Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutational inactivation of p53, a potential tumor-suppressor gene, has been found in many tumors of humans as well as rodents. The p53 status in normal and transformed mouse liver cell lines has, however, not been investigated. We examined possible point mutations and compared mRNA and protein expression of the p53 gene in normal vs. transformed mouse liver cells. The transformed cells studied included lines spontaneously transformed by sub-culture, virally transformed by simian virus 40 (SV40), and chemically transformed by N-methyl-N-nitro-N-nitrosoguanidine (MNNG) or methylcholanthrene epoxide (MC). A heterozygous G-->A point mutation at codon 241, position 1, of p53 was detected in MNNG-transformed cells after screening of 5 evolutionarily conserved regions where mutation hot-spots are clustered. The mutation causes a gly-->arg substitution. No mutations were found in normal or other transformed cells. The steady-state levels of p53 mRNA were decreased in chemically transformed (both MNNG- and MC-transformed) cells. Elevated levels of p53 protein were found in spontaneously transformed and SV40-transformed cells, an observation that may reflect a longer half-life of the protein, as has been shown in other transformed lines. The low level of the p53 protein in MC-transformed cells may result from transcriptional depression of the p53 gene. We conclude from these data that abnormal p53 status, such as point mutation or altered expression, may play a role during the malignant transformation of mouse liver cells.
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PMID:Alterations of the p53 tumor-suppressor gene in transformed mouse liver cells. 750 57

Endometrial carcinogenesis induced by concurrent oral administration of ethylenethiourea (ETU) and sodium nitrite (NaNO2) was investigated in ICR (Crj:CD-1) female mice. A mixed solution of ETU (100 mg/kg) and NaNO2 (70 mg/kg) was given to animals orally once a week for up to 6 months and all surviving animals were killed at 12 months of study. During the study, estrous cycle was monitored by vaginal smear and five or 10 selected animals were subjected to interim killing at 3 month interval to observe time-related carcinogenic responses of the uterus. Treatment with ETU and NaNO2 resulted in development of endometrial adenocarcinomas in the uterine horn and the incidence reached 42% in the surviving animals at 12 months. Prior to the development of the tumor, atypical hyperplasia of endometrial glands was frequently observed and regarded as the precancerous lesion. Immunohistochemistry for bromodeoxyuridine (BrdU) incorporation revealed higher labeling indices in both hyperplastic and neoplastic endometrial glandular cells, and the index in the adenocarcinoma was more than 20% on average at any stage of the estrous cycle. Overexpression of p53 protein, which is frequently demonstrated in virulent phenotypes of human corpus cancers, was seen in three out of eight (38%) adenocarcinomas, but not in the atypical hyperplasia or normal endometrial glands. There were no treatment-related changes in the estrous cycle on vaginal smears at any interval of the study. The analyses for plasma ovarian hormones at 12 months disclosed a marked depression of progesterone in the treated animals, while the 17 beta-estradiol (E2) level was comparable to the controls. These results suggest that endometrial carcinogenesis by ETU and NaNO2 could be initiated with atypical hyperplasia of the endometrial gland and a decrease in plasma progesterone level may play an important role in the development of endometrial carcinogenesis. In addition, inactivation of the p53 gene may play a significant role in the malignant transformation of endometrial epithelial cells in mice.
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PMID:Endometrial carcinogenesis induced by concurrent oral administration of ethylenethiourea and sodium nitrite in mice. 795 72

Exposure of a wide variety of cells to ionizing (X- or gamma-) irradiation results in a division delay which may have several components including a G1 block, a G2 arrest or an S phase delay. The G1 arrest is absent in many cell lines, and the S phase delay is typically seen following relatively high doses (> 5 Gy). In contrast, the G2 arrest is seen in virtually all eukaryotic cells and occurs following high and low doses, even under 1 Gy. The mechanism underlying the G2 arrest may involve suppression of cyclin B1 mRNA and/or protein in some cell lines and tyrosine phosphorylation of p34cdc2 in others. Similar mechanisms are likely to be operative in the G2 arrest induced by various chemotherapeutic agents including nitrogen mustard and etoposide. The upstream signal transduction pathways involved in the G2 arrest following ionizing radiation remain obscure in mammalian cells; however, in the budding yeast the rad9 gene and in the fission yeast the chk1/rad27 gene are involved. There is evidence indicating that shortening of the G2 arrest results in decreased survival which has led to the hypothesis that during this block, cells repair damaged DNA following exposure to genotoxic agents. In cell lines examined to date, wildtype p53 is required for the G1 arrest following ionizing radiation. The gadd45 gene may also have a role in this arrest. Elimination of the G1 arrest leads to no change in survival following radiation in some cell lines and increased radioresistance in others. It has been suggested that this induction of radioresistance in certain cell lines is due to loss of the ability to undergo apoptosis. Relatively little is known about the mechanism underlying the S phase delay. This delay is due to a depression in the rate of DNA synthesis and has both a slow and a fast component. In some cells the S phase delay can be abolished by staurosporine, suggesting involvement of a protein kinase. Understanding the molecular mechanisms behind these delays may lead to improvement in the efficacy of radiotherapy and/or chemotherapy if they can be exploited to decrease repair or increase apoptosis following exposure to those agents.
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PMID:The molecular basis for cell cycle delays following ionizing radiation: a review. 804 94

