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 tumour suppressor protein p53 plays a key role in the cell's decision to arrest the cell cycle or undergo apoptosis following a genotoxic insult. p53 is stabilized and activated after DNA damage, however the cascade of events signalling from DNA lesions to p53 stabilization and activation is still controversial. Poly (ADP-ribosylation) of different nuclear acceptors by PARP-1 is an early event when a single strand DNA lesion is produced. We present here evidences that interplay between PARP-1 and p53 is dependent on the type of damage induced to DNA. Primary mouse embryonic fibroblasts derived from parp-1 -/- mice exhibited decreased p53 accumulation and activation following gamma-irradiation compared to parp-1 proficient cells. On the other hand, treatment with the single alkylating agent 2'-methyl-2'-nitrose-urea (MNU), resulted in the rapid and sustained accumulation and activation of p53 in parp-1-deficient cells, while very little accumulation was observed in parp-1 +/+ cells. After IR, the turnover of the p53 inhibitory protein MDM-2 is perturbed and the level of phosphorylation of p53 at serine-15 is blunted in parp-1 -/- cells. PARP-1 is determinant in the cytotoxic response to alkylating agents but only partially contributes to radiation-induced cell killing, as determined by colony forming assay. Altogether, these results suggest that PARP-1 participates in the p53 response following irradiation, resides upstream of p53 and indirectly modulates the level of phosphorylation of key substrates in this pathway while treatment with MNU results in an enhanced p53-mediated response in parp-1-null cells.
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PMID:PARP-1 modifies the effectiveness of p53-mediated DNA damage response. 1185 Aug 28

Recent studies suggest that several proteins can transverse biological membranes through protein transduction. The protein transduction domains of these proteins, 10-16 residues long, have been identified as critical domains for the protein transduction. Poly-arginine peptide also has the ability of protein transduction. Here, we show that the protein delivery system using 11 poly-arginine peptides (11R) is a powerful tool for the transduction of the biologically active tumor suppressor protein, p53, to suppress the proliferation of oral cancer cells. The 11R-fused p53 proteins (11R-p53) effectively penetrated across the plasma membrane of the cancer cells and translocated into the nucleus. The proteins induced the activity of the p21/WAF promoter and inhibited the proliferation of human oral cancer cells, in which the p53 gene was mutated. The effect was equivalent to that of the adenovirus-mediated p53 gene transduction system. Moreover, 11R-p53 enhanced the cisplatin-dependent induction of apoptosis of the cells. These data suggest that this protein transduction method may become a promising cancer therapy.
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PMID:Development of p53 protein transduction therapy using membrane-permeable peptides and the application to oral cancer cells. 1248 27

(1) The macrolid FK506 is widely used in transplantation to suppress allograft rejection. FK506 and its derivatives are powerful neuroprotective molecules, but the underlying mechanisms remain to be resolved. We have previously shown that the FK506 mediated neuroprotection against oxygen radicals is independent of the inhibition of calcineurin but depends on de novo protein synthesis. (2) Here, we have shown that FK506 mediates protection against H(2)O(2), UV-light or thapsigargin in neuronal cell lines, but not in non-neuronal cells such as R3T3 fibroblasts. We compared in detail the effect of FK506 on apoptotic features in PC12 cells after H(2)O(2) with V-10,367 which binds to FKBPs but does not inhibit calcineurin. Both molecules exert the same neuroprotective effect after H(2)O(2) stimulation. FK506, but not V-10,367, inhibited the cytochrome c release out of the mitochondria and the caspase 3 activation, while both molecules inhibited the cleavage of Poly-(ADP-ribose)-polymerase (Parp) and prevented the expression of p53. (3) FK506 and V-10,367 rapidly induced the expression of Hsp70 and Hsp27, but not Hsp90. Their neuroprotective actions could be completely blocked by quercetin, a functional inhibitor of the heat shock proteins. (4) We conclude that immunophilin-ligands such as FK506 and V-10,367 exert their neuroprotection independent of calcineurin through the induction of the heat shock response. The identification of the underlying signal transduction from application of immunophilin ligands to the expression of heat shock proteins represents a novel target cascade for neuroprotection.
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PMID:The immunophilin-ligands FK506 and V-10,367 mediate neuroprotection by the heat shock response. 1264 3

