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)

The tumor suppressor gene p53 encodes for an important cell cycle regulatory protein. Loss of the protein's function is probably important for the development of a variety of malignant diseases, including oral cancer. Up to present knowledge, the mutations of the p53 gene are one of the most frequent genetic alterations detectable in human cancer. The aim of this study was to explore the capability of molecular diagnostics to identify p53 mutations (exon 5-8) in smears of the oral mucosa (polymerase chain reaction, temperature gradient gel electrophoresis). Thirty two patients with oral squamous cell carcinoma comprised the study. Biopsies of the tumor, smears of the ulcer, and smears of apparently healthy mucosa were collected from these cancer patients. Smears of 35 healthy volunteers served as controls. P53-mutations were detected in 14 of the 32 cancer patients (44%). The same mutations was also detected in the biopsy in all cases. In addition, swabs of apparently normal mucosa harboured p53-mutated cells in 4 of these 14 patients. No mutation was found in healthy volunteers. Our investigation showed the suitability of swabs for gaining sufficient material to detect p53 gene mutations in oral squamous cell carcinoma.
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PMID:P53-mutation in smears of oral squamous cell carcinoma. 1132 41

The isoflavones daidzein and biochanin A induced a biphasic growth response in T-47D human breast cancer cells. At growth stimulatory concentrations, daidzein increased the percentage of cells entering the S phase, while at a growth inhibitory concentration, daidzein obstructed the progression of the cell cycle in the G2/M phase. Biochanin A regulated the cell cycle progression in a similar manner and showed a delay in the progression from the S phase to the G2/M phase at growth inhibitory concentrations. The levels of a cell cycle regulatory protein, P53, in response to the treatment of isoflavones, were also determined. Cells that became de-attached and floated in the medium after treatment with growth inhibitory concentrations of daidzein or biochanin A, showed higher P53 levels than cells that remained attached. These results suggest that daidzein and biochanin A influence T-47D cell proliferation and cell cycle progression, and that the underlying mechanisms might be associated with the P53 protein levels.
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PMID:Growth and cell cycle regulation by isoflavones in human breast carcinoma cells. 1219 76

p21(WAF1/Cip1) was initially identified as a cell cycle regulatory protein that can cause cell cycle arrest. It is induced by both p53-dependent and p53-independent mechanisms. This mini-review briefly discusses its currently known functions in apoptosis and drug sensitivity. As an inhibitor of cell proliferation, p21(WAF1/Cip1) plays an important role in drug-induced tumor suppression. Nevertheless, a number of recent studies have shown that p21(WAF1/Cip1) can assume both pro- or anti-apoptotic functions in response to anti-tumor agents depending on cell type and cellular context. This dual role of p21(WAF1/Cip1) in cancer cells complicates using p21(WAF1/Cip1) status to predict response to anti-tumor agents. However, it is possible to develop p21(WAF1/Cip1)-targeted reagents or p21(WAF1/Cip1) gene transfer techniques to have a beneficial effect within a well-defined therapeutic context. Better understanding of the roles of p21(WAF1/Cip1) in tumors should enable a more rational approach to anti-tumor drug design and therapy.
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PMID:Differential effects of cell cycle regulatory protein p21(WAF1/Cip1) on apoptosis and sensitivity to cancer chemotherapy. 1296 84

Among the first nutrients to be linked to cancer were methyl group containing nutrients including methionine. Methionine and its metabolic derivatives are essential components in several indispensable biological reactions including protein synthesis, polyamine synthesis, and many transmethylation reactions. The purpose of this study was to determine the extent to which methionine excess affects the proliferation and gene expression of the human breast cancer cell line MCF-7. Cells were first grown in control medium; the medium was then replaced with either control or methionine-supplemented treatment media. We found that 5 and 10 g/L methionine significantly suppressed cell growth on day 1, and no further growth was detected after 3 d of treatment. Cell proliferation in the methionine treated group was significantly lower than that of the control group. Northern analysis revealed that expression of p53 in methionine-treated MCF-7 cells was approximately 70% lower than that of control cells. p53 is a key cell cycle regulatory protein that has been implicated in tumorigenesis and cancer progression. Alteration of the p53 tumor suppressor gene is the most common genetic change found in a wide variety of malignancies, including cancer. This study shows that excess methionine (5 g/L) inhibited proliferation of MCF-7 breast cancer cells, and down regulation of p53 is correlated with this inhibition. These findings may aid in the development of nutritional strategies for breast cancer therapy.
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PMID:Methionine cytotoxicity in the human breast cancer cell line MCF-7. 1450 37

