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)

The neurotoxic activity of beta-amyloid (beta A) and prion protein (PrP) fragments contributed to the hypothesis concerning a causal role of amyloid deposits in Alzheimer disease (AD) and in prion-related encephalopathies. In this study, we investigated some aspects of the molecular mechanisms associated with neurotoxic activity of synthetic peptides homologous to beta A (beta 25-35) or PrP (PrP106-126) fragments. Chronic (5-7 d) exposure to both peptides induced neuronal death by apoptosis, as suggested by biochemical and morphological analysis. The apoptotic mechanism was confirmed by ultrastructural examination. The intracellular cascade of events activated by peptides was investigated by Northern blot and PCR analysis of expression of early genes (c-fos, c-jun, c-myc) and other proteins (p53, SGP-2 bcl-2, HSP70, Ich-1) potentially involved in apoptosis. With the exception of bcl-2 mRNA decrease and a slight increase of SGP-2 in PrP106-126-treated cells, no consistent alterations of these mRNA expressions were found in neuronal cells exposed to beta 25-35 or PrP106-126. Furthermore, we synthesized amidated homologs of both peptides with low amyloidogenic activity to test directly the relationship between amyloid fibrils and cell death. The neurotoxicity exhibited by PrP106-126-NH2 was similar to that observed with original peptide, whereas the amidation of beta 25-35 partially reduced the neurotoxicity of this peptide.
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PMID:Apoptosis-mediated neurotoxicity induced by beta-amyloid and PrP fragments. 887 55

The Interleukin-1beta converting enzyme (ICE) family of proteins, homologs of the C elegans cell death gene product CED-3, play important roles in controlling vertebrate programmed cell death. Because inhibition of apoptosis may be an essential step in tumorigenesis, we investigated the interaction of the simian virus 40 large T antigen (T ag) with the ICE family. COS-1 cells which were transformed by the simian virus 40 do not die when transfected with expression constructs of Ice or Ich-1(L). We found that expression of T ag alone significantly prevents the ICE-induced apoptosis. p53, but not pRb or p107, antagonizes the effect of T ag on the suppression of ICE-induced cell death, but not on ICH-1(L)-mediated cell death. Thus, wild type p53 may potentiate ICE-induced apoptosis. Expression of a temperature sensitive mutant p53Val(135) sensitizes COS-1 cells to apoptosis induced by ICE at permissive but not at non-permissive temperature. While induction of bax, p21(WAF1/CIP), or cyclin D1 gene expression is observed in the COS-1 p53Val(135) cells at the permissive temperature, overexpression of bax, but not p21(WAF1/CIP) or cyclin D1, potentiates ICE-induced COS-1 cell death. Taken together, these results suggest that T ag may modulate the cells' susceptibility to death by suppressing activity of the ICE family through inhibiting p53.
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PMID:Suppression of interleukin-1beta converting enzyme (ICE)-induced apoptosis by SV40 large T antigen. 912 70

c-Myc is a transcriptional activator implicated in the control of cell proliferation, differentiation and transformation, but is also involved in the regulation of programmed cell death, apoptosis. Despite intensive research, the molecular mechanisms by which c-Myc triggers and executes cell death remain still elusive. Here, we made use of Rat 1A MycER cells expressing a conditionally active c-Myc protein and tested first the hypothesis that ornithine decarboxylase (ODC), which is a transcriptional target of c-Myc, were a mediator of c-Myc-induced apoptosis. However, our results show that the activity of ODC is not required for the c-Myc-mediated apoptosis to occur in these cells. We also found that the expression of p53, p21waf1/cip1, Bcl-2, Bax, Bcl-xL, Bad and cyclins D1, E, A and B did not show any significant changes following c-Myc induction. But, our studies revealed that the c-Myc induced apoptosis is associated with a specific cleavage of poly(ADPribose) polymerase (PARP), suggesting that a cysteine protease of the ICE/CED-3 family is involved. Moreover, we found that the cysteine protease CPP32/Caspase-3, which is known to cleave PARP, is processed from its inactive form to an active protease composed of 17 and 12 kDa subunits; whilst Ich-1/Caspase-2 belonging to another subset of this protease family was not processed/ activated following c-Myc activation. The activation of CPP32 and apoptotic cell death were inhibited by addition of Z-VAD-fmk, a universal inhibitor of ICE-like proteases. Further, a selective inhibitor of CPP32-like proteases (Z-DEVD-fmk) partly inhibited apoptosis. These results provide evidence that the ICE/CED3-family proteases, CPP32 and likely others, play a critical role in the execution of a nuclear proto-oncogene, c-Myc-induced apoptosis.
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PMID:Involvement of CPP32/Caspase-3 in c-Myc-induced apoptosis. 946 64

