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)

In this report, we examine how the Ras protein regulates neuronal survival, focusing on sympathetic neurons. Adenovirus-expressed constitutively activated Ras (RasV12) enhanced survival and the phosphorylation of Akt (protein kinase B) and MAP kinase (MAPK), two targets of Ras activity. Functional inhibition of endogenous Ras by adenovirus-expressed dominant-inhibitory Ras (N17Ras) decreased nerve growth factor (NGF)-dependent survival and both Akt and MAPK phosphorylation as well. To determine the signaling pathways through which Ras mediates survival, we used Ras effector mutants and pharmacological inhibitors that selectively suppress phosphatidylinositol 3-kinase (PI3-K)/Akt or MAP kinase kinase (MEK)/MAPK pathways. The Ras effector mutant Ras(V12)Y40C, which selectively stimulates PI3-K and Akt, rescued survival in the absence of NGF, and the PI3-K inhibitor LY 294002 inhibited both Ras- and NGF-dependent survival. Ras(V12)T(35)S, which activates MEK/MAPK but not PI3-K/Akt, was less effective at rescuing survival, whereas the MEK inhibitor PD 098059 also partially suppressed Ras-dependent survival. To investigate the mechanisms by which Ras suppresses neuronal death, we examined whether Ras functions by inhibiting the proapoptotic p53 pathway (Jun-N-terminal kinase/p53/BAX) that is necessary for neuronal death after NGF withdrawal and p75NTR activation. We found that RasV12 suppressed c-jun, BAX, and p53 levels, whereas inhibition of NGF-induced Ras-survival activity via N17Ras increased the levels of these proteins. Furthermore, the E1B55K protein, which suppresses p53 activity, blocked N17Ras-induced neuronal death. Together, these results indicate that Ras is, in part, both necessary and sufficient for survival of sympathetic neurons and that this effect is mediated by activation of both the PI3-K- and MEK-signaling cascades, which in turn suppress a proapoptotic p53 pathway.
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PMID:Ras regulates sympathetic neuron survival by suppressing the p53-mediated cell death pathway. 1055 81

Adenovirus (Ad) E1A induces apoptosis in cells expressing wild-type p53, and stable transformation by Ad E1A requires the co-introduction of an anti-apoptotic gene such as Ad E1B 19K. Thus, cells immortalized by Ad E1A alone might have lost functional p53. In order to analyze the p53 in rat cells expressing Ad E1A, we established rat cell lines by transfecting primary rat embryo fibroblast (REF) and baby rat kidney (BRK) cells with cloned Ad5 E1A. By using a yeast functional assay, we analyzed p53 in six primary REF and three BRK cell lines immortalized by Ad5 E1A as well as five spontaneously immortalized rat cell lines (REF52, NRK, WFB, Rat-1 and 3Y1). The yeast functional assay revealed that all of the spontaneously and Ad5 ElA-immortalized rat cell lines except for 3Y1 expressed wild-type p53. All of the Ad5 E1A-immortalized rat cell lines contained p53 detectable by immunoprecipitation. Recombinant adenovirus expressing rat p53 cloned from a REF cell line immortalized by Ad5 E1A, as well as that expressing murine wild-type p53, induced apoptosis in p53-null cells in collaboration with E1A. Thus, it is suggested that the mutation of p53 appears to be not frequent in the spontaneous immortalization of primary rat cells, and that the functional loss of wild-type p53 is not a prerequisite of E1A-mediated immortalization.
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PMID:Adenovirus type 5 E1A immortalizes primary rat cells expressing wild-type p53. 1060 13

