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)

Nuclear factor kappaB (NF-kappaB) appears to participate in the excitotoxin-induced apoptosis of striatal medium spiny neurons. To elucidate molecular mechanisms by which this transcription factor contributes to NMDA receptor-triggered apoptotic cascades in vivo, rats were given the NMDA receptor agonist quinolinic acid (QA) by intrastriatal infusion, and the role of NF-kappaB in the induction of apoptosis-related genes and gene products was evaluated. QA administration induced time-dependent NF-kappaB nuclear translocation. The nuclear NF-kappaB protein after QA treatment was comprised mainly of p65 and c-Rel subunits as detected by gel supershift assay. Levels of c-Myc and p53 mRNA and protein were markedly increased at the time of QA-induced NF-kappaB nuclear translocation. Immunohistochemical analysis showed that c-Myc and p53 induction occurred in the excitotoxin-sensitive medium-sized striatal neurons. NF-kappaB nuclear translocation was blocked in a dose-dependent manner by the cell-permeable recombinant peptide NF-kappaB SN50, but not by the NF-kappaB SN50 control peptide. NF-kappaB SN50 significantly inhibited the QA-induced elevation in levels of c-Myc and p53 mRNA and protein. Pretreatment or posttreatment with NF-kappaB SN50, but not the control peptide, also substantially reduced the intensity of QA-induced internucleosomal DNA fragmentation. The results suggest that NF-kappaB may promote an apoptotic response in striatal medium-sized neurons to excitotoxic insult through upregulation of c-Myc and p53. This study also provides evidence indicating an unique signaling pathway from the cytoplasm to the nucleus, which regulates p53 and c-Myc levels in these neurons during apoptosis.
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PMID:Nuclear factor kappaB nuclear translocation upregulates c-Myc and p53 expression during NMDA receptor-mediated apoptosis in rat striatum. 1023 31

Mad protein has been shown as an antagonist of c-Myc protein in some cell lines. The effect of Mad protein to the malignant phenotype of human hepatoma BEL-7404 cell line was investigated experimentally. An eukarryotic vector pCDNA III containing full ORF fragment of mad cDNA was transfected into targeted cells. Under G418 selection, stable Mad-overexpressed cells were cloned. Studies on the effect of Mad over-expression in cell proliferation and cell cycle revealed that cell morphology of the Mad-overexpressed BEL-7404-M1 cells was significantly different from the parent and control vector transfected cells. DNA synthesis, cell proliferation and anchorage-independent growth in soft-agar of the mad-transfected cells were partially inhibited in comparison to control cells. Flow Cytometry analysis indicated that mad over-expression might block more transfectant cells at G0/G1 phase, resulting in the retardation of cell proliferation. RT-PCR detected a marked inhibition of the expression of cdc25A, an important regulator gene of G0/G1 to S phase in cell cycle. It was also found that Mad protein overexpression could greatly suppress p53-mediated apoptosis in BEL-7404-M1 cells in the absence of serume. Thus, Mad proteins may function as a negative regulator antagonizing c-Myc activity in the control of cell growth and apoptosis in human hepatocellular carcinoma BEL-7404 cells.
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PMID:Mad-overexpression down regulates the malignant growth and p53 mediated apoptosis in human hepatocellular carcinoma BEL-7404 cells. 1032 88

