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)

Preclinical studies in animal models and human clinical trials have evaluated the safety and efficacy of adenoviral vectors for cancer gene therapy. These studies have indicated that gene delivery via adenoviral vectors, including p53 gene therapy, represents a promising therapeutic modality for many types of human cancers. This review focuses on novel strategies to induce apoptosis in glioma cells by transduction with adenoviral vectors carrying a variety of apoptosis-related genes, including Fas ligand, Fas, FADD, caspase-8, p53, p33ING1, p73alpha, Bax, Apaf-1, caspase-9, IkappaBdN, caspase-3, Bcl-2, and Bcl-X(L). We conclude that adenoviral vector-mediated delivery of apoptosis-related genes other than p53 is a potentially useful gene therapy approach toward the treatment of human brain tumors.
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PMID:Gene therapy using an adenovirus vector for apoptosis-related genes is a highly effective therapeutic modality for killing glioma cells. 1265 7

The p53 mutant 143Ala is a human temperature-sensitive mutant with two conformational states. To definitively determine whether the Fas signal transduction pathway and the function of the pathway are dependent on p53 status, we have established stable transfectants of p53 mutant 143Ala in two human cancer cell lines: H1299 (lung cancer line) and PC-3 (prostate cancer line), the native state of which contains null p53 status and can grow at 37 degrees C and 32.5 degrees C. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell cycle analysis showed inhibition of the growth of cells overexpressing p53 mutant 143Ala in the wild-type p53 form at 32.5 degrees C because of induction of G0/G1 arrest. Transfected cells had increased protein expression of p21, Fas, and MDM2 at the wild-type p53 conformation at 32.5 degrees C, but not in the mutant p53 form at 37 degrees C. However, there was no change in protein expression of FADD, FAP-1, Bcl-2, or Bax at 32.5 or 37 degrees C. Assays for apoptosis demonstrated that anti-Fas antibody CH-11 and FasL induced apoptosis only in cells that overexpress p53 mutant 143Ala at 32.5 degrees C with the wild-type p53 form. Both caspase-3 and caspase-8 activities were increased by anti-Fas antibody CH-11 only in cells at 32.5 degrees C with wild-type p53. Our results demonstrated that Fas-mediated apoptosis in H1299 and PC-3 cells expressing p53 mutant 143Ala occurred only with the wild-type p53 phenotype. These results support the hypothesis that Fas-mediated apoptosis is dependent, at least partially, on the presence of a functional wild-type p53 state. This model may be a useful tool for dissecting the specific interactions between wild-type p53 and the Fas signal transduction pathway in human cancer cells.
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PMID:Fas-mediated apoptosis is dependent on wild-type p53 status in human cancer cells expressing a temperature-sensitive p53 mutant alanine-143. 1267 Sep

Flavopiridol, a synthetic flavone, has been previously shown to induce apoptosis in B-cell chronic lymphocytic leukaemia (B-CLL) cells in vitro. The apoptosis was associated with a concomitant activation of caspase-3 without evidence of dependence on functional p53 or Bcl-2 family modulation. In this study, we examined flavopiridol-induced apoptosis in terms of upstream caspase activity, cell cycle distribution and signal transduction, in order to elucidate the mechanism of action of this potent cytotoxic agent. Flavopiridol-induced apoptosis was significantly abrogated by the caspase-9 inhibitor Z-LEHD-FMK (p = 0.002; paired t-test) but was not altered by the caspase-8 inhibitor Z-IETD-FMK (p = 0.37; paired t-test). There was a concentration-dependent increase in a sub G0/G1 peak indicative of apoptotic cells but if these cells were excluded by gating no other cell cycle perturbations were observed suggesting that flavopiridol is capable of inducing apoptosis in cells in all phases of the cell cycle. Significantly, apoptosis was associated with activation of p38 MAP kinase and suppression of ERK activity (p = 0.0036 and p = 0.0048, respectively; paired t-test). These results show for the first time that flavopiridol modulates specific cellular signal transduction pathways in B-CLL cells thereby altering the balance between survival and cell death signals and providing a rationale for the p53-independent nature of flavopiridol-induced apoptosis. Further work is required to identify whether combinations of conventional chemotherapeutic drugs and novel agents like flavopiridol can be used to improve patient outcomes in the treatment of B-CLL.
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PMID:Flavopiridol induces apoptosis in B-cell chronic lymphocytic leukaemia cells through a p38 and ERK MAP kinase-dependent mechanism. 1268 54

