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)

Chemotherapeutic agents and gamma-irradiation used in the treatment of brain tumors, the most common solid tumors of childhood, have been shown to act primarily by inducing apoptosis. Here, we report that activation of the CD95 pathway was involved in drug- and gamma-irradiation-induced apoptosis of medulloblastoma and glioblastoma cells. Upon treatment CD95 ligand (CD95-L) was induced that stimulated the CD95 pathway by crosslinking CD95 via an autocrine/paracrine loop. Blocking CD95-L/receptor interaction using F(ab')2 anti-CD95 antibody fragments strongly reduced apoptosis. Apoptosis depended on activation of caspases (interleukin 1beta-converting enzyme/Ced-3 like proteases) as it was almost completely abrograted by the broad range caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone. Apoptosis was mediated by cleavage of the receptor proximal caspase FLICE/MACH (caspase-8) and the downstream caspase CPP32 (caspase-3, Apopain) resulting in cleavage of the prototype caspase substrate PARP. Moreover, CD95 was upregulated in wild-type p53 cells thereby increasing responsiveness towards CD95 triggering. Since activation of the CD95 system upon treatment was also found in primary medulloblastoma cells ex vivo, these findings may have implications to define chemosensitivity and to develop novel therapeutic strategies in the management of malignant brain tumors.
 ...
PMID:Activation of the CD95 (APO-1/Fas) pathway in drug- and gamma-irradiation-induced apoptosis of brain tumor cells. 1020 87

1. Activation of macrophages with lipopolysaccharide (LPS) and low doses of interferon-gamma (IFN-gamma) induced apoptotic death through a nitric oxide-dependent pathway. 2. Treatment of cells with the immunosuppressors cyclosporin A (CsA) or FK506 inhibited the activation-dependent apoptosis. 3. These drugs decreased the up-regulation of p53 and Bax characteristic of activated macrophages. Moreover, incubation of activated macrophages with CsA and FK506 contributed to maintain higher levels of Bcl-2 than in LPS/IFN-gamma treated cells. 4. The inhibition of apoptosis exerted by CsA and FK506 in macrophages was also observed when cell death was induced by treatment with chemical nitric oxide donors. 5. Incubation of macrophages with LPS/IFN-gamma barely affected caspase-1 but promoted an important activation of caspase-3. Both CsA and FK506 inhibited pathways leading to caspase-3 activation. Moreover, the cleavage of poly(ADP-ribose) polymerase, a well established caspase substrate, was reduced by these immunosuppressive drugs. 6. CsA and FK506 reduced the release of cytochrome c to the cytosol and the activation of caspase-3 in cells treated with nitric oxide donors. 7. These results indicate that CsA and FK506 protect macrophages from nitric oxide-dependent apoptosis and suggest a contribution of the macrophage to innate immunity under conditions of immunosuppression of the host.
 ...
PMID:Protective effect of cyclosporin A and FK506 from nitric oxide-dependent apoptosis in activated macrophages. 1020 1

We performed balloon injury in the rat carotid artery and identified intimal thickening after injury. Balloon-injured carotid arteries showed maximum thickness of the neointima on the 14th day before complete endothelial cell regeneration. In this lesion we identified apoptosis of vascular smooth muscle cells (VSMCs) by in situ DNA labelling and electron microscopy in the neointima on the 14th day after injury. mRNA expression levels of bcl-2, bax, bcl-x, p53 and caspase-1 were determined by the reverse transcriptase-polymerase chain reaction method both in injured and uninjured carotid arteries. Neither bcl-2 nor bcl-xl mRNA expression was detected in either injured or uninjured arteries, whereas bax and p53 mRNA expression was identified and their mRNA levels were not altered after balloon injury. In contrast, both bcl-xs and caspase-1 mRNA was detected and was markedly induced only in the injured carotid artery. Positive staining for immunoreactive Bcl-x was observed specifically in the injured arterial wall and co-localized with positive staining of nuclei identified by in situ DNA labelling. We conclude that two opposite cellular responses, VSMC proliferation and apoptosis, exist together in the neointima of the rat carotid artery after balloon injury, and selective induction of Bcl-xs expression is a key regulator of VSMC apoptosis in the process of vascular remodelling.
 ...
PMID:Apoptosis and Bcl-xs in the intimal thickening of balloon-injured carotid arteries. 1033 66

