Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apolipoprotein J/clusterin is an enigmatic protein highly regulated in inflammation, apoptosis, and cancer. Despite extensive studies, its biological function has remained obscure. Here we show that apolipoprotein J inhibits neuroblastoma cell invasion. Since this function can be regulated by NF-kappaB, we explored the possibility that apolipoprotein J might interfere with NF-kappaB signaling. Ectopic apolipoprotein J expression strongly inhibited NF-kappaB activity in human neuroblastoma cells and murine embryonic fibroblasts by stabilizing inhibitors of NF-kappaB (IkappaBs). Steady state levels of IkappaB proteins are drastically reduced in mouse embryo fibroblasts after disruption of the apolipoprotein J gene. Absence of apolipoprotein J causes reduction of IkappaB stability, a tumor necrosis factor-dependent increase in NF-kappaB activity, increased transcription of the NF-kappaB target gene c-IAP and down-modulation of p53 protein. These results suggest that an unexpected physiological role of apolipoprotein J is to inhibit NF-kappaB signaling through stabilization of IkappaBs and that this activity may result in suppression of tumor cell motility.
 ...
PMID:Essential requirement of apolipoprotein J (clusterin) signaling for IkappaB expression and regulation of NF-kappaB activity. 1288 85

X-linked inhibitor of apoptosis (XIAP) is the most potent member of the IAP family that exerts antiapoptotic effects by interfering with the activities of caspases. Recently, XIAP-associated factor 1 (XAF1) and two mitochondrial proteins, Smac/DIABLO and HtrA2, have been identified to negatively regulate the caspase-inhibiting activity of XIAP. To explore the candidacy of XAF1, Smac/DIABLO, and HtrA2 as a tumor suppressor in gastric tumorigenesis, we investigated the expression and mutation status of the genes in 123 gastric tissues and 15 cancer cell lines. Whereas Smac/DIABLO and HtrA2 transcripts were normally expressed in all cancer specimens we examined, XAF1 transcript was not expressed or present at extremely low levels in 40% (6 of 15) of cancer cell lines and in 23% (20 of 87) of primary carcinomas. Abnormal reduction of XAF1 expression showed a strong correlation with stage and grade of tumors, and a tumor-specific down-regulation of XAF1 was observed in 45% (9 of 20) of matched sets. Unlike XAF1, XIAP expression exhibited no detectable alteration in cancers. Whereas loss of heterozygosity within the XAF1 region or somatic mutations of the gene was not detected, expression of XAF1 transcript was reactivated in all nonexpressor cell lines after 5-aza-2-deoxycytidine treatment. The 5' upstream region of the XAF1 gene encompasses no gastric cell-rich region that rigorously satisfies the formal criteria for CpG islands. However, bisulfite DNA sequencing analysis for 34 CpG sites in the promoter region revealed a strong association between hypermethylation and gene silencing. Moreover, transcriptional silencing of XAF1 was tightly associated with hypermethylation of seven CpGs located in the 5' proximal region (nucleotides -23 to -234). Additionally, loss or abnormal reduction of XAF1 expression was found to inversely correlate with p53 mutations, suggesting that epigenetic inactivation of XAF1 and mutational alteration of p53 might be mutually exclusive events in gastric tumorigenesis. Collectively, our study suggests that epigenetic silencing of XAF1 by aberrant promoter methylation may contribute to the malignant progression of human gastric tumors.
 ...
PMID:Hypermethylation of XIAP-associated factor 1, a putative tumor suppressor gene from the 17p13.2 locus, in human gastric adenocarcinomas. 1461 97

Radioresistance markedly impairs the efficacy of tumor radiotherapy and may involve antiapoptotic signal transduction pathways that prevent radiation-induced cell death. A common cellular response to genotoxic stress induced by radiation is the activation of the nuclear factor kappa B (NF-kappaB). NF-kappaB activation in turn can lead to an inhibition of radiation-induced apoptotic cell death. Thus, inhibition of NF-kappaB activation is commonly regarded as an important strategy to abolish radioresistance. Among other compounds, the fungal metabolite gliotoxin (GT) has been reported to be a highly selective inhibitor of NF-kappaB activation. Indeed, low doses of GT were sufficient to significantly enhance radiation-induced apoptosis in HL-60 cells. However, this effect turned out to be largely independent of NF-kappaB activation since radiation of HL-60 cells with clinically relevant doses of radiation induced only a marginal increase in NF-kappaB activity, and selective inhibition of NF-kappaB by SN50 did not result in a marked enhancement of GT-induced apoptosis. GT induced activation of JNKs, cytochrome c release from the mitochondria and potently stimulated the caspase cascade inducing cleavage of caspases -9, -8, -7 and -3. Furthermore, cleavage of the antiapoptotic protein X-linked IAP and downregulation of the G2/M-specific IAP-family member survivin were observed during GT-induced apoptosis. Finally, the radiation-induced G2/M arrest was markedly reduced in GT-treated cells most likely due to the rapid induction of apoptosis. Our data demonstrate that various other pathways apart from the NF-kappaB signaling complex can sensitize tumor cells to radiation and propose a novel mechanism for radiosensitization by GT, the interference with the G2/M checkpoint that is important for repair of radiation-induced DNA damage in p53-deficient tumor cells.
 ...
PMID:Evidence for radiosensitizing by gliotoxin in HL-60 cells: implications for a role of NF-kappaB independent mechanisms. 1464 73

