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)

WISP-1 (Wnt-1-induced secreted protein) was identified as an oncogene regulated by the Wnt-1-beta-catenin pathway. WISP-1 belongs to the CCN family of growth factors, which are cysteine-rich, heparin-binding, secreted proteins associated with the extracellular matrix, and can interact with cellular integrins. Expression of WISP-1 in some cells results in transformation and tumorigenesis. Here it is shown that WISP-1 can activate the antiapoptotic Akt/PKB signaling pathway. It also is demonstrated that WISP-1 can prevent cells from undergoing apoptosis following DNA damage through inhibition of the mitochondrial release of cytochrome c and up-regulation of antiapoptotic Bcl-X(L). Furthermore, the results show that WISP-1 protects cells from p53-dependent cell death, but not Fas-ligand activated cell death, suggesting that there may be cross talk between the tumor suppressor protein p53 and WISP-1 signaling pathways. WISP-1 acts to block cell death at a late stage in the p53-mediated apoptosis pathway.
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PMID:WISP-1 attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase. 1178 44

The p53 tumor suppressor protein and the Akt/PKB kinase play important roles in the transduction of pro-apoptotic and anti-apoptotic signals, respectively. We provide evidence that conflicting signals transduced by Akt and p53 are integrated via negative feedback between the two pathways. On the one hand, the combination of ionizing radiation and survival factor deprivation, which leads to rapid apoptosis of IL-3 dependent DA-1 cells, entails a caspase- and p53-dependent destruction of Akt. This destruction of Akt is not a secondary consequence of apoptosis, since it is not seen when the same cells are triggered to undergo apoptosis under different conditions. On the other hand upon serum stimulation, when Akt becomes active and enhances cell survival, phosphorylation occurs at an Akt consensus site (serine 166) within the Mdm2 protein, a key regulator of p53 function. Taken together, our findings suggest that depending on the balance of signals, p53-dependent downregulation of Akt may promote an irreversible commitment to apoptotic cell death, whereas effective recruitment of Akt by appropriate survival signals may lead to activation of Mdm2, inactivation of p53, and eventually inhibition of p53-dependent apoptosis.
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PMID:Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. 1185 Aug 50

Adrenocortical carcinoma is a rare tumor that carries a very poor prognosis. Despite efforts to develop new therapeutic regimens to treat this disease, surgery remains the mainstay of treatment. Laboratory studies of adrenocortical cancers have revealed a wide variety of signaling pathways that can be altered in these neoplasms. Although ACTH signaling through adenylyl cyclase and protein kinase A is important for normal adrenal cellular physiology, there is evidence to suggest that this pathway may inhibit the growth of adrenocortical tumors, and that inactivation of the ACTH receptor may promote tumor formation. Although multiple signal transduction pathways are essential for normal adrenal growth and hormone secretion, efforts to identify events required for neoplastic transformation have met with limited success. Alterations that have frequently been observed in adrenocortical carcinoma include up-regulation of the IGF-II system, as well as mutations in TP53 and RAS. Current studies aim to elucidate the mechanisms of tumor growth by studying proproliferative signaling pathways, such as those involving Akt/PKB and the mitogen-activated protein kinases (MAPKs). Although studies of single pathways have been helpful in guiding investigations, new tools to study the integration and multiplicity of signaling pathways hold the hope of improved understanding of the signaling pathway alterations in adrenocortical cancer.
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PMID:Signaling pathways in adrenocortical cancer. 1211 79

Various cytokines have been shown to protect cells from p53-dependent apoptosis. To investigate the mechanism underlying cytokine-mediated survival, we used a Friend virus-transformed erythroleukemia cell line that expresses a temperature-sensitive p53 allele. These cells express the spleen focus-forming virus-encoded envelope glycoprotein gp55 that allows the cells to proliferate in the absence of erythropoietin (EPO). These cells respond to p53 activation at 32 degrees C by undergoing G(1) cell cycle arrest and apoptosis. In the presence of EPO, p53 activation leads only to prolonged but viable G(1) arrest. These findings indicate that EPO functions as a survival factor and that gp55/EPO receptor signaling is distinct from EPO/EPO receptor signaling. We demonstrate that p53-dependent apoptosis results in mitochondrial damage as shown by loss of mitochondrial membrane potential, increase in intracellular calcium, and release of mitochondrial cytochrome c into the cytosol. EPO prevented all of these changes including the subsequent activation of caspases. We identify an intrinsic phosphatidylinositol-3'-OH kinase/protein kinase B (PI3'K/PKB)-dependent survival pathway that is constitutively active in these cells. This survival pathway limits p53-dependent apoptosis. We propose that EPO promotes survival through a distinct pathway that is dependent on JAK2 but independent of STAT5 and PI3'K.
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PMID:The death-promoting activity of p53 can be inhibited by distinct signaling pathways. 1239 87