The HPV-16 E2 protein is a major regulator of viral DNA replication and gene expression. Through interactions with the viral origin binding protein, E1, it localizes E1 to the origin of replication and stimulates the initiation of viral DNA replication. However, several recent reports have described a number of diverse activities of E2 relating to the induction of apoptosis through both p53 dependent and independent mechanisms, and to induction of growth arrest in both the G1 and G2M phases of the cell cycle. Recent studies have also shown that p53 can specifically inhibit HPV DNA replication, albeit through an unknown mechanism. Since p53 has been described in the replication centres of Herpes Viruses, Adenovirus and SV40 we decided to investigate whether any of the above activities of E2 may be related to an association with p53. We show, in a series of in vitro assays, specific interaction between p53 and HPV-16 E2 via residues in the carboxy terminal half of the E2 protein. Mutational analysis of p53 indicates that sequences in both the DNA binding and oligomerization domains are essential for the interaction, and a mutant of p53 which is unable to bind E2 is also unable to inhibit HPV DNA replication. Finally, using an inducible system of p53 expression we also show that E2 will complex with p53 in vivo. These results raise the intriguing possibility that p53 may also be involved in HPV DNA replication centres, and also provides explanations for some of the diverse activities reported for the HPV E2 proteins.
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PMID:Interaction between the HPV-16 E2 transcriptional activator and p53. 1061 15

Pancreatic cancer has a poor prognosis even when surgical treatment can be accomplished. Studies have demonstrated that pancreatic cancer is associated with various genetic abnormalities in oncogenes and tumor suppressor genes including p53. New therapeutic approaches for pancreatic cancer can be developed by targeting these genetic alterations. Adenovirus (Adv) lacking the 55-kDa E1B protein (E1B55K) replicates preferentially in p53-deficient cancer cells. We constructed E1B55K-deleted Adv (AxE1AdB), and studied its replication and cytopathic effect on pancreatic cancer cells. AxE1AdB replicated in and caused cell death of the p53-deficient pancreatic cancer cell lines tested (e.g., PANC-1, MIAPaCa-2, SU.86.86, BxPC-3, and PK-1). To enhance its therapeutic effect, we examined the combination of coinfecting this restricted replication-competent adenovirus (RRCA) with other Adv. Coinfection of E1-deficient Adv expressing the reporter lacZ gene (AxCAlacZ) together with AxE1AdB resulted in the replication of both viruses and a marked increase in reporter gene expression. PANC-1 cells coinfected with AxE1AdB and the Adv for human IL-2 (AxCAhIL2), produced 110 times more IL-2 than those infected with AxCAhIL2 alone. Similarly, coinfection of AxE1AdB and Adv for human IL-12 augmented the IL-12 production by 370-fold. Injecting AxE1AdB into the PANC-1 tumor of severe combined immunodeficient mice (SCID mice) resulted in marked reduction of the volume of the tumor. Moreover, injecting AxE1AdB with AxCAhIL2 into the PANC-1 tumor resulted in complete regression of the established tumors. These data suggest that RRCA, which augments the antitumor effect of a viral transgene (i.e., cytokines), may be a powerful tool for treating p53-deficient pancreatic cancer.
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PMID:Effective gene therapy for pancreatic cancer by cytokines mediated by restricted replication-competent adenovirus. 1068 Aug 37

Although the mechanisms involved in responses to extracellular or mitochondrial apoptotic signals have received considerable attention, the mechanisms utilized within the nucleus to transduce apoptotic signals are not well understood. We have characterized apoptosis induced by the nuclear death domain-containing protein p84N5. Adenovirus-mediated N5 gene transfer or transfection of p84N5 expression vectors induces apoptosis in tumor cell lines with nearly 100% efficiency as indicated by cellular morphology, DNA fragmentation, and annexin V staining. Using peptide substrates and Western blotting, we have determined that N5-induced apoptosis is initially accompanied by activation of caspase-6. Activation of caspases-3 and -9 does not peak until 3 days after the peak of caspase-6 activity. Expression of p84N5 also leads to activation of NF-kappaB as indicated by nuclear translocation of p65RelA and transcriptional activation of a NF-kappaB-dependent reporter promoter. Changes in the relative expression level of Bcl-2 family proteins, including Bak and Bcl-Xs, are also observed during p84N5-induced apoptosis. Finally, we demonstrate that p84N5-induced apoptosis does not require p53 and is not inhibited by p53 coexpression. We propose that p84N5 is involved in an apoptotic pathway distinct from those triggered by death domain-containing receptors or by p53.
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PMID:Apoptosis induced by the nuclear death domain protein p84N5 is associated with caspase-6 and NF-kappa B activation. 1084 29