Proapoptotic gene transfer to promote death or to augment killing by DNA-damaging agents represents a promising strategy for cancer therapy. We have constructed an adenoviral Tet-Off trade mark vector with tightly controlled expression of Bid (Ad-Bid) (Clontech, Palo Alto, CA). Using the non-small cell lung cancer cell lines H460, H358, and A549, low dose Ad-Bid was shown to induce high levels of full-length Bid as well as caspase-3 and -9 activity. Although only a small fraction of Bid was processed to truncated Bid (a step inhibited by benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone), Ad-Bid gene transfer resulted in mitochondrial changes consistent with apoptosis (mitochondrial depolarization, cytochrome c release), DNA fragmentation, and a dramatic loss of cell viability. The proapoptotic effects of Ad-Bid were independent of p53 status and were augmented markedly by caspase-8 activators such as the DNA-damaging agent cisplatin. When Ad-Bid and cisplatin were used together, chemosensitivity was restored in p53-null H358 cells, increasing death from 35% following treatment with cisplatin and Ad-LacZ to >90% death with Ad-Bid and cisplatin (Ad-Bid alone induced 50% cell death under these conditions). Ad-Bid can induce apoptosis in malignant cells and enhance chemosensitivity in the absence of p53, suggesting this approach as a potential cancer therapy.
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PMID:Adenoviral Bid overexpression induces caspase-dependent cleavage of truncated Bid and p53-independent apoptosis in human non-small cell lung cancers. 1269 Jan 7

Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer especially in India and displays resistance to anticancer treatment. In our earlier study we had isolated a cDNA clone from rat thymocytes induced to undergo apoptosis, which was found to encode S29 ribosomal protein [Biochem. Biophys. Res. Commun. 277 (2000) 476]. In the present study an attempt has been made to find out whether enhanced expression of S29 cDNA can kill NSCLC H520 cells. We found that S29 induced apoptosis and augmented the effect of anticancer drugs. Expressions of several molecular determinants of apoptosis were analyzed in order to understand the mechanism of apoptosis induced by S29. We observed downregulation of the expression of inhibitors of apoptosis proteins (IAPs) Bcl-2, Bcl-X(L), and survivin and upregulation of pro-apoptotic p53 and Bax as assessed by Western blotting. Mitochondrial release of cytochrome c and activation of initiator caspase-8 and -9 and effector caspase-3, followed by cleavage of nuclear substrate poly(ADP-ribose) polymerase, were also observed. Permeability transition as determined by changes in DeltaPsi(m) was not a requirement for cytochrome c release. There was a marginal increase in the release of apoptosis inducing factor (AIF) and reduction of NF-kappaB dependent transcriptional activity. There was non-involvement of calcium and the telomerase activity, a proliferation marker.
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PMID:S29 ribosomal protein induces apoptosis in H520 cells and sensitizes them to chemotherapy. 1270 79

Polycyclic aromatic hydrocarbons (PAHs) are known immunotoxins and carcinogens. Our laboratory and others have demonstrated that metabolism of these compounds by CYP1B1 is required for carcinogenicity and immunotoxicity to occur. Previously, our laboratory reported significantly decreased bone marrow cellularity in mice following 7,12-dimethlybenz[a]anthracene (DMBA) administration. In addition, we have observed that DMBA causes apoptosis via activation of both caspase-8 and -9 in pre-B cells co-cultured with bone marrow stromal cells in vitro. In this study, we investigated the importance of the p53 protein in the bone marrow response to DMBA. Through the use of p53 gene knockout mice, we demonstrated that the effect of DMBA on bone marrow cellularity is p53-dependent. In addition, apoptosis of primary cultures of progenitor B cells cultured with bone marrow stromal cells and DMBA is also p53-dependent. The results of this study provide evidence for the importance of p53 in the signaling pathways by which PAHs cause immunotoxicity.
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PMID:7,12-Dimethylbenz[a]anthracene-induced bone marrow toxicity is p53-dependent. 1273 Jun 9