The p53 tumor suppressor protein provides a major anti-cancer defense mechanism, as underscored by the fact that the p53 gene is the most frequent target for genetic alterations in human cancer. Recent work has led to the realization that p53 lies at the hub of a very complex network of signaling pathways that integrate a variety of intracellular and extracellular inputs. Part of this network consists of an array of autoregulatory feedback loops, where p53 exhibits very intricate interactions with other proteins known to play important roles in the determination of cell fate. We discuss two such loops, one involving the beta-catenin protein and the other centering on the Akt/PKB protein kinase. In both cases, the central module is the interplay between p53 and the Mdm2 protein, which inactivates p53 and targets it for rapid proteolysis. Whereas deregulated beta-catenin can lead to Mdm2 inactivation and p53 accumulation, active p53 can promote the degradation and down-regulation of beta-catenin. Similarly, Akt can block p53 activation by potentiating Mdm2, whereas activated p53 can tune down Akt in several different ways. In each case, the actual output of the loop is determined by the delicate balance between the opposing effects of its different components. Often, this balance is dictated by additional signaling processes that occur simultaneously within the same cell. Genetic alterations characteristic of cancer are capable of severely distorting this balance, thereby overriding the tumor suppressor effects of p53 in a manner that facilitates neoplastic conversion.
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PMID:Regulation of p53: intricate loops and delicate balances. 1248 97

The p53 tumor-suppressor plays a critical role in the prevention of human cancer. In the absence of cellular stress, the p53 protein is maintained at low steady-state levels and exerts very little, if any, effect on cell fate. However, in response to various types of stress, p53 becomes activated; this is reflected in elevated protein levels, as well as augmented biochemical capabilities. As a consequence of p53 activation, cells can undergo marked phenotypic changes, ranging from increased DNA repair to senescence and apoptosis. This review deals with the mechanisms that underlie the apoptotic activities of p53, as well as the complex interactions between p53 and central regulatory signaling networks. In p53-mediated apoptosis, the major role is played by the ability of p53 to transactivate specific target genes. The choice of particular subsets of target genes, dictated by covalent p53 modifications and protein-protein interactions, can make the difference between life and apoptotic death of a cell. In addition, transcriptional repression of antiapoptotic genes, as well as transcription-independent activities of p53, can also contribute to the apoptotic effects of p53. Regarding the crosstalk between p53 and signaling networks, this review focuses on the interplay between p53 and two pivotal regulatory proteins: beta-catenin and Akt/PKB. Both proteins can regulate p53 as well as be regulated by it. In addition, p53 interacts with the GSK-3beta kinase, which serves as a link between Akt and beta-catenin. This review discusses how the functional balance between these different interactions might dictate the likelihood of a given cell to become cancerous or be eliminated from the replicative pool, resulting in suppression of cancer.
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PMID:Decision making by p53: life, death and cancer. 1271 14

Activated Notch1 (AcN1) alleles cooperate with oncogenes from DNA tumor viruses in transformation of epithelial cells. AcN1 signaling has pleiotropic effects, and suggested oncogenic roles include driving proliferation through cyclin D1 or the generation of resistance to apoptosis on matrix withdrawal through a phosphatidylinositol 3-kinase (PI3K)-PKB/Akt-dependent pathway. Here, we extend the antiapoptotic role for AcN1 by showing inhibition of p53-induced apoptosis and transactivation. Chemical inhibitors of the PI3K pathway block AcN1-induced inhibition of p53-dependent apoptosis and nuclear localization of Hdm2. We show that expression of wild-type p53 does not inhibit synergistic transformation by AcN1 and human papillomavirus E6 and E7 oncogenes. We suggest that activation of Notch signaling may serve as an additional mechanism to inhibit wild-type p53 function in papillomavirus-associated neoplasia.
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PMID:Activated Notch1 inhibits p53-induced apoptosis and sustains transformation by human papillomavirus type 16 E6 and E7 oncogenes through a PI3K-PKB/Akt-dependent pathway. 1276 30