We have recently shown that staurosporine (ST) can trigger apoptosis of CaSki and HeLa cervical tumor cells from G2/M checkpoint, though the mechanism remains elusive. In this study, we reported that ST induced the inhibition of E6 and E7 viral oncogene and MDM2 expression, while it led to increased levels of p53, which was transiently located to mitochondria. Additionally, the proteins of the p53-regulated genes, p21(WAF1) and Bax, were increased with a similar time, while Bcl-2 and Bcl-X(L) expression was lowered. Upon ST treatment, the cytochrome c was released into the cytosol and, then, activation of caspases-9 and -3 led to Poly(ADP)RibosePolymerase (PARP) cleavage. Finally, characteristic morphological signs confirmed the apoptosis execution. Thus, taken together, all these observations suggest that apoptosis can be reactivated in HPV-positive human carcinoma cells and highlight that ST could be used as a potently chemotherapy agent to enhance the sensitivity of tumor cells to apoptosis.
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PMID:Human papillomaviruses type 16+ and 18+ cervical carcinoma cells are sensitive to staurosporine-mediated apoptosis. 1275 50

BACKGROUND: Malignant rhabdoid tumors (MRTs) are extremely aggressive and resist current radio- and chemotherapic treatments. To gain insight into the dysfunctions of MRT cells, the apoptotic response of a model cell line, MON, was analyzed after exposure to several genotoxic and non-genotoxic agents employed separately or in association. RESULTS: Fluorescence microscopy of chromatin morphology and electrophoretic analysis of internucleosomal DNA fragmentation revealed that MON cells were, comparatively to HeLa cells, resistant to apoptosis after treatment with etoposide, cisplatin (CisPt) or X-rays, but underwent some degree of apoptosis after ultraviolet (UV) C irradiation. Concomitant treatment of MON cells with X-rays or vinblastine and the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin resulted in synergistic induction of apoptosis. Western blot analysis showed that the p53 protein was upregulated in MON cells after exposure to all the different agents tested, singly or in combination. In treated cells, the p53 downstream effectors p21WAF1/CIP1, Mdm2 and Bax were induced with some inconsistency with regard to the accumulation of p53. Poly ADP-ribose polymerase (PARP) cleavage, indicative of ongoing apoptosis, occurred in UVC-irradiated cells and, especially, in cells treated with combinations of X-rays or vinblastine with wortmannin. However, there was moderate or no PARP cleavage in cells treated with CisPt, X-rays, vinblastine or wortmannin singly or with the combinations X-rays plus CisPt or vinblastine and CisPt plus vinblastine or wortmannin. The synergistic effect on the induction of apoptosis exerted by some agent combinations corresponded with synergy in respect of MON cell growth inhibition. CONCLUSION: These results suggest abnormalities in the p53 pathway and apoptosis control in MRT cells. The Ras/PI3-K/AKT signaling pathway might also be deregulated in these cells by generating an excess of survival factors. These dysfunctions might contribute to the resistance of MRTs to current antineoplastic treatments and could warrant consideration in the search of new therapeutic approaches.
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PMID:Apoptotic response of malignant rhabdoid tumor cells. 1290 67

