Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Benzamide riboside (BR) is a nucleoside prodrug that is phosphorylated to its 5'-monophosphate (BRMP) and then converted to its active metabolite, BAD (benzamide adenine dinucleotide), an analogue of NAD by the action of NMN adenylyltransferase (NMNAT). BAD is a potent, reversible, and noncompetitive inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH) resulting in depletion of guanylates (GTP and dGTP). IMPDH inhibitors such as BR induce differentiation and apoptosis as a consequence of GTP depletion. Tiazofurin (TR) and selenazofurin (SR) require similar metabolism by NMNAT. NMNAT is the rate-limiting step in the synthesis of NAD and NAD analogues. BR- and TR-sensitive leukemic cells contain high NMNAT activity, whereas resistant clones have greatly downregulated NMNAT activity (<0.1% of wild type). Perhaps the applicability of BR and analogues could be enhanced if combined with NMNAT gene expression in BR-resistant leukemic blasts. NAD has important regulatory role in repair of DNA damage and cell growth since it is a substrate for poly(ADP-ribose) polymerase (PARP). PARP appears to direct short-patch base excision repair and induce p53 upregulation leading to apoptosis. BR inhibits PARP at high concentrations when assayed in permeabilized leukemic cells. Several other IMPDH inhibitors (TR, mycophenolic acid, and ribavirin) exhibit similar PARP inhibitory activity. Although this inhibition was reversible, it was not prevented by the addition of guanosine, GTP, or its nonhydrolyzable analog gamma-S-GTP. Therefore, it can be concluded that IMPDH inhibitors directly inhibit PARP. Presumably, the shared IMP-NAD active site of IMPDH has a similar architecture to the NAD-binding pocket of PARP.
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PMID:Modulation of cytotoxicity of benzamide riboside by expression of NMN adenylyltransferase. 1196 38

Concurrent and pre-exposure of A431 human epidermoid cancer cells to UCN-01, an investigational anticancer drug, with 5-fluoro--2'-deoxyuridine (FdUrd), which targets thymidylate synthase, produced more than additive cytotoxicty. A 24-h exposure to 10 nM FdUrd led to inhibition of TS, a 2.5-fold increase in total thymidylate synthase protein content, profound dTTP depletion and a 6.3-fold increase in the ratio of dATP to dTTP, but did not cause single-strand breaks in DNA. However, FdUrd enhanced UCN-01-associated DNA strand breaks. Concurrent thymidine exposure led to repletion of dTTP pools, and cytoprotection against FdUrd alone and with UCN-01. UCN-01 arrested cells in G1, decreased the percentage of FdUrd-treated cells in S phase and reduced FdUrd-DNA incorporation, suggesting the latter was not important for cytotoxicity. Delayed induction of high molecular mass DNA fragmentation and poly(ADP-ribose) polymerase cleavage was observed with the combination of UCN-01 and FdUrd. These findings suggest that while FdUrd-mediated deoxynucleotide imbalance alone was insufficient to induce apoptosis in this p53-mutant cell line, it magnified UCN-01's effects, most likely by interfering with DNA repair. The clinical evaluation of UCN-01 combined with 5-fluoropyrimidines may be of interest.
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PMID:Biochemical and molecular effects of UCN-01 in combination with 5-fluorodeoxyuridine in A431 human epidermoid cancer cells. 1198 70