Human malignant gliomas arise from neural progenitor cells and/or dedifferentiated astrocytes. By now, they are genetically so well characterized that several murine glioma models have emerged that faithfully reiterate the typical histological features of the disease. In experimental animals, only one or two elements of the growth factor/Ras, PI3K/PTEN/PKB, p53/ARF/HDM2, and p16/Rb/cyclinD/CDK4 pathways are targeted. In human gliomas, many additional genes and pathways are targeted due to a most severe mutator phenotype that leads to the accumulation of countless epigenetic and genetic alterations. Changes that convey a growth advantage are selected for, leading to overgrowth of precursor cell populations with increasingly malignant tumor cell clones. While murine models represent a powerful tool for elucidating the role of genetic pathways, mechanisms of response and resistance to new therapeutic agents might be fundamentally different due to the high degree of genomic instability in the human disease. In fact, little is known about the molecular causes of genomic instability involved in gliomas, except for the rare Turcot's syndrome, O(6)-methylguanine-DNA methyltransferase, and the apurinic/apyrimidinic endonuclease Ape-1. Novel approaches that selectively exploit fundamental metabolic differences between tumor and normal cells have to consider these fundamental differences between human disease and presently available, highly sophisticated animal models.
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PMID:Genes and pathways driving glioblastomas in humans and murine disease models. 1278 72

Sodium salicylate is known to induce apoptosis in a variety of cancer cells. However, the molecular mechanism for salicylate-induced apoptosis is yet unclear. Here we show that in HCT116 colon carcinoma cells, 10 mM sodium salicylate induces caspase-3 activation and degradation of its substrates, poly(ADP-ribose) polymerase (PARP), beta-catenin, and retinoblastoma (Rb). In contrast, sodium salicylate did not exert any significant effects on the expression of Fas L that is implicated in extrinsic apoptotic pathway and the levels of Bcl-2 family proteins, Bcl-2, Bcl-xsl, and Bad, which are involved in intrinsic apoptotic pathway, and anti-apoptotic molecules, c-IAP1 and HSP73. In addition, 10 mM salicylate induced p53 tumor suppressor protein that plays an important role in cell cycle arrest or apoptosis and the induction seemed to be linked to its phosphorylation at Set 15. To investigate the signal pathways for salicylate-induced apoptosis, we examined the effects of sodium salicylate on protein kinase activities. Sodium salicylate activated p38MAPK through phosphorylation at Thr 180/Tyr 182 and Akt/PKB at Ser 473, whereas it partially activated ERK1/2 through its phosphorylation at Thr 202/Tyr 204. We also show that SB203580 (a specific p38MAPK inhibitor), but not other protein kinase inhibitors (PD98059, LY294002, and wortmannin), significantly prevented salicylate-induced apoptosis. These results suggest that sodium salicylate-induced apoptosis in HCT116 colorectal cancer cells is mediated by p38MAPK.
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PMID:Sodium salicylate induces apoptosis in HCT116 colorectal cancer cells through activation of p38MAPK. 1285 2

We demonstrated that enhancement of X-ray-induced apoptosis/rapid cell death by wortmannin accompanied by increased activation of JNK/SAPK in human leukemia MOLT-4 cells. Rapid cell death/apoptosis was determined either by the dye exclusion test or by the appearance of Annexin V-positive cells and cleaved PARP fragments. Enhancement was observed only at higher concentrations of wortmannin, i.e. 1 microM or more. At these high concentrations, both DNA-PK and ATM were inhibited. X-ray-induced phosphorylation of Ser 15 of p53/TP53, accumulation of both p53/TP53 and p21/WAF1/CDKN1A, and phosphorylation of XRCC4 were all suppressed. The enhancement of apoptosis/rapid cell death by wortmannin was prevented by addition of caspase inhibitors, Z-VAD-FMK or Ac-DEVD-CHO, or by transfection and overexpression of mouse Bcl2, which is known as an anti-apoptosis protein. The requirement for a high concentration of wortmannin, i.e. 1 microM or more, indicates that inhibition of both DNA-PK and ATM was necessary for the enhanced apoptosis/rapid cell death. Phosphorylation of AKT/PKB was completely suppressed at a much lower concentration, i.e. 0.1 microM wortmannin, where no enhancement of X-ray-induced apoptosis/rapid cell death was observed. On the other hand, X-ray-induced phosphorylation of JNK and its kinase activity as well as apoptosis/rapid cell death were all significantly enhanced only at high concentrations of wortmannin, i.e. 1 microM or more. Furthermore, the extent of enhancement of both JNK phosphorylation and of apoptosis/rapid cell death by wortmannin was less in Rh1a cells, which are ceramide- and radiation-resistant variant cells compared to the parental MOLT-4 cells. Therefore, activation of the JNK pathway was considered important for the enhancement of X-ray-induced apoptosis/rapid cell death of MOLT-4 cells by wortmannin, because of the requirement for a higher concentration of wortmannin than that required for inhibition of AKT phosphorylation. The suppression of the AKT-dependent pathway by wortmannin may have some underlying role in activating the JNK pathway toward the enhancement of cell death in the current system.
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PMID:Wortmannin-enhanced X-ray-induced apoptosis of human T-cell leukemia MOLT-4 cells possibly through the JNK/SAPK pathway. 1296 28


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