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)

To investigate glial carcinogenesis in vitro, fetal rat brain cells were cultured and exposed to ENU (approximately 200 micrograms/ml). The cells were passaged weekly thereafter. Morphological changes were observed under the phase contrast microscope. When mutant colonies where the cells lost contact inhibition and grew in a multilayer fashion appeared, the cells were cloned. To assess the biological characters of cells, expression of GFAP, vimentin, A2B5 and p53 product were determined by immunohistochemistry and flow cytometry. Tumor forming ability of the cells was evaluated by both colony forming efficiency in low serum medium (LSM; 2% FBS, 300 cells/100 mm dish) and transplantability to nude mice. Both primary cultured and ENU-treated cells were positive for GFAP and vimentin, but population of A2B5 positive cells was less than 5%, thus indicating that these cells were astroglial in origin. The mutant colonies appeared 7 weeks after ENU treatment. These cells grew rapidly with cell doubling time ranging between 18 to 26 hours, while non-ENU-treated astroglias had a longer cell doubling time (48 to 55 hours). The cloned mutant glial cell lines formed large colonies in LSM (efficiency 20-40%), but astroglial cells did not. The mutant astroglial cells also developed tumors in nude mice. p53 protein was never detected in normal astroglia, however, some glial cells treated by ENU abruptly became p53 positive after several passages. These p53 positive cells formed stratified colonies thereafter. These results indicate that mutant astroglial cells can be induced by a single dose of ENU in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[In vitro ENU-induced carcinogenesis of rat fetal astroglia--biological character of mutant glial cell]. 833 19

The changes in subcellular localization of metallothionein (MT) during differentiation were studied in two muscle cell lines, L6 and H9C2, myoblasts in order to understand the nuclear presence of MT and its antiapoptotic property. In myoblasts, MT and zinc were localized mainly in the cytoplasm but were translocated into the nucleus of newly formed myotubes during early stage of differentiation, which was initiated by lowering FBS from 10% to 1%. In fully differentiated myotubes, metallothionein content was decreased with a cytoplasmic localization. These changes in subcellular localization of MT and Zn were accompanied by increased apoptosis in myotubes. The changes in the apoptosis at different stages of differentiation were measured by both DNA ladder formation and TUNEL technique. The results also show that the apoptosis may be initiated by free radical generation and may be accompanied by p53 expression. The H9C2 cells contained high levels of MT, differentiated slowly, and had low incidence of apoptotic bodies compared to L6 cell line.
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PMID:Metallothionein and apoptosis during differentiation of myoblasts to myotubes: protection against free radical toxicity. 1048 4

In search for angiogenesis inhibitors, we tested protease and proteasome inhibitors for the induction of G1 arrest and selective inhibition of growth of human umbilical vein endothelial cells (HUVECs). Serine protease-, cysteine protease-, aspartate protease-, and aminopeptidase-inhibitors did not inhibit bFGF/FBS-induced S-phase induction in HUVECs, but a proteasome inhibitor, lactacystin did inhibit it reversibly. Lactacystin increased the cellular level of p53 and cdk2-associated p21WAF1/CIP1 leading to cdk2 inactivation. In addition to the angiogenesis inhibitor TNP-470, lactacystin also inhibited the growth of HUVECs selectively at about a 20 times lower concentration than that of other human cell lines, including normal fibroblasts and carcinoma cells. Lactacystin induced p53-dependent p21WAF1/CIP1 expression at lower concentrations in HUVECs than in other cells. These cellular effects were also observed with a tripeptide-type proteasome inhibitor, N-Ac-Leu-Leu-norleucinal.
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PMID:Induction of G1 arrest and selective growth inhibition by lactacystin in human umbilical vein endothelial cells. 1062 38