Two systems are essential in humans for genome integrity, DNA repair and apoptosis. Cells that are defective in DNA repair tend to accumulate excess DNA damage. Cells defective in apoptosis tend to survive with excess DNA damage and thus allow DNA replication past DNA damages, causing mutations leading to carcinogenesis. It has recently become apparent that key proteins which contribute to cellular survival by acting in DNA repair become executioners in the face of excess DNA damage. Five major DNA repair pathways are homologous recombinational repair (HRR), non-homologous end joining (NHEJ), nucleotide excision repair (NER), base excision repair (BER) and mismatch repair (MMR). In each of these DNA repair pathways, key proteins occur with dual functions in DNA damage sensing/repair and apoptosis. Proteins with these dual roles occur in: (1) HRR (BRCA1, ATM, ATR, WRN, BLM, Tip60 and p53); (2) NHEJ (the catalytic subunit of DNA-PK); (3) NER (XPB, XPD, p53 and p33(ING1b)); (4) BER (Ref-1/Ape, poly(ADP-ribose) polymerase-1 (PARP-1) and p53); (5) MMR (MSH2, MSH6, MLH1 and PMS2). For a number of these dual-role proteins, germ line mutations causing them to be defective also predispose individuals to cancer. Such proteins include BRCA1, ATM, WRN, BLM, p53, XPB, XPD, MSH2, MSH6, MLH1 and PMS2.
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PMID:DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. 1205 32

Human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, plays a pivotal role in the maintenance of telomeres and cell proliferation. Here we report that down-regulation of hTERT induces apoptosis independently of telomerase enzymatic activity in human breast cancer cells. Expression of a hTERT mutant lacking telomerase activity rescues the cells with lowered telomerase without inducing cell death. With similar patterns of subcellular distribution to that of the tumor suppressor protein p53 during mitosis, hTERT interacts with p53 and poly(ADP-ribose) polymerase (PARP). Decreasing p53 expression in intact cells worsens, and increasing p53 prevents, cell death induced by lowering hTERT. Thus, hTERT maintains cell survival and proliferation via both telomerase enzymatic activity-dependent telomere lengthening and enzymatic activity-independent intermolecular interactions involving p53 and PARP.
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PMID:TERT regulates cell survival independent of telomerase enzymatic activity. 1208 28

Wogonin and fisetin are flavonoids, which are widely distributed in plants. Our recent study demonstrated that, among seven structurally related flavonoids, wogonin and fisetin showed the most potent apoptosis-inducing activities in human promyeloleukemic cells HL-60. In the present investigation, we performed molecular studies to assess the apoptotic effects of wogonin and fisetin on hepatocellular carcinoma cells SK-HEP-1. Both wogonin and fisetin showed dose-dependent cytotoxic effects on SK-HEP-1 cells, accompanied by DNA fragmentation. Microscopic observation under Giemsa staining showed that wogonin and fisetin, at the dose of 80 microM, induced cellular swelling and the appearance of apoptotic bodies, characteristics of apoptosis, in SK-HEP-1 cells. Furthermore, flow cytometry analysis showed an increase of hypodiploid cells in wogonin- and fisetin-treated SK-HEP-1 cells. These data demonstrated that wogonin and fisetin were effective inducers of apoptosis in SK-HEP-1 cells. Treatment with an apoptosis-inducing concentration of wogonin or fisetin caused induction of caspase 3/CPP32 activity, but not of caspase 1 activity. In addition, a caspase 3 inhibitor, Ac-DEVD-CHO, but not the caspase 1 inhibitor Ac-YVAD-CHO, reversed the cytotoxic effects of wogonin and fisetin on SK-HEP-1 cells. Further, cleavage of caspase 3 substrates including poly(ADP-ribose) polymerase (PARP) and D4-GDI protein, and decrease of pro-caspase 3 protein were detected in wogonin- and fisetin-treated SK-HEP-1 cells. Increase of p53 protein was associated with wogonin- and fisetin-induced apoptosis; however, a p53-controlled gene, p21(Waf/Cip-1), was only induced in wogonin- (not fisetin-) treated SK-HEP-1 cells. Serum starvation elevated p21(Waf/Cip-1) protein expression, and enhanced the apoptotic induction activity of wogonin (not fiseitn) in SK-HEP-1 cells. Our study has provided molecular evidence to demonstrate that wogonin and fisetin had effective cytotoxic effects through apoptosis induction in hepatocellular carcinoma cells SK-HEP-1; activation of caspase 3 cascade, induction of p53 protein and alternative expression of p21(Waf/Cip-1) protein were involved.
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PMID:Wogonin and fisetin induction of apoptosis through activation of caspase 3 cascade and alternative expression of p21 protein in hepatocellular carcinoma cells SK-HEP-1. 1210 53

