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 pathogenesis of non-glutamatergic, depolarization-induced cell death is still enigmatic. Recently, we have shown that veratridine induces apoptosis in chromaffin cells, and we have demonstrated protective effects of antioxidants in this system, suggesting a role for Na+ channels and oxidative stress in depolarization-induced cell death. We examined the possible contribution of p53, a transcription factor that has a major role in determining cell fate, and the mitochondrial apoptosis pathway in veratridine-induced cell death of cultured bovine chromaffin cells. Nuclear condensation and fragmentation were detected several hours after a 60-min exposure to 30 microM veratridine. Apoptosis was associated with a transitory increase in p53 protein levels. Veratridine induced transcription of the pro-apoptotic p53 target gene PUMA, but not of bax or pig3. Using transient transfection experiments, we found that wild-type p53, but not the mutant form p53-273H, was sufficient to induce cell death in the chromaffin cells, which was caspase-9 dependent. The down-regulation of either p53, by overexpressing p53-273H, or caspase-9 activity using a dominant-negative caspase-9 mutant protected chromaffin cells against veratridine-induced toxicity. Our data demonstrate the importance of p53 and the downstream activation of the mitochondrial apoptosis pathway in depolarization-induced apoptosis.
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PMID:Activation of p53 and the pro-apoptotic p53 target gene PUMA during depolarization-induced apoptosis of chromaffin cells. 1611 13

Mutations in the p53 tumor suppressor gene occur in more than 50% of human cancers. In response to various cellular stresses, such as DNA damage, the p53 protein rapidly accumulates by posttranscriptional mechanism(s) and activates the expression of genes that play a major role in cellular responses leading to cell cycle arrest, DNA repair and apoptosis as a transcriptional activator. In particular, the induction of apoptosis is considered to be an important function in tumor suppression by p53. Recently, two BH3-only members of the Bcl-2 family, Noxa and PUMA, have been identified as p53 target genes. Furthermore, the analysis of mice doubly deficient in multidomain Bcl-2 family proteins, Bax and Bak, revealed that apoptosis induced by the BH3-only protein is completely dependent on Bax and Bak. More recently, it was demonstrated using gene knockout mice that Noxa and PUMA function as the effectors of p53-induced apoptosis. These analyses revealed that p53-induced apoptosis is regulated by these Bcl-2 family proteins. In this photogravure, the regulation of these Bcl-2 family proteins in p53-induced apoptosis was visualized by fluorescent protein fusion and immune fluorescence methods.
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PMID:Involvement of Bcl-2 family proteins in p53-induced apoptosis. 1611 88

The Trp53 tumor suppressor gene product (p53) functions in the nucleus to regulate proapoptotic genes, whereas cytoplasmic p53 directly activates proapoptotic Bcl-2 proteins to permeabilize mitochondria and initiate apoptosis. Here, we demonstrate that a tripartite nexus between Bcl-xL, cytoplasmic p53, and PUMA coordinates these distinct p53 functions. After genotoxic stress, Bcl-xL sequestered cytoplasmic p53. Nuclear p53 caused expression of PUMA, which then displaced p53 from Bcl-xL, allowing p53 to induce mitochondrial permeabilization. Mutant Bcl-xL that bound p53, but not PUMA, rendered cells resistant to p53-induced apoptosis irrespective of PUMA expression. Thus, PUMA couples the nuclear and cytoplasmic proapoptotic functions of p53.
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PMID:PUMA couples the nuclear and cytoplasmic proapoptotic function of p53. 1799 94

6-Hydroxydopamine (6-OHDA) is widely used in vivo and in vitro to mimic the selective neuronal degeneration that characterizes Parkinson disease (PD). To uncover candidate genes that may mediate neuron death in PD, we previously used SAGE to identify transcripts that are rapidly induced by 6-OHDA in neuronally differentiated PC12 cells. Among induced pro-apoptotic genes was that encoding the BH3-only protein PUMA. Here, we confirm that 6-OHDA induces both PUMA mRNA and protein. 6-OHDA additionally induced Bim, another pro-apoptotic BH3-only protein. Using specific siRNAs, we demonstrate that PUMA, but not Bim, is required for death evoked by 6-OHDA. PUMA is a target of p53, a transcription factor activated by 6-OHDA. Involvement of p53 in 6-OHDA evoked death was confirmed by the protective actions of a DN p53 and pifithrin alpha, inhibitors of p53 signaling. Our findings thus indicate that p53 and PUMA play required roles in a cellular model of PD.
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PMID:Puma and p53 play required roles in death evoked in a cellular model of Parkinson disease. 1618 18

