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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate the effects of the wild-type p53 expression in normal and tumor cells, we have constructed a recombinant adenovirus vector (E1 minus) expressing human wild-type p53 cDNA (AdWTp53). Infection of normal and tumor cells of lung and mammary epithelial origin with AdWTp53 resulted in high levels of wild-type p53 expression. Production of p53 protein following infection was dependent on the dose of AdWTp53 with maximum amounts of p53 produced following infection with 50 plaque-forming units/cell. AdWTp53 infection inhibited the growth of all human cell lines studied. However, tumor cells that were null for p53 prior to infection (H-358 and MDA-MB-157) and tumor cells that expressed mutant endogenous p53 protein (MDA-MB-231 and MDA-MB-453) were more sensitive to AdWTp53 cytotoxicity than cells that contained the wild-type p53 (MCF-7, MCF-10, 184B5, and normal mammary epithelial cells). All cells exhibited WAF1/Cip1 mRNA and protein induction following AdWTp53 infection. AdWTp53-induced cytotoxicity of human tumor cell lines expressing mutant p53 was mediated by apoptosis as revealed by nucleosomal DNA fragmentation analysis. No detectable nucleosomal DNA fragmentation was observed following AdWTp53 infection of human cells expressing wild-type p53. These data suggest that endogenous p53 status is a determinant of AdWTp53-mediated cell killing of human tumor cells.
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PMID:Cytotoxic effects of adenovirus-mediated wild-type p53 protein expression in normal and tumor mammary epithelial cells. 981 59

A differentiation induction subtraction hybridization strategy is being used to identify and clone genes involved in growth control and terminal differentiation in human cancer cells. This scheme identified melanoma differentiation associated gene-7 (mda-7), whose expression is up-regulated as a consequence of terminal differentiation in human melanoma cells. Forced expression of mda-7 is growth inhibitory toward diverse human tumor cells. The present studies elucidate the mechanism by which mda-7 selectively suppresses the growth of human breast cancer cells and the consequence of ectopic expression of mda-7 on human breast tumor formation in vivo in nude mice. Infection of wild-type, mutant, and null p53 human breast cancer cells with a recombinant type 5 adenovirus expressing mda-7, Ad.mda-7 S, inhibited growth and induced programmed cell death (apoptosis). Induction of apoptosis correlated with an increase in BAX protein, an established inducer of programmed cell death, and an increase in the ratio of BAX to BCL-2, an established inhibitor of apoptosis. Infection of breast carcinoma cells with Ad.mda-7 S before injection into nude mice inhibited tumor development. In contrast, ectopic expression of mda-7 did not significantly alter cell cycle kinetics, growth rate, or survival in normal human mammary epithelial cells. These data suggest that mda-7 induces its selective anticancer properties in human breast carcinoma cells by promoting apoptosis that occurs independent of p53 status. On the basis of its selective anticancer inhibitory activity and its direct antitumor effects, mda-7 may represent a new class of cancer suppressor genes that could prove useful for the targeted therapy of human cancer.
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PMID:The cancer growth suppressor gene mda-7 selectively induces apoptosis in human breast cancer cells and inhibits tumor growth in nude mice. 982 12

Esophageal squamous cell carcinoma (ESCC) demonstrates wide regional variation in incidence and causal associations. Human papillomavirus (HPV) has been implicated in ESCC, particularly the sub-types 16 and 18. Transforming proteins E6 and E7 from these high risk sub-types, interact with p53 protein and Rb protein respectively, leading to loss of function of these tumor suppressor gene products. These interactions further lead to inactivation of the growth suppressive effects of the p53 and Rb proteins, resulting in abnormal proliferative states. p53 protein expression has been found in both HPV-positive and -negative tumors, indicating that HPV and p53 protein expression are not mutually exclusive and can occur together in the same tumor. It has been observed that HPV plays a more significant role in esophageal carcinogenesis in geographic areas with a high prevalence of the disease. A variation in the association between HPV and ESCC worldwide may be due to environmental and geographic factors, or to genetic susceptibility to esophageal HPV infections. Variations in the sensitivity of techniques used in the detection of the virus and in the methodology for processing the tumor tissues, may also be responsible for global differences. Esophageal carcinogenesis is a complex multistep process with a multifactorial etiology. Infection with oncogenic HPV types may be an integral part in a multistep process that leads to ESCC.
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PMID:The role of the human papilloma virus in esophageal cancer. 983 8