Adenovirus-p53-mediated apoptosis has been extensively evaluated in animal xenografts derived from human epithelial tumors and recently began testing in phase I clinical trials, but has not been evaluated for lymphoid malignancies. Cell lines derived from anaplastic large cell lymphoma (ALCL) carrying the t(2;5) translocation are efficiently transduced by adenoviral vector expressing p53 and undergo apoptosis. To test the in vivo efficiency of adenovirus-mediated-p53 expression and apoptosis induction, SUDHL-1 cells (derived from human ALCL) were injected subcutaneously into athymic nude mice. Cells from the xenograft had typical morphology of human ALCL by standard hematoxylin-eosin staining, CD5+, CD45+ and CD30+ immunophenotype, the t(2;5) translocation by PCR. Six tumors from an initial set of mice were evaluated for apoptosis by TUNEL and for necrosis by hematoxylin-eosin staining 48-72 h after injection with 1 x 108 p.f.u. of AdWTp53 (adenoviral vector expressing p53), of AdNull (adenoviral vector backbone) and PBS (mock), respectively. TUNEL staining was positive only in tumors injected with AdWTp53 and was mainly localized around the needle track. Differences of the means of the counts of the necrotic cells were statistically significant at P = 0.02 between AdWTp53 and mock and only borderline between AdWTp53 and AdNull. Twenty-three tumors from a separate set of mice were subsequently injected with AdWTp53, AdNull and PBS and evaluated for in vivo tumor response. Three total injections of viral vectors (1 x 108 p.f.u.) and PBS were given every 48-72 h. Only tumors injected with AdWTp53 showed tumor growth inhibition with a mean final tumor volume that was statistically significantly smaller than AdNull (P = 0.007) and mock (P = 0.002). Based on these results we foresee a potential application of adenovirus-mediated p53 apoptosis as gene therapy of lymphomas.
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PMID:Adenovirus-p53-mediated gene therapy of anaplastic large cell lymphoma with t(2;5) in a nude mouse model. 1084 52

Survival factors suppress apoptosis by activating the serine/threonine kinase Akt. To investigate the molecular mechanism underlying activated Akt's ability to protect neurons from hypoxia or nitric oxide (NO) toxicity, we focused on the apoptosis-related functions of p53 and caspases. We eliminated p53 by employing p53-deficient neurons and increased p53 by infection with recombinant adenovirus capable of transducing p53 expression, and we now show that p53 is implicated in the apoptosis induced by hypoxia or NO treatments of primary cultured hippocampal neurons. Although hypoxia and NO induced p53, treatment with insulin-like growth factor-1 significantly inhibited caspase-3-like activation, neuronal death and transcriptional activity of p53. These insulin-like growth factor-1 effects are prevented by wortmannin, a phosphatidylinositol 3-kinase inhibitor. Adenovirus-mediated expression of activated-Akt kinase suppressed p53-dependent transcriptional activation of responsive genes such as Bax, suppressed caspase-3-like protease activity and suppressed neuronal cell death with no effect on the cellular accumulation and nuclear translocation of p53. In contrast, overexpression of kinase-defective Akt failed to suppress these same activities. These results suggest a mechanism where Akt kinase activation reduces p53's transcriptional activity that ultimately rescues neurons from hypoxia- or NO-mediated cell death.
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PMID:Akt activation protects hippocampal neurons from apoptosis by inhibiting transcriptional activity of p53. 1105 21

