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)

Tumor necrosis factor-related apoptosis-inducing ligand or Apo 2 ligand (TRAIL/Apo2L) is a member of the tumor necrosis factor (TNF) family of ligands capable of initiating apoptosis through engagement of its death receptors. TRAIL selectively induces apoptosis of a variety of tumor cells and transformed cells, but not most normal cells, and therefore has garnered intense interest as a promising agent for cancer therapy. TRAIL is expressed on different cells of the immune system and plays a role in both T-cell- and natural killer cell-mediated tumor surveillance and suppression of suppressing tumor metastasis. Some mismatch-repair-deficient tumors evade TRAIL-induced apoptosis and acquire TRAIL resistance through different mechanisms. Death receptors, members of the TNF receptor family, signal apoptosis independently of the p53 tumor-suppressor gene. TRAIL treatment in combination with chemo- or radiotherapy enhances TRAIL sensitivity or reverses TRAIL resistance by regulating the downstream effectors. Efforts to identify agents that activate death receptors or block specific effectors may improve therapeutic design. In this review, we summarize recent insights into the apoptosis-signaling pathways stimulated by TRAIL, present our current understanding of the physiological role of this ligand and the potential of its application for cancer therapy and prevention.
 ...
PMID:TRAIL and apoptosis induction by TNF-family death receptors. 1463 24

TRAIL is a cytokine that can induce tumor-specific apoptosis through its specific death receptors (DR4 and DR5) and p53 has been proven to increase the expression of death receptors. To examine their interaction in tumor suppression, p53 and TRAIL genes were inserted in recombinant adenovirus vectors and transferred simultaneously into non-small cell lung cancer cell lines (NCI-H157, NCI-H358, NCI-H460 and A549). Western blot assay demonstrated production of TRAIL protein in NCI-H157 and A549 cell lines. Increased expressions of DR4 and DR5 of NCI-H157 and DR4 of A549 after p53 overexpression were confirmed by flow cytometry. p53 or TRAIL gene transfer increased sub-G1 fraction in cell cycle analysis and inhibited the tumor growth dose-dependently and the degree was potentiated by co-transfer. But isobologram analysis indicated an additive effect. Together, these data indicate that p53 and TRAIL interact additively on tumor apoptosis despite theoretical synergism.
 ...
PMID:Additive effect of TRAIL and p53 gene transfer on apoptosis of human lung cancer cell lines. 1465 92

Survivin is a member of the inhibitor of apoptosis protein (IAP) family that has been implicated in both apoptosis inhibition and cell cycle control. Recently, Survivin has attracted growing attention because of its tumor-specific expression and potential applications in tumor therapy. However, its inhibitory mechanism and subcellular localization remain controversial. Here, we report a novel Survivin mutant Surv-D53A, which displays a function opposite to Survivin and a distinctive subcellular distribution compared with its wild-type counterpart. Surv-D53A was shown to induce apoptosis in a p53-independent manner, indicating that tumor suppressor p53 is not involved in its apoptosis pathway. Surv-D53A was shown to markedly sensitize apoptosis induced by TRAIL, doxorubicin, and RIP3. We also demonstrated that similar to wild-type Survivin, Surv-D53A was localized in cytoplasm in interphase and to midbody at telophase. However, it fails to colocalize in chromosomes with Aurora-B in metaphase as wt-Survivin. Surv-D53A mutant is less stable than wt-Survivin and is degraded more rapidly by ubiquitin-proteasome pathway. Additionally, we found that Surv-D53A interacts with wt-Survivin to form heterodimer or with itself to form mutant homodimer, which may account for the loss of its antiapoptotic function. Finally, unlike Survivin*Survivin, neither Surv-D53A*Survivin nor Surv-D53A*Surv-D53A is able to bind to Smac/DIABLO, which may explain the underlying mechanism for its abolishment of antiapoptotic activity of Survivin.
 ...
PMID:A single amino acid change (Asp 53 --> Ala53) converts Survivin from anti-apoptotic to pro-apoptotic. 1469 67