To understand the role of the cell cycle regulatory protein in the control of smooth muscle cell (SMC) proliferation, we tested the overexpression of p21Waf1, a cyclin-dependent kinase inhibitor, in human normal (MS9) and immortalized SMCs (ISS10) transfected with ori-minus simian virus 40 DNA, using an adenovirus-mediated system. In MS9, overexpression of p21Waf1 resulted in the inhibition of cell cycle progression at the G1/S boundary without apoptosis. On the other hand, in ISS10, overexpression of p21Waf1 induced marked apoptosis. In these cells, immunohistochemistry revealed that overexpressed p21Waf1 was localized in the nucleus. No differential expression pattern of either p53 or SV40T was observed in p21Waf1- and control gene (beta-galactosidase)-infected cells. Old-passaged ISS10 cells eventually showed growth arrest and a senescent-like phenotype. Immunohistochemistry revealed that p21Waf1 was localized in the cytoplasm of the early-passaged cells, but was found in the nucleus of the old-passaged cells. Our data suggested that nuclear accumulation of p21Waf1 plays a role in the cell death of immortalized SMC, which carries dysfunction of the cell cycle regulatory proteins such as p53. This culture model may be useful for studying the process of SMC proliferation, cell death, senescence, and cell cycle regulation.
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PMID:Overexpression of p21Waf1 induces apoptosis in immortalized human vascular smooth muscle cells. 1456 87

High embryo loss occurs in the first week of bovine embryo development, with a high percentage of embryonic arrest. We hypothesized that arrested embryos enter a 'senescence-like state' and that both the cell cycle regulatory protein p53 and the stress-related protein p66(shc), which are involved in the onset of senescence in somatic cells, are responsible for this early embryonic arrest. In our in vitro production system, 13.5 +/- 0.5% of embryos arrest at the 2-4-cell stage. First cleavage occurs between 26 and 48 h post insemination (hpi), with early cleaving embryos showing only 0.6 +/- 0.3% arrest, with later cleaving embryos exhibiting up to 14.2 +/- 0.9% arrest. We compared 2-4-cell embryos collected at 28 hpi with those arrested at the 2-4-cell stage collected at day 8 post insemination. Quantification by real-time PCR and by semi-quantitative immunofluorescence showed significantly higher p66(shc) mRNA and protein levels in both arrested and late cleaving embryos versus 28 hpi embryos. By comparison, no significant changes in p53 mRNA, protein and phosphorylation levels were detected. Taken together, these results demonstrate that embryonic developmental potential is related to the time of first cleavage and that p66(shc), but not p53, is up-regulated in early arrested in vitro-produced bovine embryos.
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PMID:p66shc, but not p53, is involved in early arrest of in vitro-produced bovine embryos. 1506 48

Thiols such as N-acetylcysteine (NAC) are increasingly used in clinical trials of platinum chemotherapy as chemoprotectants. NAC can prevent cisdiamminedichloroplatinum (cisplatin)-induced ototoxicity, nephrotoxicity, and gastrointestinal toxicity; however, the molecular mechanisms of NAC on apoptosis and cisplatin cytotoxicity remain unknown. We investigated cisplatin cytotoxicity and NAC chemoprotection in human tumor cell lines, as assessed by immunoblotting and immunocytochemistry. Cisplatin cytotoxicity was associated with nuclear translocation of apoptosis induction factor, expression of the pro-apoptotic Bax protein, cleavage of caspases 3 and 9, and cleavage of PARP. NAC administration reversed the cytotoxic and apoptotic effects if added concurrent with cisplatin or up to 2 h after cisplatin, but chemoprotection was reduced if NAC administration was delayed more than 2 h and was minimal by 8 h after cisplatin. Expression of tumor suppressor p53 and the cell cycle regulatory protein p21 was stimulated within 5 to 10 min by cisplatin in p53-positive LX-1 small cell lung carcinoma cells, and this effect was blocked by NAC. In p53-negative SKOV3 cells, cisplatin toxicity and NAC chemoprotection remained effective, suggesting that chemoprotection may be mediated through both p53-dependent and -independent pathways. Specific kinase inhibitors demonstrated that cisplatin induced apoptosis through the p38 mitogen-activated protein kinase (MAPK) pathway, not the extracellular signal-regulated kinase MAPK pathway. These results show that NAC blocks both the death receptor and the mitochondrial apoptotic pathways induced by cisplatin. The time course for NAC chemoprotection after cisplatin matches our previous in vivo results and provides an opportunity to manipulate route and timing to maintain cisplatin antitumor efficacy while protecting against chemotherapy side effects.
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PMID:The chemoprotective agent N-acetylcysteine blocks cisplatin-induced apoptosis through caspase signaling pathway. 1549 15

