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

c-Myc and wild-type p53 have been shown to play important roles in the regulation of cellular proliferation and oncogenic transformation. We have previously shown that the p53 promoter contains a conserved consensus recognition sequence for the basic-helix-loop-helix-containing proteins, identical to the specific binding site for c-Myc/Max heterodimers. Here, we demonstrate that this element, which is required for full promoter activity, is bound by in vitro translated c-Myc/Max heterodimers. Furthermore, we found that in cotransfection assays, c-Myc trans-activates the p53 promoter as well as a hybrid herpes simplex virus-thymidine kinase promoter containing multiple copies of a synthetic p53-derived c-Myc binding site. The p53 promoter deleted of the basic-helix-loop-helix consensus recognition sequence is not trans-activated by c-Myc, thus suggesting that c-Myc trans-activates the p53 promoter through the basic-helix-loop-helix recognition motif. These findings raise the possibility that the p53 gene may be a potential target for trans-activation by c-Myc in vivo.
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PMID:c-Myc trans-activates the p53 promoter through a required downstream CACGTG motif. 849 84

This study investigates whether insulin (a differentiation factor for lens epithelial cells) acts as a survival factor. In the absence of insulin, 6-day embryonic chicken lens epithelial explants undergo apoptosis as shown by changes in cell morphology, DNA fragmentation, and loss of trypan blue exclusion. Insulin inhibits these changes and promotes survival of the cells. Aurintricarboxylic acid suppresses the apoptosis of lens explants. In contrast to 6-day embryonic explants, 19-day embryonic explants survive in the absence of insulin, presumably due to an endogenous survival factor. To explore the mechanism of the action of insulin as a survival factor for 6-day embryonic lens explants, we compared the pattern of cell cycle markers (c-fos, c-jun, c-myc, p53, histone H3, thymidine kinase, and cyclin B) in both apoptotic and differentiating lens explants. In the presence of insulin, the expression of c-fos and c-jun was down-regulated after an initial induction. Expression of these genes was also induced in the absence of insulin, but mRNA levels remained elevated as the cells underwent apoptosis. In contrast, expression of c-myc, p53, histone H3, thymidine kinase, and cyclin B showed only minor differences in differentiating and apoptotic cells. Since c-fos and c-jun have been shown to play a role in apoptosis in other cell types, the ability of insulin to regulate expression of these genes may be central to its ability to act as a survival factor for lens epithelial cells.
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PMID:Insulin regulates expression of c-fos and c-jun and suppresses apoptosis of lens epithelial cells. 854 23

p53 is a nuclear phosphoprotein whose function is classified as tumor suppression. Studies have shown that p53 functions by binding to p53 DNA recognition sequences and regulates transcription of growth-regulatory genes. Various p53 recognition sequences have recently been identified. pOST2 contained two copies of a palindromic high-affinity DNA-binding sequence for p53; the other p53 recognition sequences included p53-binding fragments found in the human ribosomal gene cluster (pRGC) region and in the murine muscle creatine kinase promoter (pMCK). The purpose of this study was to compare the abilities of various p53 recognition sequences to mediate transcription in the presence of endogenously produced wild-type (wt) or mutant p53. Three p53-responsive chloramphenicol acetyltransferase (CAT) reporter constructs (pOST2, pRGC, and pMCK) that contain one or two copies of p53 recognition sequences upstream of a herpes thymidine kinase (TK) promoter and CAT reporter cDNA were constructed. Either a p53-responsive gene or a control reporter gene was transfected into human carcinoma cell lines (having various p53 mutations) either with or without a wt or mutant p53 expression vector. CAT activity was assayed to measure transactivation through the various p53-responsive elements. We showed that pOST2 had a greater ability to mediate transactivation by p53 than either pRGC or pMCK. p53 with a mutation at either codon 175 or 248 was unable to transactivate a reporter gene with pOST2, pRGC, or pMCK. We found it interesting that pOST2, but not pRGC or pMCK, was able to mediate transactivation in cell lines that produce codon 273-mutant p53. These findings suggest that various sensitivities of the different p53-responsive elements to specific mutant and wt p53s may be an important factor in the role of p53 as a transcriptional activator both under normal physiological conditions and during carcinogenesis.
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PMID:p53 transactivation through various p53-responsive elements. 864 24

