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)

We and other workers found markedly increased levels of proinflammatory cytokines and apoptosis-related proteins in parkinsonian brain. Although the pathogenesis of Parkinson's disease (PD) remains enigmatic, apoptosis might be involved in the degeneration of dopaminergic neurons in PD. To investigate the possible presence of other inflammatory cytokines and/or apoptosis-related protein, the levels of p53 protein, interferon-gamma, and NF-kappaB were measured for the first time in the brain (substantia nigra, caudate nucleus, putamen, cerebellum, and frontal cortex) from control and parkinsonian patients by a highly sensitive sandwich enzyme-linked immunosorbent assay. The p53 protein level in the caudate nucleus was significantly higher in parkinsonian patients than in controls (P<0.05), whereas this protein in the substantia nigra, putamen, and cerebral cortex showed no significant difference between parkinsonian and control subjects. The interferon-gamma level was significantly higher in the nigrostriatal dopaminergic regions (substantia nigra, caudate nucleus, and putamen) in parkinsonian patients than in the controls (P<0.05), but was not significantly different in the cerebellum or frontal cortex between the two groups. In accordance with previous immunohistochemical analysis, the NF-kappaB level in the nigrostriatal dopaminergic regions was significantly higher in parkinsonian patients than in the controls (P<0.05). These data suggest that the significant increase in the levels of p53 protein, interferon-gamma, and NF-kappaB reflect apoptosis and the inflammatory state in the parkinsonian brain and that their elevation is involved in the degeneration of the nigrostriatal dopaminergic neurons.
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PMID:p53 protein, interferon-gamma, and NF-kappaB levels are elevated in the parkinsonian brain. 1719 47

Many cancers are chemotherapy-resistant. Chemotherapy combined with immunotherapy offers a potential avenue for the treatment of chemotherapy-resistant cancers. In this study, we investigated the apoptotic pathways induced by combined interferon-gamma/adriamycin treatment in Hep G2 cells. Our data showed that Hep G2 cells treated with combined interferon-gamma/adriamycin enhanced cell apoptosis in comparison with that of cells treated with adriamycin. Interferon-y increased TNFR-1, CSE1L/CAS (cellular apoptosis susceptibility protein), Bax, and Bad levels. Adriamycin increased p53 and Bax, but not TNFR- 1 and CAS levels. Interferon-y did not increase p53 accumulation; nevertheless it enhanced adriamycin-induced p53 accumulation. Overexpression of IRF-1 augmented the combined interferon-gamma/adriamycin-induced p53 accumulation. Interferon-gamma co-treatment increased the stability of p53 protein induced by adriamycin. Our data suggest that TNF-gamma may greatly enhance the combined interferon-gamma/chemotherapeutic drug-induced apoptosis of cancers. Our findings also indicate that CAS, TN-FR-1, p53, Bax, and Bad may be the targets for the interferon-y-based chemo-immunotherapy of the chemotherapy-resistant cancers.
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PMID:Synergic CSE1L/CAS, TNFR-1, and p53 apoptotic pathways in combined interferon-gamma/adriamycin-induced apoptosis of Hep G2 hepatoma cells. 1755 Jan 37

Growth and development of placentas in all pregnancy periods and that of fetuses in late pregnancy were inhibited after administration of interferon-gamma (IFN-gamma). Apoptosis can be detected by TUNEL at the maternal-fetal interface during normal rat pregnancy. Apoptosis locations at the maternal-fetal interface changed according to the period of pregnancy. The results of immunohistochemistry and the DNA ladder assay showed that IFN-gamma could promote the apoptosis levels during the entire pregnancy, but it did not change the apoptosis locations. IFN regulatory factor-1 (IRF-1), FasL, and p53 expressions were modulated by IFN-gamma during the entire pregnancy. In vitro cell proliferation assay indicated that IFN-gamma could inhibit proliferation of human cytotrophoblast cells, and flow assay showed that this effect was mainly due to apoptosis induction. TUNEL and Hoechst staining also showed that IFN-gamma could induce apoptosis of human cytotrophoblast cells. Expression of IRF-1 was induced and expression of active caspase-3 was promoted by IFN-gamma treatment, but IFN-gamma did not affect the expression of IFNGR and p53.
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PMID:IFN-gamma promotes apoptosis of the uterus and placenta in pregnant rat and human cytotrophoblast cells. 1765 Oct 18