Infection by the intestinal nematode Nippostrongylus brasiliensis induces acceleration of apoptosis in the small intestinal villus epithelial cells in vivo. In the present study, we examined whether worm extract or excretory-secretory product induces apoptosis in the rat intestinal epithelial cell line IEC-6 in vitro. In the presence of worm extract or excretory-secretory product (> or =6 microg/ml), IEC-6 cell growth was significantly suppressed, and there was a concomitant increase in the number of detached cells in culture dishes. Detached cells showed nuclear fragmentation, activation of caspase-3, and specific cleavage of poly(ADP-ribose) polymerase, suggesting that apoptosis was induced in these cells. Semiquantitative reverse transcription-PCR showed that expression of Fas (CD95) mRNA was up-regulated as early as 6 h after addition of excretory-secretory product, while Fas ligand expression and p53 expression were not up-regulated. Fluorescence-activated cell sorter analyses revealed a significant increase in Fas expression and a slight increase in FasL expression in IEC-6 cells cultured in the presence of excretory-secretory product, while control IEC-6 cells expressed neither Fas or FasL. These results indicated that N. brasiliensis worms produce and secrete biologically active molecules that trigger apoptosis in intestinal epithelial cells together with up-regulation of Fas expression, although the mechanism of induction of apoptosis remains to be elucidated.
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PMID:Up-regulation of Fas (CD95) and induction of apoptosis in intestinal epithelial cells by nematode-derived molecules. 1211 5

We observed stronger cytotoxic effect of CHS 828 on poly(ADP-ribose) polymerase-1(PARP-1) knock-out cells as compared with the normal counterpart. The proliferation of PARP-1 -/- cells was inhibited by a drug concentration approximately 3-fold lower than that in the normal cells. The monitoring of p53 levels revealed that CHS 828 induced p53 response in a dose-dependent manner in only normal cells. The drug, however, failed to activate the p53 protein in PARP-1-deficient cells even after combined treatment with multidrug-resistant modulators. These results show that the PARP-1 inactivation sensitizes cells to the novel anticancer drug CHS 828 and that the drug is able to activate different cellular pathways depending on PARP-1 status.
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PMID:Action of a novel anticancer agent, CHS 828, on mouse fibroblasts: increased sensitivity of cells lacking poly (ADP-Ribose) polymerase-1. 1215 20

Activating transcription factor 3 (ATF3) is a transcriptional repressor that is rapidly induced in cells exposed to a wide range of stress stimuli. To clarify the role of ATF3 in determining cell fate, we overexpressed it in human umbilical vein endothelial cells (HUVECs) by adenovirus-mediated gene transfer. ATF3 protected these cells from tumor necrosis factor (TNF)-alpha-induced apoptosis, as measured by flow cytometric analysis, trypan blue exclusion assay, and cleavage of procaspase 3 and poly(ADP-ribose) polymerase. Northern blot and nuclear run on assay showed that the transcription of tumor suppressor gene p53 was down-regulated in the ATF3-overexpressing cells. In the transient expression assay, ATF3 suppressed the p53 gene promoter activity through its specific binding to an atypical AP-1 element, PF-1 site, in the p53 gene promoter. Furthermore, the cell-protecting effect of ATF3 was remarkably reduced in p53-deficient cells. These results demonstrate that overexpression of ATF3 suppresses TNF-alpha-induced cell death of HUVECs, at least in part, through down-regulating the transcription of p53 gene. ATF3 may function as a cell survival factor of endothelial cells during vascular inflammation and atherogenesis.
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PMID:Transcriptional repressor activating transcription factor 3 protects human umbilical vein endothelial cells from tumor necrosis factor-alpha-induced apoptosis through down-regulation of p53 transcription. 1216 27

