Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ancient DNA (aDNA) samples extracted from the bone remains of six equids buried by the Vesuvius eruption in 79 AD were investigated to test pre-amplification and enzymatic repair procedures designed to enhance the rescue of nuclear genes. The extracts, which proved all positive for Equidae mtDNA amplification, proved positive only four times out of 18 when tested for single-copy Equidae nuclear genes (epsilon globin, p53 and gamma interferon). Pre-amplification did not change the number of retrieved aDNA sequences but 10 times out of 14 enzymatic repair restored the amplifiability of the genes analysed, proving that repair increases the rate of successful rescue from 22 to alpha(lambda)mu(omicron)sigma(tau) 80%. These findings support the hypothesis that some of these cross-linked aDNA molecules, which are not completely separated when DNA is extracted under denaturing conditions, become homoduplex substrates for Pol I and/or T4 ligase action upon renaturation. aDNA authenticity is proved by the homology of the nucleotide sequences of loci tested to the corresponding modern Equidae sequences. Data also indicate that cross-linked homoduplex molecules selected by denaturation of the extract are repaired without any chimera formation. The general features of aDNA amplification with and without denaturation and enzymatic repair are discussed.
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PMID:Enzymatic repair of selected cross-linked homoduplex molecules enhances nuclear gene rescue from Pompeii and Herculaneum remains. 1184 22

Infection with the human immunodeficiency virus (HIV) invariably leads to the development of acquired immunodeficiency syndrome (AIDS) in most infected humans, yet does so rarely, if at all, in HIV-infected chimpanzees. The differences between the two species are not due to differences in cellular receptors or an inability of the chimpanzee to be infected, but rather to the lack of pan-immune activation in the infected primate. This results in reduced apoptotic death in CD4+ T-helper lymphocytes and a lower viral load. In humans the degree of chronic immune activation correlates with virus load and clinical outcome with high immune activation leading to high viral loads and the more rapid progression to AIDS and death. The type of immune perturbation seen in HIV-associated AIDS is similar to that of chronic graft-versus-host disease (GVHD) where reduced cell-mediated immune (CMI) responses occur early in the course of the disease and where humoral responses (HI) predominate. A reduced CMI response occurs in a number of chronic infectious diseases, including tuberculosis and leishmaniasis. More recently, it has become increasingly apparent that the CMI response is suppressed in virtually all malignant diseases, including melanoma and colorectal and prostate cancer. This raises the possibility that, as the malignant process develops, the cancer cells evolve to subvert the CMI response. Moreover, the reduced CMI response seen in colorectal cancer (CRC) patients is completely reversed following curative surgery strongly supporting the hypothesis that CRC can suppress the systemic immune response. Wound healing, ovulation, embryo implantation, and fetal growth are all associated with suppressed CMI and neovascularization (the formation of new blood vessels) or angiogenesis (the formation of new blood vessels from an existing vasculature). If unresolved, wound healing results in chronic inflammation, which can give rise to the phenomenon of "scar cancers." Indeed all the chronic inflammatory conditions known to be associated with the subsequent development of malignant disease, including chronic obstructive airway disease (COPD), ulcerative colitis (UC), and asbestosis, give rise to similar proangiogenic, suppressed CMI, and HI-predominant environments. In keeping with this CMI-associated cytokines such as interleukin (IL)-2 and interferon (IFN)-gamma tend to be antiangiogenic, whereas HI cytokines such as IL-6 tend to be proangiogenic. Furthermore, chronic immune activation leads to the synthesis and release of factors such as macrophage inflammatory protein (MIP)-1 that inhibit apoptosis through suppression of p53 activity. The "Golden Triangle" of suppressed CMI, angiogenesis, and reduced apoptosis would provide the ideal environment for the serial mutations to occur that are required for the development of malignant disease. If the observed association is relevant to carcinogenesis, then treatments aimed at reducing the components of these inflammatory conditions may be useful both in the setting of chemoprevention and the therapeutic management of established disease.
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PMID:Chronic immune activation and inflammation in the pathogenesis of AIDS and cancer. 1188 29