The aim of this study was to understand the role of tumor progression in the growth properties of tumor cells and their susceptibility to the cytotoxicity of chemotherapeutic drugs. A murine transplantable T cell lymphoma of spontaneous origin, designated as Dalton's lymphoma, was used as a model tumor for this investigation. Tumor cells were harvested from the early (5 days after tumor transplantation) and late tumor-bearing stages (17 days after tumor transplantation), with or without in-vivo administration of the chemotherapeutic drugs, cisplatin or doxorubicin. Tumor cells harvested at the late tumor-bearing stages showed a higher proliferative ability in vitro. Tumor progression was found to be associated with a decline in the tumor cytotoxicity of the chemotherapeutic drugs. Similar results were also obtained when tumor cells were cultured at low (10(5) cells/ml) and high (10(9) cells/ml) cell densities in vitro in medium alone or in one containing the chemotherapeutic drugs. An increase in the expression of heat shock protein (Hsp70), vascular endothelial growth factor, interleukin-2 receptor and interleukin-2 proteins along with an inhibition in the expression of caspase-activated DNase and p53 proteins was observed during the late tumor-bearing stage and also in the Dalton's lymphoma cells when cultured in vitro at a higher cell density. The ascitic fluid obtained from the late tumor-bearing stage and the culture supernatant of tumor cells incubated in vitro at high cell density showed high levels of cell growth-regulating cytokines: interleukin-1, interleukin-2, interferon-gamma, vascular endothelial growth factor, tumor growth factor-beta and interleukin-10. In-vivo administration of cisplatin in tumor-bearing mice at the late tumor-bearing stage did not alter the level of these cytokines in the ascitic fluid. In view of the results of this investigation, it is suggested that under high cellular density-associated environmental conditions the tumor cells alter their growth properties depending on an alteration in the expression of cell growth and apoptosis-regulating proteins. Tumor cells, thus, switch to a high level of proliferation, which renders them resistant to the cytotoxicity of chemotherapeutic drugs.
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PMID:Effect of high cell density on the growth properties of tumor cells: a role in tumor cytotoxicity of chemotherapeutic drugs. 1789 12

The proteasome constitutes the central proteolytic component of the highly conserved ubiquitin-proteasome system, which is required for the maintenance and regulation of basic cellular processes, including differentiation, proliferation, cell cycling, gene transcription and apoptosis. Here we show that inhibition of proteasomal proteolytic activity by the proteasome inhibitors bortezomib and lactacystin suppresses essential immune functions of human CD4(+) T cells activated by allogeneic dendritic cells (DCs). In activated CD4(+) T cells, proteasome inhibition induces apoptosis accompanied by rapid accumulation and stabilization of the tumour suppressor protein p53. Activated CD4(+) T cells surviving proteasome inhibition undergo inhibition of proliferation by induction of G(1) phase cell-cycle arrest. Induction of G(1) arrest is accompanied by the accumulation of cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(KIP1) and the disappearance of cyclin A, cyclin D2 and proliferating cell nuclear antigen, proteins known to regulate G(1) to S phase cell-cycle transitions. Expression of the activation-associated cell surface receptors CD25, CD28, CD120b and CD134 as well as production of interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), interleukin-4 (IL-4) and IL-5 is suppressed in response to proteasome inhibition in CD4(+) T cells activated by DCs. Expression of CD25, IFN-gamma, TNF-alpha, IL-4 and IL-5 is known to be mediated by the transcriptional activity of nuclear factor of activated T cells (NFAT), and we show here that proteasome inhibition suppresses activation and nuclear translocation of NFATc2 in activated CD4(+) T cells. Thus, the proteasome is required for essential immune functions of activated CD4(+) T cells and can be defined as a molecular target for the suppression of deregulated and unwanted T-cell-mediated immune responses.
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PMID:Proteasome inhibition suppresses essential immune functions of human CD4+ T cells. 1821 57

Several important cultured marine fish are highly susceptible to an ectoparasitic condition known as amoebic gill disease (AGD). In AGD-affected fish, modulation of IL-1beta, p53 and p53-regulated transcripts is restricted to the (multi)focal AGD-associated gill lesions. To determine whether this lesion-restricted modulation of transcripts occurs on a transcriptome-wide scale and to identify mechanisms that underpin the susceptibility of fish to AGD, we compared the transcriptome of AGD lesions with "normal" tissue from AGD-affected and healthy individuals. Global gene expression profiling using a 16K salmonid microarray, revealed a total of 176 significantly regulated annotated features and of those, the modulation of 99 (56%) was lesion-restricted. Annotated transcripts were classified according to functional gene ontology. Within the immune response category, transcripts were almost universally down-regulated. In AGD-affected tissue, significant, coordinated down-regulation of the major histocompatibility complex class I (MHC I) pathway-related genes occurred during the later stages of infection and appeared to be mediated by down-regulation of interferon-regulatory factor (IRF)-1, independent of interferon-alpha, interferon-gamma and IRF-2 expression. Within this micro-environment, suppression of the MHC I and possibly the MHC II pathways may inhibit the development of acquired immunity and could explain the unusually high susceptibility of Atlantic salmon to AGD.
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PMID:Coordinated down-regulation of the antigen processing machinery in the gills of amoebic gill disease-affected Atlantic salmon (Salmo salar L.). 1828 2