Recombinant adenovirus (Adv)-mediated gene transduction is a powerful technology for cancer gene therapy. In this article, we report the generation of a fiber-mutant Adv vector, using the Adv genomic DNA-terminal protein complex (DNA-TPC) cotransfection method. First, a fiber-mutant construct in a plasmid carrying the right-side two-thirds of the human adenovirus type 5 (Ad5) genome (pTR) was cotransfected with Ad5 DNA-TPC, yielding the recombinant Adv with the desired fiber mutation. The DNA-TPC from the mutant Adv was then utilized to produce a second-step recombinant Adv with an expression cassette in the place of E1. By this procedure, we generated a fiber mutant, F/K20, that has a linker and a stretch of 20 lysine residues added at the C terminus of the fiber. By using Adv carrying a reporter lacZ gene (AxCAZ2) with either F/K20 or wild-type fiber (F/wt), we examined the transduction efficiency of F/K20-Adv. No significant difference in the transduction efficiency between F/K20 and F/wt-Adv was observed for a human fibroblast line, WI-38, or various tumor cell lines, including melanoma, prostate, esophageal, and pancreatic cancer lines. In clear contrast, F/K20-Adv showed a remarkably enhanced efficiency in genetic transduction of human glioma cells. In all four human glioma lines tested, the multiplicities of infection (MOIs) for transduction of 50% of the population (ED50) were decreased with F/K20-Adv compared with F/wt-Adv: 7-fold for T98G, 14-fold for U251, 9-fold for U373, and 42-fold for U87 cells. Therefore, we attempted to apply F/K20-Adv for gene therapy of malignant glioma. Glioma cells infected with F/K20-Adv carrying genes for interleukin 2 or interleukin 12 produced a high level of each cytokine at a much lower MOI than did cells infected with F/wt-Adv. Infection with F/K20-Adv carrying the wild-type p53 tumor suppressor gene resulted in an enhanced level of p53 protein expression and an increased incidence of F/K20-Adv in transduction efficiency for malignant glioma, providing promising tools for gene therapy.
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PMID:Generation of fiber-mutant recombinant adenoviruses for gene therapy of malignant glioma. 985 17

Recent reports suggest that an early region 1B (E1B) 55, 000-molecular-weight polypeptide (55K)-null adenovirus type 5 (Ad5) mutant (dl1520) can replicate to the same extent as wild-type (wt) Ad5 in cells either deficient or mutated in p53, implicating p53 in limiting viral replication in vivo. In contrast, we show here that the replicative capacity of Ad5 dl1520 is wholly independent of host cell p53 status, as is the replicative capacity of comparable Ad12 E1B 54K-null adenoviruses (Ad12 dl620 and Ad12 hr703). Furthermore, we show that there is no requirement for complex formation between p53 and Ad5 E1B 55K or Ad12 E1B 54K for a productive infection, such that wt Ad5 and wt Ad12 will both replicate in cells which are null for p53. In addition, we find that these Ad5 and Ad12 mutant viruses induce S phase irrespective of the p53 status of the cell and that, therefore, S-phase induction does not correlate with the replicative capacity of the virus. Interestingly, the replicative capacities of the large E1B-null adenoviruses correlated positively with the ability to express E1B 19K and were related to the ability to repress premature adenovirus-induced apoptosis. Infection of primary human cells indicated that Ad5 dl1520, wt Ad5, and wt Ad12 replicated better in cycling normal human skin fibroblasts (HSFs) than in quiescent HSFs. Thus, the cell cycle status of the host cell, upon infection, also influences viral yield.
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PMID:The replicative capacities of large E1B-null group A and group C adenoviruses are independent of host cell p53 status. 997 89

Infection of human B lymphocytes with Epstein-Barr virus (EBV) in vitro induces a G0 to G1 transition followed by DNA synthesis and cell division. The virus activation of the cell cycle closely mimics the antigen-dependent normal B cell activation pathway. Infected B cells undergo blast transformation followed by the emergence of immortalized lymphoblastoid cell lines. Numerous cellular proteins are switched on in the infected cells, including p53. In view of the frequent association of wild-type p53 (wtp53) expression with growth arrest and apoptosis, p53 expression, cell viability (absence of apoptosis) and cell cycle progression at the single cell level during the first week after EBV infection were assessed. The rate of EBV infection was scored by EBNA-5 staining between 20 and 72 h after infection and varied between 20 and 25% of the cell population. All EBNA-5-positive blasts were p53-positive as well. Double staining for p53 and for DNA ends (TUNEL) revealed that p53-positivity and apoptosis were mutually exclusive. Quantification of the DNA content by Hoechst staining and computer-assisted image analysis showed that a fraction of the p53-positive blasts had a DNA content higher than 2N, indicating entry into the S/G2 phases. Double p53 and BrdU staining of the cells, pulse-labelled with BrdU, revealed that 65% of the p53-positive blasts were in S phase 3 days after infection. Similarly, B cell activation by CD40L and IL-4 induced p53 expression without any adverse effect on cell cycle progression. Therefore, the phenomenon is not EBV-specific but correlates with immunoblast activation.
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PMID:Epstein-Barr virus infection and mitogen stimulation of normal B cells induces wild-type p53 without subsequent growth arrest or apoptosis. 1021 69