The dihydrochalcone phloretin induced apoptosis in B16 mouse melanoma 4A5 cells and HL60 human leukemia cells. Phloretin was suggested to induce apoptosis in B16 cells mainly through the inhibition of glucose transmembrane transport. The phloretin-induced apoptosis in B16 cells was inhibited by actinomycin D, Ac-YVAD-CHO caspase-1-like inhibitor, and Ac-DEVD-CHO caspase-3-like inhibitor. During the induction of apoptosis by phloretin, the expression of Bax protein in B16 cells increased and the levels of p53, Bcl-2, and Bcl-XL proteins did not change. Our results suggested that phloretin induced apoptosis through the promotion of Bax protein expression and caspases activation. On the other hand, phloretin may induce apoptosis in HL60 cells through the inhibition of protein kinase C activity because phloretin inhibited protein kinase C activity in HL60 cells more than that in B16 cells. The phloretin induced-apoptosis in HL60 cells was not inhibited by actinomycin D and the caspase-1-like inhibitor, but slightly inhibited by the caspase-3-like inhibitor. Phloretin reduced the level of caspase 3 protein in HL60 cells, but not the level of the Bcl-2 protein. Phloretin did not increase the level of Bax protein. Phloretin was suggested to induce apoptosis in HL60 cells through the inhibition of protein kinase C activity, followed by the pathway, which is different from that in B16 cells.
 ...
PMID:Phloretin-induced apoptosis in B16 melanoma 4A5 cells and HL60 human leukemia cells. 1036 85

Although phorbol 12-myristate 13-acetate (PMA) inhibits apoptosis and promotes the growth of some types of cells, it induces apoptosis in other cells. We evaluated the apoptotic effects of PMA on murine fibroblasts (L-929) that had been exposed to ultraviolet-B (UV-B) radiation at 312 nm, which promotes tumor cell growth. Exposure to PMA alone did not induce Fas, Fas-L, or apoptosis. Cells exposed to mild UV-B irradiation (80 J/m(2)) alone exhibited a slight expression of Fas and Fas-L 36 to 48 h after the exposure, and exhibited apoptosis as evidenced by DNA fragmentation 72 h after exposure. The addition of PMA (0.8 x 10(-5) to 3.2 x 10(-5) M) to the medium 24 h after the UV-B exposure markedly and dose-dependently enhanced these cell responses. Confluent untreated cells, cells cocultured with PMA, and cells cocultured with PMA for 24 h after the UV-B exposure consistently expressed mRNAs for wild-type p53, bcl-2, and ICE. Expression of c-myc mRNA was initially observed, but became undetectable in the cells cocultured for 24 h with a high concentration of PMA (3.2 x 10(-5) M) following UV-B exposure. Such cells subsequently exhibited the maximal apoptotic response. We conclude that mild exposure to UV-B altered murine fibroblast cells in such a way as to facilitate their death by apoptosis upon addition of PMA.
 ...
PMID:Phorbol ester facilitates apoptosis in murine fibroblasts pretreated by mild ultraviolet radiation. 1042 27

Bcl-2 family proteins and interleukin-1-beta converting enzyme/Caenorhabditis elegans cell death gene-3 (ICE/CED-3) family proteases (caspases) represent the basic regulators of apoptosis. However, the precise mechanism by which they interact is unclear. In this study, we found that gamma-radiation-induced apoptosis of leukemia cells was associated with activation of multiple caspases and bax up-regulation. Membrane changes and caspase activities were suppressed by specific caspase inhibitors. Similarly, the serine protease inhibitors z-Ala-Ala-Asp-cmk (AAD) and tosyl-lysine chloromethyl ketone (TLCK) also prevented caspase activation and poly(ADP-ribose) polymerase cleavage in vivo but had no effect on caspase activity in vitro. TLCK also prevented bax up-regulation as a result of its inhibitory effect on p53 function. Inhibitors of caspases and serine proteases partially prevented cell death, suggesting a caspase involvement in Bax-mediated cell death. We propose an ordering of signaling events in Bax-mediated cell death, including steps upstream and downstream of p53 and bax up-regulation.
 ...
PMID:Ionizing radiation-induced, Bax-mediated cell death is dependent on activation of cysteine and serine proteases. 1043 17