p53 protein, a tumor suppressor gene product, has been reported to play a crucial role in suppressing the growth of a variety of cancer cells. However, little information is currently available regarding the content of p53 protein in human leiomyomas. The present study was conducted to elucidate the p53 protein content in human leiomyomas and its regulation by sex steroid hormones. The content of p53 protein in leiomyomas was examined by immunohistochemical staining and Western blot analysis in comparison with that in the adjacent normal myometrium or leiomyoma specimens from GnRH agonist-treated patients. In addition, isolated human leiomyoma cells were subcultured in phenol red-free DMEM supplemented with 10% FBS for 120 h and then stepped down to serum-free conditions for an additional 72 h in the absence or presence of 17 beta-estradiol (E2; 10 ng/ml), progesterone (P4; 100 ng/ml), or E2 (10 ng/ml) plus P4 (100 ng/ml). The effects of sex steroids on p53 protein content in cultured leiomyoma cells were also assessed by Western immunoblot analysis. Immunohistochemical staining and Western blot analysis revealed that p53 protein content was highest in leiomyomas treated with GnRH agonist for 16 wk, lower in leiomyomas in the secretory, P4-dominated phase, and lowest in leiomyomas in the proliferative, E2-dominated phase of the menstrual cycle. There was no difference in p53 content between leiomyomas and the adjacent normal myometrium. Western blot analysis of cultured leiomyoma cell extracts revealed that E2 treatment significantly decreased p53 protein content compared with the control cultures, whereas either P4 treatment or combined treatment with E2 and P4 did not affect p53 protein content in cultured leiomyoma cells. The concentrations of sex steroid hormones used were within the physiological tissue concentrations in leiomyomas and myometrium described earlier. The present study suggests that E2 down-regulates p53 protein content, whereas P4 is ineffective in those cells. The E2-induced decrease in p53 protein content in leiomyoma cells leads us to propose that E2 may regulate human leiomyoma growth in part by down-regulating p53 tumor suppressor protein content in those cells.
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PMID:p53 Tumor suppressor protein content in human uterine leiomyomas and its down-regulation by 17 beta-estradiol. 1216 33

Use of dietary supplements and botanical products is widely accepted by patients diagnosed with prostate cancer (CaP) as a primary or complementary form of treatment for their medical conditions in the U.S. Yet, the majority of these products have not been rigorously studied with regard to scientific mechanism(s). Because many of the available products are mixtures of multiple extracts derived from plants, some of which are not necessarily native to the U.S., we consider mechanistic studies under defined laboratory conditions to be valuable and essential, not only from the standpoint of standardization and possible contamination with the products, but also in providing insights and scientific evidence for the clinical efficacy some of these products purportedly demonstrate. In previous studies from this laboratory, Equiguard, a composite supplement consisting of standardized extracts from nine Chinese herbs, which was originally formulated to correct physiological decline in kidney functions associated with age, was fortuitously found to display anti-CaP properties. Using a panel of CaP cells, we showed that ethanol extracts of Equiguard significantly inhibited cancer cell growth, induced apoptosis, lowered expression of the androgen receptor (AR), decreased intracellular and secreted prostate-specific antigen (PSA) levels and completely abolished the colony forming activities of CaP cells. Since responsiveness to Equiguard was observed in cells mimicking the androgen-dependent (AD) and androgen-independent (AI) states of CaP, our results raise the interesting possibility that this herbal supplement may potentially prevent, delay or circumvent the onset of AI, and thereby induce chronic instead of terminal CaP. Since androgen ablation therapy (chemical or surgical castration) is the mainstay for localized CaP, we questioned whether Equiguard might still exert the aforementioned activities in experimental settings modeled after androgen ablation. Accordingly, we studied the effects of Equiguard in LNCaP cells, cultured in androgen-proficient (FBS) or -deficient (CS-FBS) media that simulate the hormonal status pre- and post-castration in vivo. Extracts of Equiguard were effective in reducing colony formation, proliferation and PCNA expression of cells cultured in CS-FBS. Moreover, within a concentration range of Equiguard, the prostate-specific genes, PSA and AR, were affected to a similar extent in cells cultured either in FBS or CS-FBS, and were correlated with increased phosphorylation at serine-15 of the tumor suppressor gene p53. These results are consistent with the interpretation that the anti-proliferative and gene modulatory properties of Equiguard are largely independent of the status of androgens in the culture media.
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PMID:Inhibition of proliferation and expression of AR/PSA by herbal supplement Equiguard in LNCaP cells cultured in androgen-proficient FBS and androgen-deficient charcoal-stripped FBS is correlated with increased serine-15 phosphorylation of the tumor suppressor gene p53. 1289 32