Caspase-8, also known as MACH/FLICE/Mch5, is the most upstream-located cysteine-aspartyl-protease (caspase) in a caspase cascade involved in apoptosis triggered by members of the tumor necrosis factor receptor superfamily or other stimuli such as chemotherapeutic agents. Regulation of caspase-8 expression on a post-translational level has been studied in detail, whereas only little information is available on its control by gene transcription. We identified and cloned the human caspase-8 promoter, determined the transcriptional start site of the caspase-8 gene, and examined the regulatory mechanisms of the promoter with respect to its basal activity as well as to its inducibility upon apoptotic stimuli in human hepatoma cells. We identified two minimal sequences essential for basal transcription of caspase-8 and demonstrate that a single SP1 and an ETS-like binding motif mediate this effect. We further show that the caspase-8 promoter is inducible and demonstrate that adenoviral infection increases caspase-8 mRNA levels. However, the increase in caspase-8 gene transcription after adenoviral infection absolutely depends on the p53 status of the hepatoma cell line, implying that caspase-8 is a target gene of p53. We show that delivery of exogenous p53 alone is sufficient to induce the caspase-8 promoter even in p53-deficient Hep3B hepatoma cells. Subsequent promoter deletion analysis in combination with luciferase reporter assays identified a p53-responsive element downstream of the transcriptional start site. We demonstrate that this p53-responsive sequence overlaps with the ETS-like binding site and suggest that an additional p53-inducible, yet unknown factor interacts with this region of the caspase-8 promoter. In summary, our study contributes to the understanding of the transcriptional regulation of the caspase-8 gene by basal (SP1- and ETS-dependent) and inducible (p53-dependent) mechanisms.
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PMID:The human caspase-8 promoter sustains basal activity through SP1 and ETS-like transcription factors and can be up-regulated by a p53-dependent mechanism. 1274 79

All members of the gamma-herpesvirus family encode genes capable of inhibiting apoptosis. Inhibition of a variety of types of apoptotic stimuli have been demonstrated for specific viral genes, including pathways induced by the immune system as well as internal pathways. Virally encoded genes inhibit the activation of caspase-8 by the TNF receptor and Fas; activate NF-kappaB to increase expression of antiapoptotic genes; inhibit interferon response; bind to p53, thereby blocking p53 dependent apoptosis; and interact with other pro- and antiapoptotic cellular genes. All gamma-herpesviruses also express viral homologues of cellular antiapoptotic genes, including one or two Bcl-2 homologues. The human gamma-herpesviruses encode genes that can inhibit apoptosis during both latent and lytic infection. During latent phase infection inhibition of apoptosis is likely important for persistence of the gamma-herpesviruses in the face of immune attack, but it is also required for maintenance of infected cells in culture. During lytic replication the virus inhibits apoptosis to prevent cell death before viral replication and spread occurs.
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PMID:Inhibition of apoptosis by the gamma-herpesviruses. 1295 51

SH-SY5Y neuroblastoma cells were cultured for up to three serial passages in the presence of the copper chelator triethylene tetramine (Trien). The copper-depleted neuroblastoma cell line obtained showed decreased activities of the copper enzymes Cu, Zn super-oxide dismutase and cytochrome c oxidase with concomitant increases in reactive oxygen species. Mitochondrial antioxidants (Mn superoxide dismutase and Bcl-2)were up-regulated. Overexpression and activation of p53 were early responses, leading to an increase in p21. Eventually, copper-depleted cells detached from the monolayer and underwent apoptosis. Activation of upstream caspase-9, but not caspase-8, suggested that apoptosis proceeds via a mitochondrial pathway, followed by caspase-3 activation. The addition of copper sulfate to the copper-depleted cells restored copper enzymes, normalized antioxidant levels and improved cell viability. We conclude that prolonged copper starvation in these replicating cells leads to mitochondrial damage and oxidative stress and ultimately, apoptosis.
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PMID:Prolonged copper depletion induces expression of antioxidants and triggers apoptosis in SH-SY5Y neuroblastoma cells. 1451 38

Aberrant expression of the apoptosis inhibitor bcl-2 provides a survival advantage throughout oncogenesis and can facilitate chemotherapeutic resistance in a variety of human cancers. Follicular lymphoma (FL) for example, is characterized by the chromosomal translocation t(14;18), which results in bcl-2 overexpression and initiates lymphomagenesis. Although FL cells possess ample amounts of bcl-2, they respond remarkably well to standard first-round chemotherapy. However, the vast majority of patients relapses and becomes progressively resistant to therapy. We obtained cell lines derived from chemosensitive and chemoresistant FL patients, that are characterized by the chromosomal translocation t(14;18) and expression of bcl-2, to investigate how chemotherapeutic drugs can circumvent bcl-2 anti-apoptotic function and to identify alterations in those pathways that may facilitate resistance to DNA damaging drugs. In chemosensitive FL cells, we found that DNA damaging drugs promote apoptosis through p53-dependent upregulation of the TRAIL-DR5 receptor, resulting in activation of caspase-8 and downstream executioner caspases, thereby evading bcl-2 mediated suppression of apoptosis. Examination of drug resistant FL cell lines revealed that at least two defects in this pathway can contribute to chemotherapeutic resistance: 1. p53 gene mutations that disable the transcriptional response to DNA damaging drugs, including expression of the TRAIL-DR5 receptor, and 2. transcriptional repression of the cell-death executioner enzyme caspase-3.
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PMID:Activation and suppression of the TRAIL death-receptor pathway in chemotherapy sensitive and resistant follicular lymphoma cells. 1461 23


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