Adenovirus E4orf4 protein has been shown to induce transformed cell-specific, protein phosphatase 2A-dependent, and p53-independent apoptosis. It has been further reported that the E4orf4 apoptotic pathway is caspase-independent in CHO cells. Here, we show that E4orf4 induces caspase activation in the human cell lines H1299 and 293T. Caspase activation is required for apoptosis in 293T cells, but not in H1299 cells. Dominant negative mutants of caspase-8 and the death receptor adapter protein FADD/MORT1 inhibit E4orf4-induced apoptosis in 293T cells, suggesting that E4orf4 activates the death receptor pathway. Cytochrome c is released into the cytosol in E4orf4-expressing cells, but caspase-9 is not required for induction of apoptosis. Furthermore, E4orf4 induces accumulation of reactive oxygen species (ROS) in a caspase-8- and FADD/MORT1-dependent manner, and inhibition of ROS generation by 4,5-dihydroxy-1, 3-benzene-disulfonic acid (Tiron) inhibits E4orf4-induced apoptosis. Thus, our results demonstrate that E4orf4 engages the death receptor pathway to generate at least part of the molecular events required for E4orf4-induced apoptosis.
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PMID:Caspase activation by adenovirus e4orf4 protein is cell line specific and Is mediated by the death receptor pathway. 1113 92

p73 has been shown to transcriptionally activate genes positively responsive to wild-type p53. In order to undertake a comparative study of functions of p53 and p73 we have cloned the cDNA of p73 from MCF-7 cells. Adenovirus onco-protein E1A inhibits the transactivation by p73; a deletion mutant of E1A incapable of interacting with p300 and CREB-binding protein (CBP) fails to disrupt the transactivation. Furthermore, CBP increases the transactivation mediated by p73 suggesting that CBP may function as a co-activator and E1A inhibits p73-mediated transactivation by sequestering p300 or CBP. We show that p73 can transcriptionally inhibit a number of cellular and viral promoters. However, wild-type p53, p73 alpha and p73 beta differ in their ability to inhibit transcriptional activity of different promoters. While wild-type p53 inhibits the promoters of the human cytomegalovirus (CMV) immediate-early gene, the long terminal repeat of human immunodeficiency virus type 1 (HIV LTR), human cyclin A (cyc A) gene, and insulin-like growth factor receptor I (IGF-I-R), p73 alpha only inhibits the HIV LTR and cyc A promoters significantly; and p73 beta inhibits the CMV, HIV LTR and cyc A promoters. A mutant of p73 alpha having amino acid substitutions at positions 268 and 300 on the presumptive DNA-binding domain fails to transactivate the p21 promoter but represses the CMV and the HIV LTR promoter quite efficiently showing that the mechanisms of transactivation and repression by p73 are different. Interestingly, p73 alpha transactivates the IGF-I-R promoter, which is inhibited by wild-type p53; p73 beta has no significant effect on this promoter. This is a unique situation where p73 alpha differs from p73 beta as well as p53.
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PMID:Differential modulation of cellular and viral promoters by p73 and p53. 1117 10

There is evidence that loss of function of the von Hippel-Lindau (VHL) gene causes transcriptional activation of the vascular endothelial growth factor (VEGF) gene, which in turn may lead to increased proliferation of vascular endothelial cells. We hypothesized that transfer of VHL gene, a tumor suppressor gene, into vascular endothelial cells could cause loss of viability and suppression of its proliferative ability. Human aortic endothelial cells (HAEC) were grown as monolayers and transfected with varying titers of adenovirus containing the VHL cDNA (AdVHL). The negative controls used were adenovirus containing green fluorescent protein (AdGFP), vector alone (AdNull), and infection medium without virus. Adenovirus encoding p53 (Adp53) was used as positive control. Cell viability and proliferation were determined by trypan blue dye exclusion and by a tetrazolium-based colorimetric assay. All experiments were performed in triplicate. Our results showed that proliferative activity in HAEC can be blocked and viability of HAEC reduced by adenovirus-mediated gene transfer of VHL gene. This is the first time that VHL gene has been effectively transferred to HAEC. VHL gene transfer into the vascular endothelium may have potential in limiting proliferative processes, including intimal hyperplasia.
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PMID:Von Hippel-Lindau gene therapy: a novel strategy in limiting endothelial cell proliferative activity. 1122 34


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