Functional regulation of p53 protein, a critical regulator of cell cycle and apoptosis, was investigated in fiberoptic bronchoscopy biopsy samples taken from 23 patients suffering from recurrent squamous cell lung cancer by analyzing the expression and phosphorylation status of the p53 at Ser15 and Ser20 before and after treatment with radiotherapy/cisplatin/vinorelbine. Poly(ADP-ribose) levels as a marker of cellular DNA damage, expression of wild-type and mutated p53 protein, and Ki-67 expression as a marker of proliferation was also determined. Median p53 expression increased (61% increase) after therapy. p53 phosphorylated on Ser20 was also increased by approximately 57% in radiotherapy/chemotherapy patients, and these changes correlated with Ki-67 proliferation and with elevated (by 69%; P < 0.01) poly(ADP-ribose) levels. Our data indicate that apart from changes in p53 quantity, post-translational phosphorylation/dephosphorylation-mediated alterations, especially at Ser20 may play a role in p53 stabilization and, therefore, in antiproliferative activity of drugs inducing DNA damage and apoptosis.
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PMID:p53 N-terminal Ser-15 approximately P and Ser-20 approximately P levels in squamous cell lung cancer after radio/chemotherapy. 1452 25

Adrenomedullin (AM), a potent vasorelaxant peptide, has been shown to function as an angiogenic and growth factor. The present study investigated whether antagonism of endogenous AM in rats during early gestation results in diminished placental and fetal growth and whether this occurs through induction of apoptosis. Rats on Gestational Day 8 were implanted s.c. with osmotic minipumps delivering 125 and 250 microg rat(-1) day(-1) of AM(22-52) and were killed on Gestational Day 15. In AM(22-52)-treated rats, both placental and fetal weights were dose-dependently inhibited, with 50% reduction in the group receiving 250 microg rat(-1) day(-1). In these animals, fetal resorption sites were also increased. Apoptosis was demonstrated in placenta and uterus by the TUNEL method. Apoptotic changes were more apparent in trophoblast cells in the labyrinth zone of placenta and uterine decidua of AM(22-52)-treated rats when compared with vehicle-control rats. Immunoreactivity to active caspase-3 protein was abundant in the placenta and uterus of the AM(22-52)-treated group. Western blot analysis demonstrated that in homogenates of both the placenta and uterus of AM(22-52)-treated rats, levels of active caspase-9 and -3 as well as of Poly ADP ribose polymerase were significantly increased, whereas levels of Bcl-2 protein decreased, compared with controls. However, no significant treatment-associated changes were observed in Bid, Fas, Fas ligand, p53, and caspase-8 and -10 proteins in either placenta or uterus. Bad protein was undetectable in either tissue. In mitochondrial fractions from both placenta and uterus, the levels of Bax increased with decreases in cytochrome c on AM(22-52) treatment. Conversely, in the cytosol, Bax levels decreased with increases in cytochrome c, demonstrating translocation of Bax from cytosol to mitochondria and release of cytochrome c from mitochondria with AM(22-52) treatment. In conclusion, these findings show that antagonism of AM in rats during early pregnancy caused fetoplacental growth restriction through the activation of mitochondrial apoptotic pathways.
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PMID:Adrenomedullin antagonist treatment during early gestation in rats causes fetoplacental growth restriction through apoptosis. 1522 33