7-Ketocholesterol (7kchol) is prominent in atherosclerotic lesions where apoptosis occurs. Using mouse fibroblasts lacking p53, p21(waf1), or Stat1, we found that optimal 7kchol-induced apoptosis requires p21(waf1) and Stat1 but not p53. Findings were analogous in a human cell system. Apoptosis was restored in Stat1-null human cells when wild-type Stat1 was restored. Phosphorylation of Stat1 on Ser(727) but not Tyr(701) was essential for optimum apoptosis. A neutralizing antibody against beta interferon (IFN-beta) blunted Ser(727) phosphorylation and apoptosis after 7kchol treatment; cells deficient in an IFN-beta receptor subunit exhibited blunted apoptosis. IFN-beta alone did not induce apoptosis; thus, 7kchol-induced release of IFN-beta was necessary but not sufficient for optimal apoptosis. In Stat1-null cells, expression of p21(waf1) was much less than in wild-type cells; introducing transient expression of p21(waf1) restored apoptosis. Stat1 and p21(waf1) were essential for downstream apoptotic events, including cytochrome c release from mitochondria and activation of caspases 9 and 3. Our data reveal key elements of the cellular pathway through which an important oxysterol induces apoptosis. Identification of the essential signaling events that may pertain in vivo could suggest targets for therapeutic intervention.
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PMID:Stat1-dependent, p53-independent expression of p21(waf1) modulates oxysterol-induced apoptosis. 1188 87

The poor overall survival of lung cancer patients treated with conventional therapies (chemotherapy, radiation therapy, and surgery) mandate novel approaches to treatment. Two novel approaches to treat lung cancer include gene therapy and immunologic therapy. Both treatments have preclinical data suggesting potential clinical use. In gene therapy, the identification of specific genes critical to the development of carcinogenesis has offered the opportunity to target these genes or their products for treatment. One possible gene therapy strategy that has been pursued in phase I and II lung cancer trials is to replace nonfunctional tumor suppressor genes such as mutated or deleted p53 genes with wild-type p53 genes by adenoviral gene transfer (Ad-p53). Transduction of the tumors has been accomplished with direct intratumoral injection or broncheoalveolar lavage. These studies have identified a potential role for radiosensitization of previously radiation-resistant local tumors by combining Ad-p53 with radiation or possibly chemoradiation. Another novel strategy that may allow systemic treatment of lung cancers is immunologic therapies. Immunotherapies have focused on augmenting the immune response to cancer by passive strategies (e.g., antivascular endothelial growth factor) or active nonspecific (e.g., interferon), or by specific (e.g., anti-idiotype therapy) strategies. These novel strategies are currently in clinical trials and will potentially allow additional therapeutic options for patients resistant to conventional therapies.
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PMID:Genetic and immunologic therapies for lung cancer. 1189 19

To determine whether interferon alfa (IFN-alpha) prevents in vivo oncogenesis in very-early-stage cancer cells, we evaluated the action of IFN-alpha2b over preneoplastic foci in rats. Animals were divided into 6 groups: subjected to a 2-phase model (diethylnitrosamine [DEN] plus 2-acetylaminofluorene [2-AAF]) of preneoplasia development (group 1), treated with IFN-alpha2b during the 2 phases (group 2), only during initiation with DEN (group 3), only during administration of 2-AAF (group 4), subjected only to an initiation stage (group 5), and treated with IFN-alpha2b during this period (group 6). The numbers of placental form of rat glutathione S-transferase (rGST-P)-positive foci per liver and the foci as percentage of liver were significantly reduced in groups 2, 3, and 6 but not in group 4. Rats treated with IFN-alpha2b showed a higher apoptotic index (AI) in altered hepatic foci (AHF). Levels of p53 and Bax protein in liver lysates were significantly increased in those animals. Similarly, levels of antiapoptotic proteins Bcl-2 and Bcl-x(L) in mitochondrial fraction were decreased. Finally, increased levels of Bax protein were localized in the mitochondria of rats that received IFN-alpha2b, at least during the DEN phase (groups 2, 3, and 6), whereas mitochondrial Bax expression was not increased in group 4. In conclusion, the preneoplastic hepatocytes in rats that received IFN-alpha2b during the initiation stage undergo programmed cell death as a primary result of a significant increase in the amount and translocation to the mitochondria of Bax protein.
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PMID:The in vivo apoptotic effect of interferon alfa-2b on rat preneoplastic liver involves Bax protein. 1191 28