Infection with the bacterium Helicobacter pylori is associated epidemiologically with development of gastric cancer. To better understand the role of H. pylori in carcinogenesis, we examined the effects of H. pylori on cell cycle-related events in the AGS gastric cancer cell line. During coculture, wild-type, toxigenic, cagA-positive H. pylori induced both apoptosis and inhibition of cell cycle progression at G1-S in AGS cells. These effects were most apparent in AGS cells synchronized by serum-deprivation and then stimulated to progress through the cell cycle by refeeding. An isogenic cagA-negative mutant H. pylori, produced similar effects. In contrast to changes induced by 5-fluorouracil, the inhibition of cell cycle progression from G1 to S caused by H. pylori was not accompanied by sustained changes in p53 or p21cip1, but was associated with reduced expression of p27kip1 and inhibition of transcriptional activation of the serum-response element of c-fos. Our results indicate that H. pylori inhibits cell cycle progression at G1-S and induces apoptosis, associated with reduced expression of p27kip1 in AGS gastric cancer cells. In vivo, similar effects as a result of H. pylori infection may lead to potentially deleterious compensatory hyperproliferation by nonneoplastic gastric epithelial cells.
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PMID:Helicobacter pylori inhibits the G1 to S transition in AGS gastric epithelial cells. 1034 28

Cyclin-dependent kinase inhibitors are potent suppressors of cell growth and have been proposed as targets for gene replacement therapy in cancer. Expression of either p16INK4a or p21WAF1 protected cells from the cytotoxic effects of the topoisomerase II inhibitor, etoposide. A lower level of p53 was induced in CDK inhibitor-expressing etoposide-exposed cells suggesting that protection may be due to lower levels of DNA damage in the growth arrested cells. Exposure of human osteosarcoma cells to either p16INK4a or p21WAF1 prior to and during etoposide therapy protected cells against etoposide-induced cell death. Infection of the cells by Ad-p16INK4a or Ad-p21WAF1 following exposure to etoposide resulted in loss of the protective effect with evidence of enhanced growth inhibition. The results suggest that the schedule of administration of DNA damaging etoposide chemotherapy and cell cycle inhibitory therapy is a major determinant of the resulting cytotoxicity.
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PMID:The administration schedule of cyclin-dependent kinase inhibitor gene therapy and etoposide chemotherapy is a major determinant of cytotoxicity. 1040 29

Recent studies have indicated that the loss of p16 is a frequent event in the progression of malignant gliomas. The loss of p16 promotes the acquisition of malignant characteristics in gliomas, which are among the most angiogenic of all human tumors. High-grade gliomas are distinguished from low-grade gliomas by intense angiogenesis in addition to their frequent loss of p16. New therapeutic strategies aimed at inhibiting tumor angiogenesis on the basis of molecular mechanisms are theoretically attractive. Here we evaluate the effect of p16 gene replacement on the angiogenesis of gliomas. Infection with a recombinant replication-defective adenovirus vector containing the cDNA of wild-type p16 significantly reduced the expression of vascular endothelial growth factor, which is thought to be a pivotal mediator of tumor angiogenesis, in p16-deleted glioma cells. Restoring wild-type p16 expression into p16-deleted glioma cells markedly inhibited angiogenesis induced by tumor cells in vivo. Furthermore, wild-type p16 inhibited neovascularization more potently than did wild-type p53 transfer. These findings indicate that the p16 gene plays an important role in the regulation of glioma angiogenesis, suggesting a novel function of the p16 gene.
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PMID:Restoration of wild-type p16 down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human gliomas. 1044 96

Squamous cell carcinoma of the cervix (SCCC) is one of the leading causes of death in developing countries. Infection with high-risk human papillomavirus (HPV) is the major risk factor to develop malignant lesions in the cervix. Polymorphisms of the MHC and p53 genes seem to influence the outcome of HPV infection and progression to SCCC, although controversial data have been reported. MHC are highly polymorphic genes that encode molecules involved in antigen presentation, playing a key role in immune regulation, while p53 is a tumor suppressor gene that regulates cell proliferation. The HPV E6 protein from high-risk types binds p53 and mediates its degradation by the ubiquitin pathway. The role of these polymorphisms in genetic susceptibility to HPV infection and to SCCC remains under investigation.
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PMID:Genetic susceptibility to HPV infection and cervical cancer. 1045 52


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