Degradation of extracellular matrix by hyaluronidase increases murine L929 cell sensitivity to tumor necrosis factor (TNF) cytotoxicity. Seeding and culturing L929 cells onto the matrix of serum fetuin and the hyaluronate-binding inter-alpha-inhibitor resulted in inhibition of hyaluronidase-enhanced TNF killing, suggesting that the release of these proteins from hyaluronidase-degraded matrix confers cellular TNF susceptibility. Metabolic labeling studies showed that hyaluronidase mediated de novo protein synthesis and down regulated several proteins in L929 cells. Specifically, hyaluronidase upregulated p53 protein expression (>200%) but down regulated a p85 inter-alpha-inhibitor-like protein (>90%) in L929 cells, whereas it had no effect on the protein levels of ICH-1, Bcl-xL, Bcl-2, Fas ligand, CAS (cellular apoptosis susceptible protein), TIAR (an RNA-binding protein) and alpha-tubulin. Conceivably, hyaluronidase enhancement of TNF sensitivity in L929 cells is p53-dependent and the matrix inter-alpha-inhibitor contributes a protective role against TNF cytotoxicity.
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PMID:p53 overexpression and downregulation of inter-alpha-inhibitor are associated with hyaluronidase enhancement of TNF cytotoxicity in L929 fibroblasts. 983 19

Though p53-induced apoptosis plays an important role in tumor suppression, the mechanism(s) by which p53 induces apoptosis is still unclear. To elucidate the p53-induced apoptotic pathway, we examined the role of p53 transactivation activity and caspase in J138V5C cells carrying a human temperature-sensitive (ts) p53 mutant (138Ala-->Val). The results showed that p53-induced apoptosis was not blocked by cycloheximide, which effectively prevented the expression of p53 target genes, indicating that transactivation was not essential for p53-induced apoptosis in this system. Western blot analysis showed that PARP, CPP32 and ICH-1 precursors were cleaved during apoptosis. The CPP32-preferential tetrapeptide inhibitor Ac-DEVD-CHO blocked the cleavage of ICH-1 and PARP precursors, suggesting that CPP32 or some other DEVD-sensitive caspase(s) is the upstream activator of ICH-1. We also examined the role of the Fas pathway by using Fas and Fas ligand-neutralizing antibodies. Both antibodies failed to block p53-induced apoptosis, suggesting that the Fas pathway was not essential for p53-induced apoptosis in this system. Taken together, our results indicate that p53-induced, transactivation-independent apoptosis in Jurkat cells involves sequential activation of CPP32 or some other DEVD-sensitive caspase(s) and ICH-1, via a Fas-independent pathway.
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PMID:Activation of caspases in p53-induced transactivation-independent apoptosis. 1018 88

Recent data support a role for apoptosis, under tight regulatory control by bcl-2, oxidative stress response, tumor suppressor, and CASP gene family members, in mediating granulosa cell demise during follicular atresia in the rodent and avian ovary. Herein we evaluated the occurrence of apoptosis in the human and baboon ovary relative to follicular health status, and analyzed expression of several cell death genes in these tissues. In situlocalization of DNA strand breaks in fixed human and baboon ovarian tissue sections indicated that apoptosis was essentially restricted to granulosa cells of atretic antral follicles. Biochemical analysis of DNA oligonucleosomes in individual follicles isolated from baboon ovaries during the ovulatory phase revealed the presence of apoptotic DNA fragments in subordinate but not dominant follicles, thus substantiating the in situ labeling studies. Messenger RNA transcripts encoded by the bax death susceptibility gene, the bcl-xlong survival gene, the bcl-xshort pro-apoptosis gene, the p53 tumor suppressor gene, and two members of the CASP gene family (CASP-2/Ich-1, CASP-3/CPP32), were detected by Northern blot analysis of total RNA prepared either from human ovaries or from Percoll-purified granulosa-lutein cells obtained from patients undergoing assisted reproductive technologies. Lastly, immunohistochemical localization of the BAX death-susceptibility protein in the human ovary revealed abundant expression in granulosa cells of early atretic follicles, whereas BAX protein was extremely low or non-detectable in healthy or grossly-atretic follicles. We conclude that apoptosis occurs during, and is probably responsible for, folicular atresia in the human and baboon ovary. Moreover, apoptosis in the human ovary is likely controlled by altered expression of the same cohort of cell death regulatory factors recently implicated as primary determinants of apoptosis induction or suppression in the rodent ovary.
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PMID:Analysis of apoptosis and expression of bcl-2 gene family members in the human and baboon ovary. 1020 Apr 47