Fumonisins are mycotoxins produced by Fusarium moniliforme, a prevalent fungus which infects corn or other cereal grains. Fumonisin B1 (FB1) is the most common mycotoxin produced by F. moniliforme, suggesting that it has toxicological significance. The structure of FB1 resembles sphingoid bases and it inhibits ceramide synthase. As sphingoid bases regulate cell growth, differentiation, transformation and apoptosis, it is reasonable to hypothesize that FB1 can also regulate these activities. Previous studies concluded that FB1 induced apoptosis or cell-cycle arrest in CV-1 cells (African green monkey kidney fibroblasts). In this study, we have identified genes that inhibit FB1-induced apoptosis in CV-1 cells and in two primary human cell types (lung fibroblasts and neonatal kidney cells). A baculovirus gene. inhibitor of apoptosis (IAP), protected CV-1 and the human cells from apoptosis. IAP blocks apoptosis which is induced by the tumour necrosis factor (TNF) pathway. Inhibition of interleukin converting enzymes (ICE proteases or caspases) by the baculovirus gene p35 also inhibited FB1-induced apoptosis. FB1 treatment led to cleavage of Rb (retinoblastoma protein) at its C-terminus in CV-1 or human lung cells. As the C-terminus of Rb is cleaved by ICE proteases during apoptosis, this supports an active role for ICE proteases in FB1-induced apoptosis. The tumour suppressor gene p53 was not required for FB1-induced apoptosis because p53-/- primary mouse embryo fibroblasts underwent apoptosis following FB1 treatment. Furthermore, Bcl-2 was not an effective inhibitor of FB1-induced apoptosis in CV-1 or IMR-90 cells. In summary, these results demonstrate that the TNF pathway and caspases plays an important role in FB1-induced apoptosis.
 ...
PMID:Fumonisin B1, a mycotoxin contaminant of cereal grains, and inducer of apoptosis via the tumour necrosis factor pathway and caspase activation. 1049 71

By using flow-cytometric analysis, we examined the involvement of p53, c-Myc, Bcl-2 and Bax in the glutamate-induced cell death in cultured cortical neurons. The activities of caspase-1-like and caspase-3-like proteases were also measured after the glutamate treatment. The apoptosis rate of the cells increased after 12 h and 24 h treatment with glutamate. The temporal profile of p53, c-Myc, Bcl-2, Bax expression and caspases activation after glutamate treatment suggest that Bcl-2, c-Myc and caspase-3 play important roles in the excitotoxic neuronal cell death. The down-regulation of Bcl-2 may be an important early stage event, which may cause the activation of caspase-3. c-Myc is also involved in the process of apoptosis though its precise role remains elusive. bFGF exhibited the capability to antagonize the neuronal apoptosis caused by glutamate. The antiapoptotic potential of bFGF may result from its attenuating effect on the down-regulation of Bcl-2 induced by glutamate and, subsequently, blockade of apoptosis cascade. This may provide a possible explanation for its neuroprotective effect against ischemic cell death.
 ...
PMID:Roles of p53, c-Myc, Bcl-2, Bax and caspases in glutamate-induced neuronal apoptosis and the possible neuroprotective mechanism of basic fibroblast growth factor. 1052 75

Using flow cytometric analysis, we examined the temporal changes of p53, c-Myc, Bcl-2, Bax expression in rat primary cortex neurons after serum deprivation. Activities of caspase-1 and caspase-3 were also measured. Serum deprivation induced apoptosis accompanied by a rapid down-regulation of p53, Bcl-2 and an up-regulation of c-Myc, Bax and caspase-3 activity. Pretreatment with basic fibroblast growth factor prevented the apoptosis with an attenuation of the changes of p53, Bcl-2, Bax levels and caspase-3 activity but had no effect on the change of c-Myc level. These results suggest that serum deprivation induces apoptosis through a signaling pathway involving p53, Bcl-2, Bax, c-Myc and caspase-3. The effect of the basic fibroblast growth factor against apoptosis may result from its capability of blocking the apoptosis cascade.
 ...
PMID:Roles of p53, c-Myc, Bcl-2, Bax and caspases in serum deprivation-induced neuronal apoptosis: a possible neuroprotective mechanism of basic fibroblast growth factor. 1054 28

Cytoplasmic caudal tags of maturing spermatids condense and are detached from the spermatidal cells just before the spermatids are released as spermatozoa. The detached cytoplasmic masses are termed "residual bodies." Features of residual bodies seem to be compatible with those of apoptosis and, just as occurs with apoptotic bodies, residual bodies are phagocytosed by Sertoli cells. Since in vitro studies have demonstrated that nucleus and cytoplasm apoptosis events can be independent phenomena, we reasoned that apoptosis pathways might be restricted to the caudal tag of the maturing spermatids in order to originate residual bodies. Consistent with this idea, here we showed that annexin V specifically bound the membranes of isolated residual bodies and that expression levels of caspase-1, c-jun, p53, and p21 were specifically increased in these cytoplasmic compartments. Electron microscopy of cytoplasmic lobes and residual bodies confirmed that their ultrastructural features were those of apoptosis. These data indicate that the mechanism responsible for the formation of residual bodies is similar to that for apoptotic bodies; and the study presents evidence, for the first time, that apoptotic signaling molecules can be restricted to a cytoplasmic compartment and proceed in the presence of a healthy nucleus.
 ...
PMID:Apoptosis is physiologically restricted to a specialized cytoplasmic compartment in rat spermatids. 1057 1


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