Interferon-gamma (IFN-gamma), as one of interferon family that regulates antiviral, antiproliferative, and immunomodulatory responses, has been implicated for the growth regulation of ovarian cancer cells. However, the molecular mechanisms are not yet fully defined. To analyze detailed mechanisms, the ovarian cancer cell lines (2774, PA-1, OVCAR-3, and SKOV-3) were treated with IFN-gamma. The growth of 2774 was most effectively suppressed than that of other cells in both time-course and dose-dependent experiments. The order of sensitivity in other cells was PA-1 >> OVCAR-3 > SKOV-3 (not responded at all). The DNA fragmentation and DAPI staining assays suggested that the IFN-gamma-mediated cytotoxicity could be triggered by apoptosis. The treatment induced IFN regulatory factor-1 (IRF-1) in two IFN-gamma-sensitive cells (2774, PA-1), whereas IRF-1 was not induced in two IFN-gamma-resistant cells (OVCAR-3, SKOV-3). The levels of p53 and p21WAF1 were not strikingly changed in all four cells. Interestingly, the expression of interleukin-converting enzyme (ICE, or caspase-1) was increased by the treatment in a kinetically consistent manner to the induction of IRF-1. However, CD95 (Fas/APO-1) was not changed. Apoptosis was greatly induced, when IRF-1 was transiently expressed in PA-1 without the treatment of IFN-gamma. However, it was repressed when IRF-1 together with IRF-2, an antagonist of IRF-1, were coexpressed. In addition, the effect of IFN-gamma was reduced in the 2774 and PA-1 cells stably expressing either IRF-1 antisense or IRF-2 sense, as shown by the cytotoxicity and FACS analysis. Furthermore, the IFN-gamma-induced apoptosis was greatly reduced, when inhibitors of ICE were treated into PA-1 cells. Taken together, these results suggest that IRF-1 directly mediates the IFN-gamma-induced apoptosis via the activation of caspase-1 gene expression in IFN-gamma-sensitive ovarian cancer cells.
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PMID:Interferon regulatory factor-1 mediates interferon-gamma-induced apoptosis in ovarian carcinoma cells. 1194 92

The interferon (IFN)-beta and all-trans-retinoic acid combination suppresses tumor growth by inducing apoptosis in several tumor cell lines. A genetic technique permitted the isolation of human thioredoxin reductase (TR) as a critical regulator of IFN/all-trans-retinoic acid-induced cell death. Our recent studies have shown that TR1:thioredoxin 1-regulated cell death is effected in part through the activation of p53-dependent responses. To understand its death regulatory function, we have performed a mutational analysis of TR. Human TR1 has three major structural domains, the FAD binding domain, the NADPH binding domain, and an interface domain (ID). Here, we show that the deletion of the C-terminal interface domain results in a constitutive activation of TR-dependent death responses and promotes p53-dependent gene expression. TR mutant without the ID still retains its dependence on thioredoxin for promoting these responses. Thus, our data suggest that TR-ID acts as a regulatory domain.
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PMID:Mutational analysis of human thioredoxin reductase 1. Effects on p53-mediated gene expression and interferon and retinoic acid-induced cell death. 1195 36