We have previously reported that combretastatin-A4 prodrug (CA4P), anantitubulin/antiangiogenic agent isolated from the South African willow tree Combretum caffrum, induced cell death primarily through mitotic catastrophe in a panel of human B-lymphoid tumors. In this study, we investigated the molecular aspects of the mitotic catastrophe and whether or not it shares the same pathways of apoptosis. For this we studied the effect of CA4P on selected markers of apoptosis [caspases 9 and 3, poly(ADP-ribose) polymerase (PARP), bcl-2, and bax] and G2-M protein regulators (p53, MDM2, 14-3-3sigma, GADD45, cdc2, cdc25, chk1, wee1, p21, and cyclin B1). The chronic lymphocytic leukemia cell line WSU-CLL was used for this purpose. Western blot analysis showed that 24 h of CA4P (5 nM) exposure induces caspase 9 activation and PARP cleavage. However, the addition of Z-Val-Ala-Asp-fluoromethylketone (a general caspase inhibitor) or Z-Leu-Glu(OMe)-His-Asp(OMe)-CH2F (a caspase 9 inhibitor) before CA4P treatment did not block cell death. No change in bcl-2 or bax protein expression was observed. Exposure of WSU-CLL cells to 4 and 5 nM CA4P was associated with overproduction of total p53 and no dramatic change in MDM2, 14-3-3sigma, GADD45, the cyclin-dependent kinase cdc2, its inhibitory phosphorylation, the cdc2-inhibitory kinase (wee1), chk1, or cdc25 hyperphosphorylation. The overaccumulation of p21 and cyclin B1 protein was obvious at 24 h. Furthermore, CA4P treatment showed an increase in the expression of a marker of mitosis (mitotic protein monoclonal-2 antibody) and an overaccumulation of the cyclin B in the nucleus. Our findings suggest that CA4P induces mitotic catastrophe and arrest of WSU-CLL cells mostly in the M phase independent of p53 and independent of chk1 and cdc2 phosphorylation pathways. Apoptosis is a secondary mechanism of death in a small proportion of cells through activation of caspase 9 and PARP cleavage. The two mechanisms of cell death, i.e., mitotic catastrophe and apoptosis, are independent of each other in our model.
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PMID:Combretastatin-A4 prodrug induces mitotic catastrophe in chronic lymphocytic leukemia cell line independent of caspase activation and poly(ADP-ribose) polymerase cleavage. 1217 7

This study was designed to elucidate the mechanisms leading to down-regulation of the Akt/protein kinase B (PKB) survival pathway during H2O2-induced cell death. H2O2 produced early activation of Akt/PKB and also DNA damage that was followed by stabilization of p53 levels, formation of reactive oxygen species (ROS), and generation of ceramide through activation of a glutathione-sensitive neutral sphingomyelinase. These events correlated with long term dephosphorylation and subsequent degradation of Akt. A membrane-targeted active Akt version attenuated apoptosis but not necrosis induced by H2O2 and was more resistant to dephosphorylation and proteolysis induced by apoptotic concentrations of H2O2. Proteolysis of Akt was prevented by exogenous addition of glutathione, indicating a role of ROS and ceramide in Akt degradation. However, Akt was degraded similarly in cells transfected with wild type and dominant negative p53 mutant, indicating that degradation of Akt under oxidative injury may be p53-independent. Specific inhibitors of caspase groups I and III prevented proteolysis of Akt/PKB and poly(ADP-ribose) polymerase in cells submitted to apoptotic but not necrotic H2O2 concentrations. Surprisingly, in caspase-3-deficient MCF-7 cells Akt was more sensitive to H2O2-induced degradation than the caspase-3 substrate poly(ADP-ribose) polymerase. Moreover, the Akt/PKB double mutant Akt(D108A,D119A), which is not cleaved by caspase-3, and a triple mutant (D453A,D455A,D456A), which lacks the consensus sequence for caspase-3 cleavage, were also degraded in H2O2-treated cells. Our results suggest that strong oxidants generate intracellular ROS and ceramide which in term lead to down-regulation of Akt by dephosphorylation and caspase-3-independent proteolysis.
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PMID:Ceramide and reactive oxygen species generated by H2O2 induce caspase-3-independent degradation of Akt/protein kinase B. 1221 2


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