Regucalcin is a regulatory protein in intracellular signaling pathway which is related to various protein kinases and protein phosphatases in many cells. The effect of regucalcin on the expression of tumor-related genes was investigated in the cloned rat hepatoma H4-II-E cells and the hepatoma cells (transfectants) overexpressing regucalcin. Hepatoma cells were cultured for 24-72 h in the presence of fetal bovine serum (FBS; 10%). The proliferation of hepatoma cells was significantly suppressed at 24-72 h of culture in regucalcin transfectants as compared with that of wild-type or mock-type cells. Western blot analysis showed that regucalcin was markedly expressed in transfectants. The expression of c-myc, c-fos, c-jun, Ha-ras, and p53 mRNAs was determined using reverse transcription-polymerase chain reaction (RT-PCR). Of these genes, the expression of c-myc or Ha-ras mRNAs was significantly suppressed in regucalcin transfectants. The suppression of c-myc mRNA expression in transfectants was confirmed by using Northern blot analysis; significant suppression was seen at 24, 48, or 72 h of culture in the presence of 10% FBS. Culture with 10% FBS significantly enhanced c-myc mRNA expression in the hepatoma cells (wild-type) as compared with that of 1% FBS. The enhancement was significantly abolished in the transfectants. Meanwhile, the expression of p53 mRNA in the hepatoma cells was significantly enhanced in regucalcin-overexpressing hepatoma cells. This study demonstrates that the expression of oncogene c-myc and Ha-ras mRNA in hepatoma cells overexpressing regucalcin is suppressed, and that the tumor suppression gene p53 is enhanced in the transfectants.
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PMID:Overexpression of regucalcin modulates tumor-related gene expression in cloned rat hepatoma H4-II-E cells. 1452 95

Pyrrolidine dithiocarbamate (PDTC), a metal chelating compound, is known to induce cell death in vascular smooth muscle cells (VSMC). However, the molecular mechanism for PDTC-induced VSMC death is not well understood. Addition of PDTC reduced cell growth and DNA synthesis on VSMC in low density conditions. However, in serum depleted medium, PDTC did not affect the cell viability, suggesting that certain factors in serum may mediate the cytotoxic effect of PDTC. Several metal chelators prevented the cell death induced by PDTC. In a serum-deprived condition, addition of exogenous metals, copper, iron, and zinc, restored the cytotoxic effect of PDTC. These data indicate that metals such as copper, iron, and zinc in serum may mediate the cytotoxic effect of PDTC. At low VSMC density in 10% FBS, treatment of PDTC, which induced a cell-cycle block in G1-phase, induced down-regulation of cyclins and CDKs and up-regulation of the CDK inhibitor p21 expression, whereas up-regulation of p27 or p53 by PDTC was not observed. Finally, we determined PDTC-mediated signaling pathway involved in VSMC death. Among relevant pathways, PDTC induced marked activation of p38MAPK and JNK. Expression of dominant negative p38MAPK and SB203580, a p38MAPK specific inhibitor, blocked PDTC-dependent p38MAPK, growth inhibition, and p21 expression. These data demonstrate that the p38MAPK pathway participates in p21 induction, which consequently leads to decrease of cyclin D1/cdk4 and cyclin E/cdk2 complexes and PDTC-dependent VSMC growth inhibition. In conclusion, an understanding of the molecular mechanisms of PDTC in VSMC provides a theoretical basis for clinical approaches using antioxidant therapies in atherosclerosis.
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PMID:PDTC, metal chelating compound, induces G1 phase cell cycle arrest in vascular smooth muscle cells through inducing p21Cip1 expression: involvement of p38 mitogen activated protein kinase. 1460 33