Vasostatin, a fragment of calreticulin, was transfected in the BON cell line to evaluate the feasibility of using it for gene therapy in neuroendocrine tumors. Vasostatin transfected cells were subcutaneously inoculated in nude mice. Burkitt lymphoma cell line, CA46, colorectal adenocarcinoma cell line, SW480, as well as endothelial cells PAE and SVEC4 were used for evaluating the function of vasostatin. The results demonstrated that vasostatin transfer caused enhanced malignant behavior of neuroendocrine tumor cell line, BON. Cell adhesion, spreading and cellular invasion were also enhanced in vasostatin-expressing BON cells. Tumor suppressor genes including p53, nm23, Rb and vinculin were down-regulated. Moreover, cell cycle regulatory protein, p27kip1, and cell differentiation-related protein kinase, PKR, were also significantly down-regulated. Furthermore, expression of NKG2D ligands, MICA and MICB, were down-regulated. Mice implanted with vasostatin-expressing BON cells showed an earlier and faster tumor growth compared to wild type. Anti-proliferative effects of vasostatin could not be proven in other cells except in PAE. These results indicated that vasostatin does probably not have a tumor growth inhibitory effect by itself, but rather modulates processes which are necessary for tumor growth. Therefore, one should be very careful when using vasostatin as an anti-tumoral agent in clinical trials, at least for neuroendocrine tumors.
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PMID:Gene transfer of vasostatin, a calreticulin fragment, into neuroendocrine tumor cells results in enhanced malignant behavior. 1629 70

Control of cell cycle progression/exit and differentiation of neuronal precursors is of paramount importance during brain development. BM88 is a neuronal protein associated with terminal neuron-generating divisions in vivo and is implicated in mechanisms underlying neuronal differentiation. Here we have used mouse neuroblastoma Neuro 2a cells as an in vitro model of neuronal differentiation to dissect the functional properties of BM88 by implementing gain- and loss-of-function approaches. We demonstrate that stably transfected cells overexpressing BM88 acquire a neuronal phenotype in the absence of external stimuli, as judged by enhanced expression of neuronal markers and neurite outgrowth-inducing signaling molecules. In addition, cell cycle measurements involving cell growth assays, BrdUrd incorporation, and fluorescence-activated cell sorting analysis revealed that the BM88-transfected cells have a prolonged G(1) phase, most probably corresponding to cell cycle exit at the G(0) restriction point, as compared with controls. BM88 overexpression also results in increased levels of the cell cycle regulatory protein p53, and accumulation of the hypophosphorylated form of the retinoblastoma protein leading to cell cycle arrest, with concomitant decreased levels and, in many cells, cytoplasmic localization of cyclin D1. Conversely, BM88 gene silencing using RNA interference experiments resulted in acceleration of cell proliferation accompanied by impairment of retinoic acid-induced neuronal differentiation of Neuro 2a cells. Taken together, our results suggest that BM88 plays an essential role in regulating cell cycle exit and differentiation of Neuro 2a cells toward a neuronal phenotype and further support its involvement in the proliferation/differentiation transition of neural stem/progenitor cells during embryonic development.
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PMID:BM88 is a dual function molecule inducing cell cycle exit and neuronal differentiation of neuroblastoma cells via cyclin D1 down-regulation and retinoblastoma protein hypophosphorylation. 1689 93

Silibinin, derived from the milk thistle plant, Silybum marianum, has been traditionally used as an antihepatotoxic agent for the treatment of liver disease. Our preliminary study demonstrated that silibinin has protected rat cardiac myocytes against beta-adrenergic agonist isoproterenol-induced injury through resuming mitochondrial function and regulating the expression of SIRT1 and Bcl-2 family members. In this study, we investigate whether silibinin has anti-apoptotic effect on isoproterenol-treated rat cardiac myocytes. DNA damage, detected by the TUNEL and DNA fragmentation assay, was diminished after treatment of silibinin. Results of nitrite and Western blot assays showed that the amount of NO and the expression of iNOS were decreased after treatment with silibinin, while the expression of procaspase-3 and digestion of caspase-3 substrates, the inhibitor of caspase-activated DNase (ICAD) and poly-(ADP-ribose) polymerase (PARP), were increased simultaneously. The DNA damage was reversed by down-regulation of p53 phosphorylation after treatment with silibinin. Result of flowcytometric analysis showed that the cell cycle was not affected, and the expression of cell cycle regulatory protein p21 also had no change. Consequently, silibinin protected cardiac myocytes against isoproterenol-induced DNA damage through caspase pathway and the expression of p53, but independent on regulation of cell cycle.
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PMID:Silibinin protects rat cardiac myocyte from isoproterenol-induced DNA damage independent on regulation of cell cycle. 1694 6


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