In solid tumors, p53 antibodies are found in 30% of the patients with p53 mutations, and their analysis is an interesting method for the detection of p53 mutations. We looked for circulating p53 antibodies in 83 patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), by an ELISA technique. Detection of p53 mutations was made by single stranded conformation polymorphism (SSCP) analysis of exons 4 to 10 of the P53 gene and confirmed by direct sequencing. Circulating antibodies to p53 were seen in three of the 83 (3.5%) patients analyzed, and a p53 point mutation was found in ten cases. Two of the three patients with p53 antibodies had a p53 mutation, but the remaining case had no detectable mutation. The other eight mutated cases had no detectable p53 antibodies. Our findings show that serological analysis of p53 antibodies is rarely positive in MDS and AML. This could be due to the relatively low incidence of p53 mutations seen in those disorders, but also to the immune depression to which they are often associated.
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PMID:Detection of serum anti p53 antibodies and their correlation with p53 mutations in myelodysplastic syndromes and acute myeloid leukemia. 809 36

The antioxidant alpha-tocopherol and the weaker antioxidant and prooxidant chemopreventative, beta-carotene have been shown to inhibit tumor cell growth in vivo and in vitro. In some epidemiologic studies their serum levels were demonstrated to be inversely related to the incidence of malignant tumor. We hypothesized two basic pathways triggered by antioxidants and prooxidants, which resulted in the control of tumor cell growth. These included changes in phosphorylation and ultimately transcription. Specifically, the prooxidant beta-carotene treatment produced an oxidative stress resulting in the selective induction of heat shock proteins (hsps). These proteins and other proteins that were possibly oxidized were associated with the increased expression of cyclins (A and D) and increased cdc2 kinase expression. An increase in expression of phosphoproteins, such as p53 (tumor suppressor form) was also discerned. The level of expression for the transcription factor c-fos was reduced. Growth factors that contribute to tumor cell growth were also reduced. Increased DNA fragmentation, depression of proliferation and intracellular calcium levels, the accumulation of tumor cells in G0-->G1, and morphologic changes, were consistent with programmed cell death. Antioxidants such as alpha-tocopherol bound to membrane-associated proteins could inhibit the development of peroxidation products (hydroxyl radicals (.OH)), which attack proteins and modify their function and promote their degradation. Some kinases such as, cdc2 may be increased in activity, which would explain the observed increased expression of tumor suppressor p53, the accumulation of the tumor cells in G1 of the cell cycle and the inhibition of tumor cell proliferation. A reduction in oxidant radicals could also reduce transcription factor products, such as c-myb. Indirectly this result may occur through changes in nuclear translocation (signaling) NF-AT or the Rel-related family of transcription factors, including NF-kB (p50 or p65) or inhibition of immunophilin-calmodulin activity. Although the data remains fragmentary there are common points for control for tumor cell growth resulting from the effects of alpha-tocopherol or beta-carotene treatment. These changes involve phosphorylation and protein expression. Ultimately there is a reduction of important transcription factor protein products, a reduction in response to growth factors, and suppression of cell proliferation, resulting in increased control of the cell cycle.
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PMID:Molecular and biochemical reprogramming of oncogenesis through the activity of prooxidants and antioxidants. 851 52

A case of Hodgkin's disease (HD), lymphocyte depression (LD) type in an immunosuppressive patient is described. The patient was a 48-year-old male and his parents were born in the Kyushu area, which is an endemic area for adult T cell lymphoma/leukemia (ATL). He was seropositive for ATL virus (ATLV, also referred to as HTLV-I) and showed a marked immunosuppressive condition. He developed LD-HD and Pneumocystis carinii pneumonia, and died due to respiratory failure. The immunohistochemical and in situ hybridization analyses revealed that the Reed-Sternberg-like cells in the lymph node biopsy sample were positive for Ber-H2 (CD30), Leu-M1 (CD15), L-26 (CD20), Bcl-2, p53 and EBER, the viral genome of Epstein-Barr virus (EBV).
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PMID:Epstein-Barr virus-related Hodgkin's disease showing B cell lineage in an immunosuppressive patient seropositive for HTLV-I. 941 42