Intracellular oxidative stress is a dynamic situation characterized by the accumulation of reactive oxygen metabolites, such as hydrogen peroxide. This is traditionally associated with both macromolecular damage and adaptive changes in gene expression, aimed at preventing cellular demise. However, the overall extent of such genetic changes is not well characterized. Here we present a comprehensive analysis of altered mRNA profiles in human A549 type II lung epithelial cells in response to hydrogen peroxide, at concentrations failing to induce necrotic toxicity. The results of an Affymetrix-based screen of the steady-state levels of mRNAs for several thousand genes revealed a complex pattern of transcriptional and/or posttranscriptional response to oxidative stress, which can be functionally related to both the oxidation and repair of damaged DNA, the induction and permanency of cell cycle arrest, and caspase-3 activation. Many of the genetic events can be related to activation of the p53/p21 pathway, but many other novel inductions and suppressions were detected, revealing the intricacy of the response. The data also disclosed a potential interaction between hydrogen peroxide treatment and increased sensitivity to cell killing by TRAIL, which could be functionally confirmed at the level of induction of caspase-3 activity.
 ...
PMID:The transcriptosomal response of human A549 lung cells to a hydrogen peroxide-generating system: relationship to DNA damage, cell cycle arrest, and caspase activation. 1501 73

Herpes simplex virus (HSV) can perturb the function of dendritic cells (DC). The underlying mechanisms are not defined. In the present study we demonstrate that HSV induces a substantial number of immature DC to undergo apoptosis by a mechanism involving caspase-8. We found strongly enhanced expression of TNF-alpha and TRAIL but not CD95 ligand after HSV infection. Blocking experiments suggested that these classical death ligands contribute to HSV-induced cell death of immature DC. Because uninfected DC are resistant to the apoptosis-inducing effect of death ligands we searched for a viral "competence-to-die" signal. Further analysis revealed that HSV-infected immature DC down-regulate long cellular FLICE-inhibitory protein (c-FLIP(L)) and up-regulate p53 whereas other apoptosis-regulating proteins (e.g. Bcl-2, RIP, FADD) were not affected. Down-regulation of c-FLIP(L) was not due to diminished gene transcription or reduced mRNA stability because the level of c-FLIP(L) mRNA was rather increased. Moreover, down-regulation of c-FLIP(L) could not be blocked by the anti-herpetic drug acyclovir. Finally, the underlying mechanism was also operative in human umbilical vein endothelial cells, which show a similar susceptibility to HSV infection and strength of c-FLIP(L) expression. These results suggest that HSV targets c-FLIP(L) protein in immature DC and other infectable cells to disrupt their function.
 ...
PMID:Frontline: Induction of apoptosis and modulation of c-FLIPL and p53 in immature dendritic cells infected with herpes simplex virus. 1504 4

TRAIL primarily induces apoptosis in cancer cells but not in normal cells. However, some TRAIL-resistant cancer cell lines have recently been discovered. Ionizing radiation may enhance the apoptosis inducing potential of TRAIL in sensitive cells, and sensitize TRAIL-resistant cancer cells. We assessed the influence of sequential treatment of irradiation followed by TRAIL on intracellular mechanisms of apoptosis of breast tumor cells in vitro and on tumor regression in xenografted athymic nude mice. Irradiation augmented TRAIL-induced apoptosis in breast cancer cells through up-regulation of DR5, and subsequent activation of caspases-3, -8 and -9. Inhibition of p53 by siRNA abrogated irradiation-induced DR5 expression, suggesting the requirement of p53 for DR5 induction. The pretreatment of cells with irradiation followed by TRAIL significantly induced more apoptosis than single agent alone or concurrent treatment with irradiation and TRAIL. The sequential treatment of xenografted mice with irradiation followed by TRAIL-induced apoptosis through caspase-3 activation, completely eradicated the established breast tumors, and enhanced survival of mice without detectable toxicity to normal tissues. The sequential treatment with irradiation followed by TRAIL provides an approach to enhance therapeutic potential of TRAIL. Thus, irradiation can be combined with TRAIL in breast cancer therapy.
 ...
PMID:The sequential treatment with ionizing radiation followed by TRAIL/Apo-2L reduces tumor growth and induces apoptosis of breast tumor xenografts in nude mice. 1506 34

The genetic concept of synthetic lethality provides a framework for identifying genotype-selective anticancer agents. In this approach, changes in cellular physiology that arise as a consequence of oncogene activation or tumor suppressor gene loss, rather than oncoproteins themselves, are targeted to achieve tumor selectivity. Here we show that agonists of the TRAIL death receptor DR5 potently induce apoptosis in human cells overexpressing the MYC oncogene, both in vitro and as tumor xenografts in vivo. MYC sensitizes cells to DR5 in a p53-independent manner by upregulating DR5 cell surface levels and stimulating autocatalytic processing of procaspase-8. These results identify a novel mechanism by which MYC sensitizes cells to apoptosis and validate DR5 agonists as potential MYC-selective cancer therapeutics.
 ...
PMID:Synthetic lethal targeting of MYC by activation of the DR5 death receptor pathway. 1514 57