Recent studies have shown that experimental tumors could be treated more efficiently with ionizing radiation if genetic material was transfered into tumor cells. Several approaches have been reported, and among them, the first one consisted of increasing the apoptotic response to radiation by modulating genes involved in the regulation of the apoptotic pathway. Indeed the modulation of p53 and bcl-2 gene expression has recently been used successfully in several experimental models to increase the apoptotic death after radiation. A second approach consisted of taking advantage of the conditional expression of some genes after exposure to ionizing radiation. Indeed, some genes exhibit a radio-inducible promoter which can be combined to a gene, able to enhance or decrease the biological effect of radiation. The irradiation of such a transgene under the control of a radio-inducible promoter can lead to a second biological effect, concomitant to the irradiation, as reported for the TNF alpha under the control of the EGR (early growth response) promoter. A third approach consisted of enhancing the effect of radiation induced tumor cell death by the expression of a suicide gene in these cells, as suggested recently for the HSV-tk (herpes virus thymidine kinase gene). These preliminary results obtained in experimental models appear to be very promising and might improve the efficacy and specificity of radiation therapy in a not too distant future.
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PMID:[Gene transfer and radiotherapy]. 865 4

In adult mice of the transgenic strain TG66.19, in which expression of herpes simplex type 1 virus thymidine kinase (HSVI-TK) is driven in thyrocytes from the thyroglobulin promoter, the drug Ganciclovir causes the death (ablation) of thyrocytes. Ablation occurred in the absence of thyrocyte proliferation or nuclear DNA synthesis, but was accompanied by transient expression of proliferating cell nuclear antigen and the dying thyrocytes exhibited the ultrastructural features of apoptosis. Control experiments show that the apoptosis is a result of the production of Ganciclovir phosphates in thyrocytes that express HSV1-TK. However, cell death was not dependent upon the presence of a functional copy of the oncosuppressor gene p53. We conclude that the apoptosis is probably not mediated by induction of DNA damage and occurs via a pathway that is independent of p53. The fact that Ganciclovir phosphate can kill cells by a p53-independent apoptotic pathway is encouraging in relation to tumour ablation by methods based on transfection with HSV1-tk genes and administration of Ganciclovir.
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PMID:Ganciclovir-induced ablation non-proliferating thyrocytes expressing herpesvirus thymidine kinase occurs by p53-independent apoptosis. 870 May 54

Infection of quiescent cells with the DNA tumor virus simian virus 40 induces expression of the cellular thymidine kinase (TK) gene a minimum of 10- to 20-fold, and this induction depends upon the viral protein large T antigen (T-Ag). To define both human TK promoter elements and T-Ag functional domains required for transcriptional induction, we have established a system in which stable Rat-1 transfectants harboring TK promoter-luciferase hybrid genes are infected with recombinant adenoviruses expressing either wild-type or mutant forms of T-Ag and luciferase expression is measured as an indicator of promoter activity. The results show that (i) a 135-bp TK promoter fragment is activated 10- to 15-fold by viral infection; (ii) this activation is the result of both T-Ag-dependent and -independent mechanisms; (iii) the T-Ag pRb family-binding domain, but not the p53-binding, helicase, or ATPase domain, is required for activation; and (iv) activation is severely diminished with a TK promoter fragment in which E2F-like-binding sites have been removed. These data demonstrate a requirement for both an E2F-related factor and a pRb family member in activation of the TK promoter by T-Ag. This contrasts with the promiscuous activation of many cellular and viral genes by T-Ag, which is independent of its ability to bind pRb.
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PMID:Activation of the human thymidine kinase (TK) promoter by simian virus 40 large T antigen requires both the T antigen pRb family-binding domain and TK promoter sequences resembling E2F-binding sites. 870 58

Based on the concept of circulating hematopoietic stem cells with indefinite self-renewal capacity that gives rise to all three cell lineages, peripheral blood progenitor cells (PBPCs) have widely replaced the use of bone marrow (BM) progenitors for autologous transplantation purposes in patients with malignant hematological disorders and selected solid tumors. Ex vivo purification of normal CD34+ cell subsets contained in the patient's apheresis product possibly eliminates clonogenic tumor cells, but also serves as a target cell population for gene transduction. Genetic tagging of PBPC autografts has proven that: 1) NEOR gene expression is sustained for more than 18 months and 2) clonogenic tumor cells contaminating the autograft contribute to relapse. A second generation of gene transduction studies includes new treatment strategies such as the induction of chemoprotection (multidrug resistance gene-1), chemotherapy sensitization (p53), cancer vaccination and genetic chemosensitization. Most recently allogeneic PBPC transplantation has successfully been introduced with the intention of improving the graft-versus-leukemia effect without inducing a higher incidence or more severe graft-versus-host disease (GVHD) than what is expected after BM transplantation. Introducing the herpes virus thymidine kinase cDNA into activated donor T cells makes them susceptible to gangciclovir, thus allowing the in vivo inactivation of GVHD-inducing T cells. With the close interaction of molecular genetics and clinical oncology/hematology, genetic engineering of stem cell grafts will lead into a new stage of stem cell transplantation technology.
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PMID:Blood stem cell transplantation and gene therapy of cancer. 874 97