Interferon regulatory factors (IRFs) regulate transcription of interferon genes through DNA sequence-specific binding to these targets. Using a differential display method for examining gene expression in p53-defective cells infected with adenovirus containing wild-type p53, we found that expression of interferon regulatory factor 5 (IRF-5) mRNA was increased in the presence of exogenous p53. An electrophoretic mobility-shift assay showed that a potential p53 binding site (p53BS) detected in exon 2 of the IRF-5 gene could in fact bind to p53 protein. Moreover, a heterologous reporter assay revealed that the p53BS possessed p53-dependent transcriptional activity. Expression of IRF-5 was induced in p53+/+ cells (MCF7 and NHDF), but not inp53-/- cells (H1299) when DNA was damaged by gamma-irradiation, UV-radiation, or adriamycin treatment in a wild-type p53-dependent manner. These results suggest that IRF-5 is a novel p53-target, and that it might mediate the p53-dependent immune response.
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PMID:Identification of the interferon regulatory factor 5 gene (IRF-5) as a direct target for p53. 1197 53

Mimecan is a small leucine-rich proteoglycan (SLRP) that may play an important role in the regulation of cellular growth as illustrated by ability of growth factors and cytokines to modulate its expression and by recent demonstration that bovine mimecan is transcriptionally activated by p53 through a conserved intronic recognition site. To investigate transcriptional regulation of human mimecan, the upstream region and the first intron of this gene were cloned and analyzed. Within a 296-bp upstream region required for basal gene expression, there are three initiator (Inr) elements, an E-box and Oct-1, metal response element (MRE), and NF-kappa B recognition sites. Upstream stimulatory factor (USF)-1, Oct-1 and MRE-binding proteins were identified as proteins that bind to these regulatory elements and support transcription of mimecan in MG-63 cells. The first intron of human mimecan contains enhancer and silencer elements. Reporter gene transfections demonstrated that cooperation of upstream region and intronic enhancer elements are required for maximal gene expression in both p53-deficient and wild-type p53-expressing cells. Within the footprinted intronic enhancer region an interferon-stimulated response element (ISRE) is present. Using electrophoretic mobility shift assay (EMSA), interferon regulatory factor (IRF)-1 was identified as a protein that binds to this region in MG-63 but not in U-937 cells. In vitro translated IRF-1 also was shown to bind to this ISRE. These results demonstrate that the first intron of human mimecan gene carries important regulatory elements, including p53 DNA-binding site and ISRE, and should promote a better understanding of molecular bases for cell type-specific regulation of mimecan transcription.
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PMID:Analysis of the promoter region of human mimecan gene. 1202 Aug 27

In contrast to the US, the incidence and mortality rates of bladder cancer are still increasing in some European countries, despite the fact that most new cases are diagnosed as early, superficial tumours. The standard of care of superficial tumours consists of cytoscopic electroresection of the tumour followed by intravesical immunotherapy or chemotherapy. Immunotherapy with bacillus-Calmette Guerin (BCG) prevents recurrence in most treated patients and has a positive impact on survival; however, approximately 30% are BCG-refractory, progressive tumours. Pharmacogenomics will enable to distinguish those high-risk patients in clinical practice soon. New immunotherapy approaches, such as BCG combined with low-dose interferon or recombinant BCG strains, are promising approaches which need to be explored in prospective trials. The use of neoadjuvant or adjuvant chemotherapy is still controversial but the results of recent trials of neoadjuvant chemotherapy in locally-advanced bladder tumours convinced some leading centres to implement neoadjuvant chemotherapy in selected groups of patients. By far, the four-drug methotrexate-vinblastine-doxorubicin-cisplatin regimen was widely used in metastatic and locally-advanced disease. Recently, two-drug combination gemcitabine-cisplatin proved to be equally effective and less toxic. New chemotherapies tested in clinical trials include gemcitabine, taxanes and new drugs that interfere with signal transduction. Individualisation of established and investigational treatment options based on molecular tumour characteristics, such as p53 status, is probably the future of bladder cancer pharmacotherapy.
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PMID:Pharmacotherapy of bladder cancer--practice and prospects. 1203 6


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