The endoplasmic reticulum (ER) is the principal organelle for the biosynthesis of proteins, steroids and many lipids, and is highly sensitive to alterations in its environment. Perturbation of Ca(2+) homeostasis, elevated secretory protein synthesis, deprivation of glucose or other sugars, altered glycosylation and/or the accumulation of misfolded proteins may all result in ER stress, and prolonged ER stress triggers cell death. Studies from multiple laboratories have identified the roles of several ER stress-induced cell-death modulators and effectors through the use of biochemical, pharmacological and genetic tools. In the present work, we describe the role of p23, a small chaperone protein, in preventing ER stress-induced cell death. p23 is a highly conserved chaperone protein that modulates HSP90 activity and is also a component of the steroid receptors. p23 is cleaved during ER stress-induced cell death; this cleavage, which occurs close to the carboxy-terminus, requires caspase-3 and/or caspase-7, but not caspase-8. Blockage of the caspase cleavage site of p23 was associated with decreased cell death induced by ER stress. Immunodepletion of p23 or inhibition of p23 expression by siRNA resulted in enhancement of ER stress-induced cell death. While p23 co-immunoprecipitated with the BH3-only protein PUMA (p53-upregulated modulator of apoptosis) in untreated cells, prolonged ER stress disrupted this interaction. The results define a protective role for p23, and provide further support for a model in which ER stress is coupled to the mitochondrial intrinsic apoptotic pathway through the activities of BH3 family proteins.
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PMID:Coupling endoplasmic reticulum stress to the cell-death program: a novel HSP90-independent role for the small chaperone protein p23. 1619 41

The efficacy of chemotherapeutic agents on tumor cells has been shown to be modulated by tumor suppressor gene p53 and its target genes such as Bcl-2 family members (Bax, Noxa, and PUMA). However, various chemotherapeutic agents can induce cell death in tumor cells that do not express the functional p53, suggesting that some chemotherapeutic agents may induce cell death in a p53-independent pathway. Here we showed that etoposide can induce the similar degree of cell death in p53-deficient HCT 116 cells, whereas 5'-FU-mediated cell death is strongly dependent on the existence of functional p53 in HCT 116 cells. Further, we provide the evidence that etoposide can induce the cytochrome c release from isolated mitochondria, and etoposide-induced cytochrome c release is not accompanied with the large amplitude swelling of mitochondria. These data suggest that etoposide can directly induce the mitochondrial dysfunction irrespective of p53 status, and it may, at least in part, account for the p53-independent pathway in cell death induced by chemotherapeutic agents.
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PMID:Release of cytochrome c from isolated mitochondria by etoposide. 1620 44

Hydroxyurea (HU) is a competitive inhibitor of ribonucleotide reductase that is used for the treatment of myeloproliferative disorders. HU inhibits DNA replication and induces apoptosis in a cell type-dependent manner, yet the relevant pathways that mediate apoptosis in response to this agent are not well characterized. In this study, we employed the human myeloid leukemia 1 (ML-1) cell line as a model to investigate the mechanisms of HU-induced apoptosis. Exposure of ML-1 cells to HU caused rapid cell death that was accompanied by hallmark features of apoptosis, including membrane blebbing, phosphatidylserine translocation, and caspase activation. HU-induced apoptosis required new protein synthesis, was induced by HU exposures as short as 15 min, and correlated with the accumulation of p53 and induction of the p53 target gene PUMA. p53 induction in ML-1 cells was ATR dependent and downregulation of p53 through RNAi delayed HU-induced apoptosis. HU did not induce p53 or induce apoptosis in Molt-3 leukemia cells, even though exposure to HU induced a comparable level of DNA damage and robustly activated the ATR pathway. The microtubule inhibitor nocodazole suppressed HU-induced p53 accumulation in ML-1 cells suggesting that a microtubule-dependent event contributes to p53 induction and apoptosis in this cell line. Our findings outline an HU-induced cell death pathway and suggest that activation of ATR is necessary, but not sufficient, for stabilization of p53 in response to DNA replication stress.
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PMID:ATR activation necessary but not sufficient for p53 induction and apoptosis in hydroxyurea-hypersensitive myeloid leukemia cells. 1625 78

