of this work was to determine in a sample of women the frequency of proline-arginine alleles and genotypes of p53 codon 72. The study was conducted in a sample of inpatient women at the hospital. p53 codon 72 alleles were determined in genomic ADN by amplification of specific sequences by chi 2 test. From 102 analyzed samples, p53-arginine allele corresponded to 67.64% and p53-proline allele corresponded to 32.36%; 47 women (46.10%) were arg/arg homocygotes, 11 women (10.77%) were pro/pro homocygotes, 44 women (43.13%) were arg/pro heterocigotes; the genotype distribution was within the Hardy-Weinberg equilibrium. The detection of a high percentage of arginine homocygotes suggests that this genotype, considered as a risk factor for cancer associated to oncogenic HPV, has a high prevalence in the north of Mexico. The determination of this kind of polymorphisms is important as preventive action with regard to identification of risk factors for CaCu associated to HPV infection.
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PMID:[Risk factors for cervico-uterine cancer associated to HPV: p53 codon 72 polymorphism in women attending hospital care]. 1270 45


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