Evidence for a relationship between overexpression of wild-type p53 and telomerase activity remains controversial. We investigated whether p53 gene transduction could cause telomerase inhibition in pancreatic cancer cell lines, focusing on the relation of transduction to growth arrest, cell cycle arrest, and apoptotic cell death. The cells were infected with recombinant adenovirus expressing wild-type p53 or p21WAF1 at a multiplicity of infection of 100 or were continuously exposed to 10 microM VP-16, which is well known to induce apoptosis. Adenovirus-mediated p53 gene transduction caused G1 cell cycle arrest, apoptosis, and resultant growth inhibition in MIA PaCa-2 cells; the cell number 2 days after infection was 50% of preinfection value, and 13% of the cells were dead. Moreover, the transduction resulted in complete depression of telomerase activity through down-regulation of hTERT mRNA expression. In contrast, p21WAF1 gene transduction only arrested cell growth and cell cycle at G1 phase, and VP-16 treatment inhibited cell growth with G2-M arrest and apoptosis; after treatment, the cell number was 73% of pretreatment, and 12% of the cells were dead. Neither p21WAF1 gene transduction nor VP-16 treatment caused telomerase inhibition. Similar results were obtained in two other pancreatic cancer cell lines, SUIT-2 and AsPC-1. Thus, our results demonstrate that the p53 gene transduction directly inhibits telomerase activity, independent of its effects on cell growth arrest, cell cycle arrest, and apoptosis.
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PMID:Adenovirus-mediated p53 gene transduction inhibits telomerase activity independent of its effects on cell cycle arrest and apoptosis in human pancreatic cancer cells. 1047 98

Thymidylate synthase (TS) is an essential enzyme for the de novo synthesis of thymidylate and subsequently DNA synthesis. TS has been used as a target for cancer chemotherapy in the development of fluoropyrimidines such as 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine and of novel folate-based TS inhibitors such as ZD1694 (Tomudex, Raltitrexed), ZD9331, LY231514 (ALIMTA, Pemetrexed), AG337 (Thymitaq, Nolatrexed) and AG331. Although TS has been considered as a target for chemotherapy, the precise mechanism by which TS inhibition leads to cell death is still not completely resolved. TS inhibition results in depletion of dTTP, an essential precursor for DNA, and an increase in dUTP. This results in the so-called thymine-less death due to misincorporation of dUTP into DNA; its excision, catalysed by uracil-DNA glycosylase, results in DNA damage. Both this imbalance in dTTP/dUTP and DNA damage can result in induction of downstream events, leading to apoptosis. On the other hand a specific interaction exists between oncogenes and TS, by binding of TS protein to the p53 and c-myc RNA, while wt p53 can also inhibit TS promotor activity. TS inhibition by either 5-FU or antifolates can also result in a depression of TS protein mediated inhibition of TS mRNA translation leading to induction of more TS protein synthesis, and p53 protein may further deregulate this process. These complex indirect and direct interactions between oncogenes and TS may have as yet unclear clinical implications, since most data are based on in vitro or in vivo studies and some results are contradictive. In some preliminary clinical studies evidence was postulated for a combined prognostic role for TS and p53. This knowledge should be used to design clinical studies with the aim to deliver effective treatment to potentially sensitive patients both in the adjuvant setting and in advanced stage disease.
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PMID:Downstream molecular determinants of response to 5-fluorouracil and antifolate thymidylate synthase inhibitors. 1084 55

Death of retinal photoreceptors by apoptosis is observed under many physiological and pathological conditions such as histogenesis, retinal dystrophies and light-induced photoreceptor degeneration. To date, little is known about regulatory mechanisms for apoptosis in the retina. The tumor suppressor gene p53 is a regulator of apoptosis in a number of systems, however, p53-independent apoptosis has also been described. We have therefore investigated whether the lack of p53 influences the dark-adapted ERG in C57BL/6 p53-/- mice compared to p53+/+ control littermates under physiological (regular light-dark cycle) conditions. We also recorded ERGs at 12 to 14 h in darkness following diffuse bright light exposure to 8,000 or 15,000 lux for 2 h. ERG analysis over a range of 6 logarithmic units of light intensity revealed normal and virtually identical a-, b-, c-waves and oscillatory potentials in dark-adapted p53+/+ and p53-/- mice. After exposure to diffuse white fluorescent light strong decreases of all ERG components were found to be very similar in both genotypes. These data support the notion that the p53 protein is neither essential for normal retinal function nor for processes involved in light-induced depression of the ERG in mice.
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PMID:The mouse ERG before and after light damage is independent of p53. 1085 7

We investigated the influence of lovastatin, simvastatin and pravastatin on proliferation and viability of vascular smooth muscle cells (SMC) in vitro and studied the effects of lovastatin on a mouse SMC line transgenic for a temperature-sensitive mutant of SV40 large T antigen (TAg), known to inhibit the function of p53 and pRb family members. We found that lovastatin and simvastatin inhibited cell proliferation by provoking G0/G1 phase arrest with concomitant depression of the proliferation antigen Ki-67/MIB-1. Lovastatin at high concentrations of 20 micromol/l caused cell death in the presence of serum but not under serum starved conditions, which was verified on the basis of increased DNA strand breaks, decreased DNA content and morphological alterations seen by electron microscopy. Cell death was also found for simvastatin, whereas pravastatin did not exhibit antiproliferative or cytotoxic effects. Mouse SMC transgenic for TAg did not show any impaired sensitivity to the antiproliferative and cell death inducing effect of lovastatin, but both effects could be antagonized by the supplementation of mevalonate. The data indicate that antiproliferative and cytotoxic effects of lovastatin are caused by the using up of products of mevalonate metabolism and do not require the presence of p53 or pRb.
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PMID:Differences in the effects of HMG-CoA reductase inhibitors on proliferation and viability of smooth muscle cells in culture. 1085 25


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