In response to DNA damage, the tumor suppressor p53 elicits a complex cellular response. In this issue of Cell, Wu et al. (2005) show that the transcription factor SLUG is induced by p53 and protects hematopoietic progenitor cells from apoptosis triggered by DNA damage. SLUG exerts this protective role by repressing Puma, a proapoptotic target of p53. PUMA is also a key coordinator of apoptosis mediated by both nuclear and cytoplasmic functions of p53 (Chi-puk et al., 2005).
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PMID:Slugging it out: fine tuning the p53-PUMA death connection. 1628 9

Copper toxicity associated with Wilson's disease is known to cause neuronal damage and death in the basal ganglia and frontal cortex leading to Parkinson-like symptoms and cognitive deficits. Our previous work in cultured human NTERA-2-N neurons showed that copper-induced neuronal apoptosis is dependent on the induction and nuclear translocation of the tumor suppressor protein, p53. Because p53 acts as a DNA-binding transcription factor, this work used an oligonucleotide array to identify p53 target genes that are differentially regulated in copper-loaded neurons. Arrays representing 145 human genes expressed downstream of p53 were hybridized with labeled mRNA from control and copper-treated neurons. Differentially regulated mRNAs included those involved in the regulation of the cell cycle, cytoprotective mechanisms, and apoptotic mechanisms. Transfection of cells with a dominant-negative p53 construct enabled us to determine which molecular events were dependent on p53 expression. Copper treatment resulted in the upregulation of p21, reprimo, stathmin, and Tp53INP1, all known to participate in cell cycle arrest. Protective mechanisms included the upregulation of stat-3, and the heat-shock proteins, heat-shock protein (Hsp) 70 and Hsp 27. Both p53-dependent and -independent mechanisms leading to apoptosis were identified including insulin-like growth factor binding protein-6, glutathione peroxidase, bcl-2, RB-1, PUMA, and several members of the redox active PIG family of proteins. Thus it appears that following copper-mediated neuronal DNA damage, the regulation of a variety of pro- and antiapoptotic genes are responsible for determining neuronal fate.
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PMID:Expression profiling of p53-target genes in copper-mediated neuronal apoptosis. 1639 88

Endoplasmic reticulum (ER) stress-induced apoptosis has been implicated in the development of multiple diseases. However, the in vivo signaling pathways are still not fully understood. In this report, through the use of genetically deficient mouse embryo fibroblasts (MEFs) and their matched wild-type controls, we have demonstrated that the mitochondrial apoptotic pathway mediated by Apaf-1 is an integral part of ER stress-induced apoptosis and that ER stress activates different caspases through Apaf-1-dependent and -independent mechanisms. In search of the molecular link between ER stress and the mitochondrial apoptotic pathway, we have discovered that in MEFs, ER stress selectively activates BH3-only proteins PUMA and NOXA at the transcript level through the tumor suppressor gene p53. In p53(-/-) MEFs, ER stress-induced apoptosis is partially suppressed. The p53-independent apoptotic pathway may be mediated by C/EBP homologous protein (CHOP) and caspase-12, as their activation is intact in p53(-/-) MEFs. In multiple MEF lines, p53 is primarily nuclear and its level is elevated upon ER stress. To establish the role of NOXA and PUMA in ER stress-induced apoptosis, we have shown that, in MEFs deficient in NOXA or PUMA, ER stress-induced apoptosis is reduced. Reversibly, overexpression of NOXA or PUMA induces apoptosis as evidenced by the activation of BAK and caspase-7. Our results provide new evidence that, in MEFs, in addition to PUMA, p53 and NOXA are novel components of the ER stress-induced apoptotic pathway, and both contribute to ER stress-induced apoptosis.
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PMID:Endoplasmic reticulum stress-induced apoptosis: multiple pathways and activation of p53-up-regulated modulator of apoptosis (PUMA) and NOXA by p53. 1640 91


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