In this work we have explored the use of adenoviral vectors for the purging of cancer cells from hematopoietic stem cell (HSC) autografts. We showed that a recombinant adenovirus expressing the herpes simplex-1 thymidine kinase gene (AD-tk) plus ganciclovir (GCV) killed HELA cells more effectively than did GCV alone. HELA cells were then mixed with human HSCs and exposed to AD-tk/GCV. AD-tk/GCV reduced the number of HELA colonies to 4% of control values, with no detectable reduction in the hematopoietic progenitor, colony forming unit-granulocyte/monocyte (CFU-GM). Similar studies of the JB6 non-Hodgkins lymphoma cell line showed a reduction to 5% of controls; studies of MCF-7, a breast carcinoma cell line, showed a reduction to 30% of controls, with no CFU-GM toxicity. Thus, AD-tk mediated selective killing of contaminating tumor cells. We also evaluated a recombinant adenovirus encoding the tumor suppressor gene p53 (AD-p53). AD-p53 was able to selectively kill all three cell lines (reducing tumor colonies approximately 100-fold) without any toxicity to CFU-GM. Although both AD-tk/GCV and AD-p53 were effective in these experiments, AD-p53 seemed to be more potent. Adenoviral vectors show promise for selectively targeting cancer cells that contaminate HSC autografts.
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PMID:Selective elimination (purging) of contaminating malignant cells from hematopoietic stem cell autografts using recombinant adenovirus. 885 51

Abnormalities in the p53 gene play an important role in genomic instability and tumorigenesis. Our previous work showed that p53 status is correlated with differential mutability in two closely related human lymphoblastoid cell lines, TK6 and WTK1. WTK1 cells, which contain a mutation in p53 (p53Ile237) show a remarkably increased mutability, larger genetic alterations at the thymidine kinase locus (tk), an increased ability to catalyze recombination, and a delay in the onset of apoptosis after X-irradiation, compared to TK6 (p53 +/+). In the present study, we demonstrate that after transfection and subsequent overexpression of the known dominant negative mutant p53 Ala143 allele (mp53Ala143) in TK6, there were significantly enhanced spontaneous and X-ray-induced mutant frequencies at the tk locus, and delayed onset of X-ray-induced apoptosis, to a similar extent as in WTK1. In addition, high protein expression of mp53Ala143 in transfectants was correlated with both increased mutation frequency and altered apoptosis kinetics. Similar results were obtained with p53 Ile237 transfection into TK6. Our observations indicate that the product of the p53 gene affects mutational processes. We hypothesize that p53 dysfunction can lead to increased mutagenicity at the endogenous tk gene in human lymphoblastoid cell lines either through delayed apoptosis in response to DNA damage or by mediating increased recombination.
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PMID:The tumor suppressor p53 modifies mutational processes in a human lymphoblastoid cell line. 901 57

Gene therapy as an anti-tumor strategy is becoming a powerful tool for cytokine delivery to inhibit the growth of many tumors. Several delivery systems are being utilized and designed for the expression of specific genes to achieve a therapeutic result. Liposomes, retroviral vectors, and adenoviral vectors have all been used and eventual clinical application may depend on the type of tumor, the location, the specific gene carried, and the patient's health status. Novel expression vectors may eventually achieve tissue-specific targeting and low immuno-reactivity. Inactivation of mutated oncogenes, such as ras, or re-expression of inactive suppressor genes, such as p53 have been used as strategies for anti-tumor therapy. Additionally, exogenious genes, such as viral thymidine kinase that metabolize chemotherapeutic agents to achieve local cytotoxicity have also been employed. Neuro-endocrine tumors are targets of these gentic strategies since they are often difficult to treat by conventional methods because of their location (brain tumors) or because they have spread from the primary tumor (melanoma). Further advances in the design of these vectors may achieve safe targeting of a variety of malignant tumors.
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PMID:Anti-tumor gene therapy. 904 51


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