Heme oxygenase-1 (HO-1) and p21 influence cell fate, and genetic HO-1 overexpression upregulates p21 and confers resistance to apoptosis. The present study examined the effects of heme, a metabolite incriminated in renal injury, on sensitivity to apoptosis and cell growth in conjunction with cellular expression of HO-1 and p21. Immortalized rat proximal tubular epithelial cells (IRPTCs) were exposed to hemin (10 microM) in serum-deplete media (0.1% FBS) and in standard cell culture media (5.0% FBS). In the presence of 0.1% FBS media, hemin induced p21 through an HO-dependent, p53-independent mechanism; certain products of HO activity (iron and carbon monoxide), but not others (ferritin, apoferritin, bilirubin), recapitulated these inductive effects on p21 expression. Along with this inductive effect on HO-1 and p21, hemin worsened apoptosis, the latter exacerbated by the inhibition of HO activity and loss of p21 expression. In IRPTCs maintained in 5% FBS, hemin induced HO-dependent p21 expression, provoked cell cycle arrest, and inhibited cell growth without inducing apoptosis; this inhibitory effect of hemin on cell growth was blocked by the concomitant inhibition of HO activity and loss of p21 expression. We conclude that hemin is a potent HO-dependent inducer of p21 and that hemin increases the sensitivity to apoptosis in serum-deplete conditions and decreases cell growth in serum-replete conditions; inhibiting HO activity and concomitantly ablating p21 expression exacerbate apoptosis and reverse the growth-inhibitory actions of hemin. We suggest that these effects of heme may influence the nature of, and recovery from, ischemic and nephrotoxic insults to the kidney.
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PMID:Heme: a determinant of life and death in renal tubular epithelial cells. 1470 7

Using normal canine embryonic fibroblasts (CaEF) that were shown to be senescent at passages 7th-9th, we established two spontaneously immortalized CaEF cell lines (designated CGFR-Ca-1 and -2) from normal senescent CaEF cells, and an immortal CaEF cell line by exogenous introduction of a catalytic telomerase subunit (designated CGFR-Ca-3). Immortal CGFR- Ca-1, -2 and -3 cell lines grew faster than primary CaEF counterpart in the presence of either 0.1% or 10% FBS. Cell cycle analysis demonstrated that all three immortal CaEF cell lines contained a significantly high proportion of S-phase cells compared to primary CaEF cells. CGFR-Ca-1 and -3 cell lines showed a loss of p53 mRNA and protein expression leading to inactivation of p53 regulatory function, while the CGFR-Ca-2 cell line was found to have the inactive mutant p53. Unlike the CGFR-Ca-3 cell line that down-regulated p16INK4a mRNA due to its promoter methylation but had an intact p16INK4a regulatory function, CGFR-Ca-1 and -2 cell lines expressed p16INK4a mRNA but had a functionally inactive p16INK4a regulatory pathway as judged by the lack of obvious differences in cell growth and phenotype when reconstituted with wild-type p16INK4a. All CGFR-Ca-1, -2 and -3 cell lines were shown to be untransformed but immortal as determined by anchorage-dependent assay, while these cell lines were fully transformed when overexpressed oncogenic H-rasG12V. Taken together, similar to the nature of murine embryo fibroblasts, the present study suggests that normal primary CaEF cells have relatively short in vitro lifespans and should be spontaneously immortalized at high frequency.
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PMID:Cellular characteristics of primary and immortal canine embryonic fibroblast cells. 1536 51

We have established three immortal bovine muscular epithelial (BME) cell lines, one spontaneously immortalized (BMES), the second SV40LT-mediated (BMEV) and the third hTERT-mediated (BMET). The morphology of the three immortal cell lines was similar to that of early passage primary BME cells. Each of the immortal cell lines made cytokeratin, a typical epithelial marker. BMET grew faster than the other immortal lines and the BME cells, in 10% FBS-DMEM medium, whereas neither the primary cells nor the three immortal cell lines grew in 0.5% FBS-DMEM. The primary BME cells and the immortal cell lines, with the exception of BMES, made increasing amounts of p53 protein when treated with doxorubicin, a DNA damaging agent. On the other hand, almost half of the cells in populations of the three immortal cell lines may lack p16(INK4a) regulatory function, compared to primary BME cells that were growth arrested by enforced expression of p16(INK4a). In soft-agar assays, the primary cells and immortal cell lines proved to be less transformed in phenotype than HeLa cells. The three immortal epithelial-type cell lines reported here are the first cell lines established from muscle tissue of bovine or other species.
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PMID:Establishment and characterization of three immortal bovine muscular epithelial cell lines. 1651 44


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