In the adult mouse tongue, an average of 11% of the gustatory receptor cells are replaced each day. In investigating homeostatic cell death mechanisms in gustatory renewing epithelium, we observed that taste receptor cells were selectively immunopositive for the bcl-2 family death factor, Bax, and for the protease Caspase-2 (Nedd2/Ich1). We determined that 8-10% of the taste receptor cells of the vallate papilla were Bax positive and that 11% were Caspase-2 positive. Some of these immunopositive taste cells had apoptotic morphological defects. Within the subset of vallate taste cells immunopositive for either Caspase-2 or Bax, up to 79% coexpressed both death factors. Bax and Caspase-2 first appeared in occasional vallate taste receptor cells on the same postnatal day-the day after birth. bax null mutation markedly reduced gustatory Caspase-2 immunoexpression. These observations suggest that taste cell death pathways utilize p53, Bax, and Caspase-2 to dispose of aged receptor cells. Apart from reducing Caspase-2 expression, Bax deficiency also altered taste organ development. bax(-/-) mice had a more profusely innervated vallate papilla, which grew to be 25% longer and taller, with the mean taste bud containing more than twice the normal number of taste cells. This augmentation of taste organ development with increased innervation is complementary to the well-documented reduction in taste organ development with sparse innervation. We propose that additional taste neurons survived programmed cell death in Bax-deficient mice, thereby providing an inductive boost to vallate gustatory development.
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PMID:Gustatory innervation and bax-dependent caspase-2: participants in the life and death pathways of mouse taste receptor cells. 1093 86

HIV-1 induces apoptosis and leads to CD4+ T-lymphocyte depletion in humans. It is still unclear whether HIV-1 kills infected cells directly or indirectly. To elucidate the mechanisms of HIV-1-induced apoptosis, we infected human CD4+ T cells with HIV-1. Enzymatic analysis with fluorometric substrates showed that caspase 2, 3, and 9 were activated in CD4+ T cells with peak levels 48 h after infection. Immunoblotting analysis confirmed the cleavage of pro-caspase 3 and 9, and of specific caspase substrates. Release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria was observed in HIV-infected cells. The cytochrome c and AIF release preceded the reduction of the mitochondrial transmembrane potential and nuclear chromatin condensation. H IV infection led to phosphorylation of p53 at the Ser15 residue, detectable as early as 24 h after infection. The p53 phosphorylation was followed by increased mRNA and protein expression of p21, Bax, HDM2, and p53. Up-regulation of surface FasL expression, accompanied by a down-regulation of Fas-associated proteins (FADD, DAXX, and RIP), was observed 72 h after infection. Our results suggest that HIV activates the p53 pathway, leading to cytochrome c and AIF release with ensuing caspase activation.
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PMID:HIV induces lymphocyte apoptosis by a p53-initiated, mitochondrial-mediated mechanism. 1109 84

p73, a member of the p53 family, can induce apoptosis in cancer cells. Since p53-mediated apoptosis can be augmented by various cancer chemotherapeutic agents, it has been hypothesized that the status of the endogenous p53 gene in cancer cells is a key determinant in the outcome of cancer therapy. To determine whether p73 can sensitize cancer cells to apoptosis by DNA damage agents, several MCF7 adenocarcinoma cell lines that inducibly express p73 or p53 under a tetracycline-regulated promoter were generated. We found that at relevant physiological levels, p73, but not p53, is capable of sensitizing MCF7 cells to apoptosis induced by chemotherapeutic agents. In addition, we found that p73 can cooperate with the DNA damaging agent camptothecin to activate the initiator caspase 2. Furthermore, we found that p73 can cooperate with DNA damaging agents or p53 to induce some p53 target genes and activate their promoters. In contrast, in MCF7E6 cells that ectopically express the human papillomavirus E6 oncogene and are functionally p53-null, the ability of p73 to sensitize cells to apoptosis is abrogated. Taken together, these results suggest that a functional interaction between p53 and p73 in MCF7 cells leads to enhanced induction of apoptosis.
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PMID:p73 cooperates with DNA damage agents to induce apoptosis in MCF7 cells in a p53-dependent manner. 1149 33

To dissect apoptotic genes governing the survival of colorectal carcinoma cells, we employed RNAi to silence Bcl-2 and Bcl-x(L) in isogenic clones of p53+/+ and p53-/- cells, and of Bax+/- and Bax-/- cells. We identify a novel proapoptotic function of p53 that does not require activation by genotoxic agents and that appears to be constitutively suppressed by Bcl-2. Silencing of Bcl-2 induced massive p53-dependent apoptosis. The "Bcl-2/p53 axis" requires Bax and caspase 2 as essential apoptotic mediators. This newly discovered Bcl-2/p53 functional interface represents a key regulator of apoptosis which can be activated by targeting Bcl-2 in colorectal carcinoma cells.
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PMID:Bcl-2 constitutively suppresses p53-dependent apoptosis in colorectal cancer cells. 1267 Aug 66


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