Overexpression of hypoxia inducible factor-1alpha (HIF-1alpha) in cancers has been correlated to a more aggressive tumor phenotype. We investigated the effect of HIF-1alpha knockout on the in vitro survival and death of human tongue squamous cell carcinomas (SCC-4 and SCC-9). Under normoxic condition, a basal level of HIF-1alpha protein was constitutively expressed in SCC-9 cells, albeit an undetectable level of HIF-1alpha messages. Exposure to hypoxia induced only a transient increase in mRNA transcript but a prolonged elevation of HIF-1alpha protein and its immediate downstream target gene product, VEGF. Under normoxic or hypoxic conditions, treatment of SCC-9 cells with AS-HIF-1alpha ODN suppressed both constitutive and hypoxia-induced HIF-1alpha expression at both mRNA and protein levels. Knockout of HIF-1alpha gene expression via either AS-HIF-1alpha ODN or siRNA (siRNAHIF-1alpha) treatment resulted in inhibition of cell proliferation and induced apoptosis in SCC-4 and SCC-9 cells. We also demonstrated that exposure of SCC-9 cells to hypoxia led to a time-dependent increase in the expression of bcl-2 and IAP-2, but not p53. The attenuated levels of bcl-2 and IAP-2, and the enhanced activity of caspase-3 after treatment with AS-HIF-1alpha ODN may contribute partly to the effects of HIF-1alpha blockade on SCC-9 cell death. Collectively, our data suggest that a constitutive or hypoxia-induced expression of HIF-1alpha in SCC-9 and SCC-4 cells is sufficient to confer target genes expression essential for tumor proliferation and survival. As a result, interfering with HIF-1alpha pathways by antisense or siRNA strategy may provide a therapeutic target for human tongue squamous cell carcinomas.
 ...
PMID:Treatment with siRNA and antisense oligonucleotides targeted to HIF-1alpha induced apoptosis in human tongue squamous cell carcinomas. 1530 Jul 96

Apoptosis can be induced in response to hypoxia. The severity of hypoxia determines whether cells become apoptotic or adapt to hypoxia and survive. A hypoxic environment devoid of nutrients prevents the cell undergoing energy dependent apoptosis and cells become necrotic. Apoptosis regulatory proteins are delicately balanced. In solid tumours, hypoxia is a common phenomenon. Cells adapt to this environmental stress, so that after repeated periods of hypoxia, selection for resistance to hypoxia induced apoptosis occurs. These resistant tumours probably have a more aggressive phenotype and may have decreased responsiveness to treatment. The key regulator of this process, hypoxia inducible factor 1 (HIF-1), can initiate apoptosis by inducing high concentrations of proapoptotic proteins, such as BNIP3, and can cause stabilisation of p53. However, during hypoxia, antiapoptotic proteins, such as IAP-2, can be induced, whereas the proapoptotic protein Bax can be downregulated. During hypoxia, an intricate balance exists between factors that induce or counteract apoptosis, or even stimulate proliferation. Understanding the regulation of apoptosis during hypoxia and the mechanisms of resistance to apoptosis might lead to more specific treatments for solid tumours.
 ...
PMID:The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis. 1545 50

HTLV-I associated adult T-cell leukemia (ATL) and HTLV-I-negative peripheral T-cell lymphomas are associated with poor prognosis. Using pharmacological concentrations of the proteasome inhibitor PS-341, we demonstrate inhibition of cell proliferation and induction of apoptosis in fresh ATL cells, HTLV-I transformed and HTLV-I-negative malignant T cells, while normal resting or activated T lymphocytes were resistant. Combination of PS-341 and doxorubicin or etoposide resulted in an additive growth inhibition. In HTLV-I-negative malignant cells, PS-341 treatment significantly downregulated the antiapoptotic protein X-IAP and to a lesser extent c-IAP-1 and bcl-X(L) and resulted in caspase-dependent apoptosis. In HTLV-I transformed cells, the inhibition of the proteasomal degradation of Tax by PS-341 likely explains the relative protection of HTLV-I infected cells against caspase-dependent apoptosis. PS-341 treatment of these cells stabilized IkappaBalpha, IkappaBbeta, IkappaBvarepsilon, p21, p27 and p53 proteins and selectively inhibited Rel-A DNA binding NF-kappaB complexes. In both HTLV-I-positive and -negative cells, PS-341 treatment induced ceramide accumulation that correlated with apoptosis. We conclude that PS-341 affects multiple pathways critical for the survival of HTLV-I-positive and -negative malignant T cells supporting a potential therapeutic role for PS-341 in both ATL and HTLV-I-negative T-cell lymphomas, whether alone or in combination with chemotherapy.
 ...
PMID:Efficacy and mechanism of action of the proteasome inhibitor PS-341 in T-cell lymphomas and HTLV-I associated adult T-cell leukemia/lymphoma. 1554 32