TPCK is widely used as an inhibitor of chymotrypsin-like proteases but has recently been identified as an inhibitor of the PDK1/Akt pathway. In this study, we show that TPCK inhibits TRAIL-induced caspase activity but potentiates wortmannin-dependent caspase activity in prostatic carcinoma cell lines. The inhibitory activity of TPCK was found to be death ligand-specific since TPCK inhibits TRAIL-mediated caspase activity but does not affect Fas-induced caspase activity. Our data also show that impaired TRAIL-DISC formation in the presence of TPCK is responsible for caspase inhibition. Further, TPCK induces p53 expression and inhibits the PDK1/Akt pathway resulting in BAD dephosphorylation, and the release of cytochrome c and Smac/DIABLO from mitochondria. TPCK also selectively decreases the levels of androgen receptor and caspase-2 whereas it does not change the levels of other proteins (caspases-3, -7, -8, -9; heat shock proteins 27, 70, 90). Finally, TPCK-induced degradation of caspase-2 is protected by Bcl-2 overexpression, apparently by an adapter protein since direct interaction between caspase-2 and Bcl-2 was not detected. Together, these features suggest that TPCK could be used as a therapeutic agent for treatment of those tumor cells that are resistant to ligand-induced treatment because of aberrant signaling pathways downstream of the DISC.
 ...
PMID:Multiple effects of N-alpha-tosyl-L-phenylalanyl chloromethyl ketone (TPCK) on apoptotic pathways in human prostatic carcinoma cell lines. 1519 50

Unlike conventional cancer therapeutics, death receptor ligands trigger tumor cell apoptosis independently of the p53 tumor suppressor gene, which frequently is inactivated in cancer. The death receptor ligand Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) offers promising therapeutic potential based on its ability to induce apoptosis in various cancer cell lines with little toxicity toward normal cells. Moreover, Apo2L/TRAIL displays single-agent activity and cooperates with chemotherapy or radiotherapy in a variety of tumor xenograft mouse models. Thus, Apo2L/TRAIL might be effective against tumors that have acquired resistance to conventional therapy, and could augment the efficacy of current treatment in a wide spectrum of cancers.
 ...
PMID:Targeting death receptors in cancer with Apo2L/TRAIL. 1525 Nov 25

Several natural proteins, including the cellular protein TRAIL and the viral proteins E4orf4 and Apoptin, have been found to exert a tumor-preferential apoptotic activity. These molecules are potential anti-cancer agents with direct clinical applications. Also very intriguing is their possible utility as sensors of the tumorigenic phenotype. Here, we focus on Apoptin, discussing recent research that has greatly increased our understanding of its tumor-specific processes. Apoptin, which kills tumor cells in a p53- and Bcl-2-independent, caspase-dependent manner, is biologically active as a highly stable, multimeric complex consisting of 30 to 40 monomers that form distinct superstructures upon binding cooperatively to DNA. In tumor cells, Apoptin is imported into the nucleus prior to the induction of apoptosis; this contrasts with the situation in primary or low-passage normal cell cultures where nuclear translocation of Apoptin is rare and inefficient. Apoptin contains two autonomous death-inducing domains, both of which exhibit a strong correlation between nuclear localization and killing activity. Nevertheless, forced nuclear localization of Apoptin in normal cells is insufficient to allow induction of apoptosis, indicating that another activation step particular to the tumor or transformed state is required. Indeed, a kinase activity present in cancer cells but negligible in normal cells was recently found to regulate the activity of Apoptin by phosphorylation. However, in normal cells, Apoptin can be activated by transient transforming signals conferred by ectopically expressed SV40 LT antigen, which rapidly induces Apoptin's phosphorylation, nuclear accumulation and the ability to induce apoptosis. The region on LT responsible for conferring this effect has been mapped to the N-terminal J domain. In normal cells that do not receive such signals, Apoptin becomes aggregated, epitope-shielded and is eventually degraded in the cytoplasm. Finally, Apoptin interacts with various partners of the human proteome including DEDAF, Nmi and Hippi, which may help to regulate either Apoptin's activation or execution processes. Taken together, these recent advances illustrate that elucidating the mechanism of Apoptin-induced apoptosis can lead to the discovery of novel tumor-specific pathways that may be exploitable as anti-cancer drug targets.
 ...
PMID:The viral death effector Apoptin reveals tumor-specific processes. 1525 63


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>