Poly(ADP-ribosyl) ation is a reversible post-translational protein modification implicated in the regulation of a number of biological functions. Whereas an 18 member superfamily of poly(ADP-ribose) polymerase (PARP) enzymes synthesize poly(ADP-ribose) (PAR), a single protein, PAR glycohydrolase (PARG) is responsible for the catabolism of the polymer. PARP-1 accounts for more than 90% of the poly(ADP-ribosyl)ating capacity of the cells. PARP-1 activated by DNA breaks cleaves NAD(+) into nicotinamide and ADP-ribose and uses the latter to synthesize long branching PAR polymers covalently attached to acceptor proteins including histones, DNA repair enzymes, transcription factors and PARP-1. Whereas activation of PARP-1 by mild genotoxic stimuli may facilitate DNA repair and cell survival, irreparable DNA damage triggers apoptotic or necrotic cell death. In apoptosis, early PARP activation may assist the apoptotic cascade [e.g. by stabilizing p53, by mediating the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus or by inhibiting early activation of DNases]. In most severe oxidative stress situations, excessive DNA damage causes over activation of PARP-1, which incapacitates the apoptotic machinery and switches the mode of cell death from apoptosis to necrosis. Besides serving as a cytotoxic mediator, PARP-1 is also involved in transcriptional regulation, most notably in the NF kappaB and AP-1 driven expression of inflammatory mediators. Pharmacological inhibition or genetic ablation of PARP-1 provided remarkable protection from tissue injury in various oxidative stress-related disease models ranging from stroke, diabetes, diabetic endothelial dysfunction, myocardial ischemia-reperfusion, shock, Parkinson's disease, arthritis, colitis to dermatitis and uveitis. These beneficial effects are attributed to inhibition of the PARP-1 mediated suicidal pathway and to reduced expression of inflammatory cytokines and other mediators (e.g. inducible nitric oxide synthase).
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PMID:Structure and function of poly(ADP-ribose) polymerase-1: role in oxidative stress-related pathologies. 1602 17

Overexpression of EGF receptors and constitutive cyclin D1 expression are frequently associated with human squamous carcinomas. We have now investigated whether these parameters influence susceptibility to okadaic acid induced cell death in EGF-receptor overexpressing mutant p53 A431 human carcinoma. Exposure of these cells to 20 nM okadaic acid induced apoptosis-associated caspase 3 activation, DNA fragmentation, cleavage of Poly ADP-Ribose Polymerase (PARP), p53-independent expression of pro-apoptotic bax, and loss of proliferation-promoting cyclin D1. All these alterations were antagonized by concurrent addition of exogenous EGF. Ectopic overexpression of the cyclin D1 gene in A431 carcinoma conferred resistance to 20 nM okadaic acid irrespective of exogenous EGF, associated with a parallel induction of anti-apoptotic bcl-2. Treatment with a subtoxic concentration of a bispecific bcl-2/bcl xL antisense oligonucleotide cooperated with okadaic acid to down-regulate bcl-2 and sensitize cyclin D1-overexpressing cells to okadaic acid. Although EGF protects EGF-R proficient epithelial cells from diverse apoptotic stimuli through Mcl-1, this is the first report demonstrating that cyclin D1 overexpression provides an EGF independent protection from okadaic acid-induced cell death through induction of bcl-2. We also show that this anti-apoptotic effect of cyclin D1 overexpression, can be partly antagonized with antisense strategies that down-regulate anti-apoptotic bcl-2 family members.
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PMID:Cyclin D1 overexpression induces epidermal growth factor-independent resistance to apoptosis linked to BCL-2 in human A431 carcinoma. 1637 52

To examine a possible synergistic role for p73 and cisplatin (cis-diamminedichloroplatinum II) in HeLa cells with a nonfunctional p53 protein, we established stable HeLa/p73 clones using a tetracycline inducible eukaryotic expression vector. The HeLa/p73 clones were not characterized by changes in growth or morphology. Cell death analysis, however, indicated a greater sensitivity to cisplatin in the p73-overexpressed HeLa cells than determined for the non-induced HeLa cells. This increased sensitivity seems to affect an induction of a sub-G1 population as assessed from flow cytometry analysis. The increased sub-G1 population may, in turn, result from a reduction of cyclin D1 and B1 expression by cisplatin in the presence of p73. Hoechest staining indicated an increased number of dead cells in the p73-induced cells compared to the non-induced cells. Poly ADP-ribose polymerase (PARP) cleavage was shown to be distinct in the p73-overexpressed cells compared to non-induced cells, which suggests that p73 modulates the cisplatin-induced apoptosis. Therefore, a synergistic effect of p73 and cisplatin to induce apoptosis could lead to new treatment for some types of human cancers.
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PMID:Overexpression of p73 enhances cisplatin-induced apoptosis in HeLa cells. 1652 80


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