The pharmacological sciences are taking advantage of recent discoveries that have defined the molecular pathways governing apoptosis. These signaling cascades are frequently inactivated or distorted by mutations in cancer cells. Peptides derived from critical interaction, phosphorylation, or cleavage sites are the preferred leads (starting points) for the development of new drugs. In this review we summarize recent peptide-based approaches that target MDM2, p53, NF-kappaB, ErbB2, MAPK, as well as Smac/DIABLO, IAP BIR domains, and Bcl-2 interaction domains, with a specific focus on the BH3 domain. Separate parts of the review deal with proteasome inhibitors, integrin-derived peptides, and molecules that are being tested for tumor-selective delivery of anticancer drugs ("magic bullet" approach). The proteasome inhibitors and integrin-derived peptides show a variety of effects, targeting not only tumor growth, but also angiogenesis, metastasizing potential, and other cancer cell functions. The last part of this review describes approaches that use specific properties (surface receptors, increased enzymatic activities) of cancer cells in order to target them specifically. These new generations of anticancer drugs provide the foundations for therapies with fewer side effects and higher efficacy.
 ...
PMID:Anti-tumor chemotherapy utilizing peptide-based approaches--apoptotic pathways, kinases, and proteasome as targets. 1576 76

We have previously demonstrated that a UVC-induced tumorigenic HeLa x skin fibroblast cell line could be induced to form a more normal phenotypic state ('reversion'), including loss of IAP expression. We have now used the loss of IAP expression to monitor the enhancement of this reversion in the cervical cancer cell line, HeLa, by a traditional Chinese herb medicine (TCM), Yigan Kang (YGK). IAP level decreased, and the reversion frequency increased, in a dose-dependent manner at concentrations of YGK of more than 10 mg. YGK significantly repressed E6/E7 oncogenes at the transcriptional level, with subsequent reactivation of p53 and p21 expression (P<0.01). YGK had little effect on the cell cycle of HeLa cells and slightly increased the apoptotic cell death between 20 and 40 mg. In vivo, tumorigenicity studies were performed using six different animal experimental protocols, which demonstrated that YGK was effective at inducing reversion of the tumorigenic phenotype, with YGK-treated HeLa cells showing much less aggressive tumor growth than untreated cells. YGK may raise the possibility of the continuing management of some cancers as a chronic condition in which the malignant behavior of the tumor cells is constrained.
 ...
PMID:Correction of malignant behavior of tumor cells by traditional Chinese herb medicine through a restoration of p53. 1588 24

To examine the roles of a short form of p53 in the regulation of apoptosis in chicken lymphoblastoid tumor cell lines derived from Marek's disease (MD) and avian leukosis (AL), the expressions of the p53 proteins were analyzed in these cell lines in which apoptosis was chemically induced. In MSB1-O derived from MD, the expression of a 40 kDa protein of p53 was decreased and that of a 32 kDa protein, a short form of p53, was increased during apoptosis induced by actinomycin D. In 1104B1 derived from AL, the expressions of 42 and 32 kDa of p53 were increased during the apoptosis. The short form of p53 was undetectable in these cell lines when apoptosis was blocked by the pretreatment with endonuclease inhibitor, Zn2+, protease inhibitors, TPCK and TLCK, or caspase inhibitor, Z-VAD-FMK. In the transcriptional level, the expressions of bcl-2 and IAP were decreased in these cell lines during actinomycin D-induced apoptosis, but no change was detected in the expression level of p53. These results suggest that, in these chicken tumors, the short form of p53 could play a role in the initiation of apoptosis induced by the chemotherapeutic compound, and that the regulation of its expression may be important for the maintenance of transformation status.
 ...
PMID:The presence of a short form of p53 in chicken lymphoblastoid cell lines during apoptosis. 1682 Jul 12

Here I discuss how the same mechanism--namely, inhibition of transcription during mitosis--can explain (1) apoptosis during mitotic arrest, (2) mitotic slippage, (3) G1 arrest after mitotic slippage and (4) secondary apoptosis after mitotic slippage. In fact, during mitotic arrest transcription is absent, thus depleting those short-lived proteins that have short-lived RNAs. Depletion of anti-apoptotic proteins (IAP, Mcl-1) can trigger apoptosis during prolonged mitotic arrest (apoptosis I). On the other hand, simultaneous depletion of cyclin B allows a cell to exit mitosis without division (mitotic slippage), thus preventing apoptosis I. Depletion of Mdm-2 causes accumulation of p53 during mitotic arrest. If a cell exits mitosis, transcription resumes. In turn the accumulated p53 induces p21 and Bax (and other pro-apoptotic proteins). In turn p21 can cause G1 arrest, whereas Bax can cause apoptosis II. Also, I discuss that mitotic depletion of short-lived proteins collaborates with mitotic phosphorylation of p53, Bcl-2 and BclxL. Finally this article clarifies notions of apoptosis-prone and -reluctant cells and mitotic catastrophe.
 ...
PMID:Mitotic arrest and cell fate: why and how mitotic inhibition of transcription drives mutually exclusive events. 1724 9


<< Previous 1 2 3 4 5 6 Next >>