Previously we have demonstrated that in-vivo growth of a murine T-cell lymphoma of spontaneous origin designated as Dalton's lymphoma (DL) shows sex dimorphism (J Rep Immunol 2005; 65:17-32). It remained unclear, however, if DL growth in female and male tumor-bearing hosts also shows a sex-dependent differential susceptibility to the antitumor action of cancer chemotherapeutic drugs. In this study we have demonstrated that in-vivo administration of anticancer drugs: cisplatin or doxorubicin to the DL-bearing host results in a sex-dependent different antitumor activity of the drugs, causing a sex dimorphism in the antitumor response of the drugs with respect to tumor growth inhibition. The antitumor effect of both drugs was found to be better in male tumor-bearing hosts compared with female tumor-bearing hosts. The study also shows that DL cells obtained from male and female tumor-bearing hosts display a differential growth response to following treatment with cisplatin in vitro. Cell growth regulatory proteins: interleukin-2, interferon-gamma, tumor growth factor-beta, p53, caspase-activated DNase, vascular endothelial growth factor, and interleukin-2 receptor were found to be involved in the observed sex-specific response of DL cells to the antitumor action of cisplatin. Moreover, gonadal hormones: androgen, estrogen, and their specific antagonists flutamide and tamoxifen were found to directly modulate the cytotoxicity of cisplatin against DL cells in vitro. This study, therefore, suggests for the first time that the efficacy of cancer chemotherapeutic may vary in a sex-specific manner in a host-bearing a T-cell lymphoma.
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PMID:Sex dimorphism in antitumor response of chemotherapeutic drug cisplatin in a murine host-bearing a T-cell lymphoma. 1852 17

Cytokine genes are targets of multiple epigenetic mechanisms in T lymphocytes. 5-azacytidine (5-azaC) is a nucleoside-based DNA methyltransferase inhibitor that induces demethylation and gene reactivation. In the current study, we analyzed the effect of 5-azaC in T-cell function and observed that 5-azaC inhibits T-cell proliferation and activation, blocking cell cycle in the G(0) to G(1) phase and decreasing the production of proinflammatory cytokines such as tumor necrosis factor-alpha and interferon-gamma. This effect was not attributable to a proapoptotic effect of the drug but to the down-regulation of genes involved in T-cell cycle progression and activation such as CCNG2, MTCP1, CD58, and ADK and up-regulation of genes that induce cell-growth arrest, such as DCUN1D2, U2AF2, GADD45B, or p53. A longer exposure to the drug leads to demethylation of FOXP3 promoter, overexpression of FOXP3, and expansion of regulatory T cells. Finally, the administration of 5-azaC after transplantation prevented the development of graft-versus-host disease, leading to a significant increase in survival in a fully mismatched bone marrow transplantation mouse model. In conclusion, the current study shows the effect of 5-azaC in T lymphocytes and illustrates its role in the allogeneic transplantation setting as an immunomodulatory drug, describing new pathways that must be explored to prevent graft-versus-host disease.
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PMID:Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting. 1988 73

Altered glial function may contribute to the initiation or progression of neuronal death in neurodegenerative diseases. Thus, modulation of astrocyte death may be essential for preventing pathological processes in the CNS. In recent years, metabotropic glutamate receptor (mGluR) activation has emerged as a key target for neuroprotection. We investigated the effect of subtype 3 mGluR (mGluR3) activation on nitric oxide (NO)-induced astroglial death. A mGluR3 selective agonist, LY379268, reduced inducible NO synthase expression and NO release induced by bacterial lipopolysaccharide and interferon-gamma in cultured rat astrocytes. In turn, a NO donor (diethylenetriamine/NO) induced apoptotic-like death in cultured astrocytes, which showed apoptotic morphology and DNA fragmentation, but no caspase 3 activation. LY379268 prevented astrocyte death induced by NO exposure, which correlates with a reduction in: phosphatidylserine externalization, p53 and Bax activation and mitochondrial permeability. The reported effects of LY379268 were prevented by the mGluR3 antagonist (s)-alpha-ethylglutamic acid. All together, these findings show the protective effect of mGluR3 activation on astroglial death and provide further evidence of a role of these receptors in preventing CNS injury triggered by several inflammatory processes associated with dysregulated NO production.
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PMID:Metabotropic glutamate receptor 3 activation prevents nitric oxide-induced death in cultured rat astrocytes. 2008 13

Apoptosis has been implicated as an important mediator of immunosuppression associated with a depleted nutritional state. Since a number of cytokines are likely to influence the rate of apoptosis, we determined the effect of interferon-gamma (IFN-gamma) on apoptosis of macrophages in serum/amino acid deprived cell culture conditions. IFN-gamma further increased the rate of apoptosis compared to trophically stressed macrophages. In addition, we showed that enhancement of apoptosis by IFN-gamma is caused by a decrease in mitochondrial membrane potential due to upregulation of p53 and Bax and down-regulation of Bcl-xL. Moreover, we found that IFN-gamma increases caspase-3 activity that had been induced by serum/amino acid depletion, and that JAK1 signaling is involved in capase-3 activation and in the enhancement of apoptosis by IFN-gamma.
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PMID:Interferon-gamma enhances the apoptosis of macrophages under trophic stress through activation of p53 and the JAK1 pathway. 2019 30


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