The contact of natural killer (NK) cells with foreign cells and with certain virus-infected or tumor cells triggers the cytolytic machinery of NK cells. This triggering leads to exocytosis of the cytotoxic NK cell granules. The oncoproteins c-Myc and E1A render cells vulnerable to NK cell mediated cytolysis yet the mechanisms of sensitization are not well understood. In a model where foreign cells (rat fibroblasts) were cocultured with human IL-2 activated NK cells, we observed that NK cells were capable of efficiently killing their targets only if the cells overexpressed the oncogene c-Myc or E1A. Both the parental and the oncogene expressing fibroblasts similarly triggered phosphoinositide hydrolysis in the bound NK cells, demonstrating that NK cells were cytolytically activated in contact with both resistant parental and oncogene expressing sensitive target fibroblasts. The cell death was independent of wild-type p53 and was not inhibited by an anti-apoptotic protein EIB19K. These results provided evidence that c-Myc and E1A activated the NK cell induced cytolysis at a post-triggering stage of NK cell-target cell interaction. In consistence, the c-Myc and E1A overexpressing fibroblasts were more sensitive to the cytolytic effects of isolated NK cell-derived granules than parental cells. The data indicate that oncogenes activate the cytotoxicity of NK cell granules. This mechanism can have a role in directing the cytolytic action of NK cells towards the virus-infected and cancer cells.
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PMID:c-Myc and E1A induced cellular sensitivity to activated NK cells involves cytotoxic granules as death effectors. 1032 64

The nuclear factor-kappaB (NF-kappaB)/Rel family of transcription factors has been implicated in promoting hepatocyte survival during development and liver regeneration following partial hepatectomy. Inhibition of NF-kappaB/Rel activity by microinjection of the specific inhibitor IkappaB-alpha induces apoptosis in a nontransformed normal murine hepatocyte (NMH) cell line. Here, we demonstrate that apoptosis resulting from such inhibition requires down-regulation of the c-Myc proto-oncoprotein and occurs independently of p53 tumor suppressor function. NMH cells plated at low density displayed low sensitivity to IkappaB-alpha-induced apoptosis and high levels of c-Myc protein expression. Comicroinjection of IkappaB-alpha with the c-Myc antagonist Mad1-glutathione S-transferase fusion protein greatly enhanced cell death. In addition, transient cotransfection of low-density NMH and AML12 hepatocytes with vectors expressing IkappaB-alpha and antisense c-myc transcripts promoted cell death. Conversely, ectopic c-myc expression significantly decreased the extent of cell death in NMH cells plated at saturating density, which were characterized by very low levels of c-Myc and high susceptibility to NF-kappaB inhibition-induced cell death. Finally, IkappaB-alpha-induced apoptosis was unaffected in NMH cells expressing a dominant negative p53 protein. Thus, NF-kappaB cooperates with c-Myc in promoting murine hepatocyte survival in a manner independent of p53 tumor suppressor activity.
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PMID:Nuclear factor kappaB cooperates with c-Myc in promoting murine hepatocyte survival in a manner independent of p53 tumor suppressor function. 1035 10

NF-kappaB is an inducible transcription factor, which is regulated by interaction with inhibitory IkappaB proteins. Previous studies linked the activity of NF-kappaB to the proliferative state of the cell. Here we have analysed the function of NF-kappaB in the cell cycle. Inhibition of NF-kappaB in HeLa cells by stable overexpression of a transdominant negative IkappaB-alpha protein reduced cell growth. A kinetic analysis of the cell cycle revealed a retarded G1/S transition. The IkappaB-alpha overexpressing cell clones showed a decreased percentage of cells in the S phase and an impaired incorporation of bromodeoxyuridine (BrdU). The amounts of cyclins A, B1, D1, D3, and E were unchanged, but the G1-specific proteins cyclin D2 and cdk2 were strongly elevated in the IkappaB-alpha overexpressing cell clones. These cell clones also displayed an increase in cyclin D1-dependent kinase activity, pointing to a cell cycle arrest at the late G1 phase. IkappaB-alpha overexpression crosstalked to cell cycle checkpoints via a reduction of transcription factor p53 and elevation of p21WAF. Surprisingly, the IkappaB-alpha overexpressing cells showed an enrichment of c-Myc in the nucleoli, although the total amount of c-Myc protein was unchanged. These experiments identify an important contribution of the NF-kappaB/IkappaB system for the growth of HeLa cells.
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PMID:Repression of NF-kappaB impairs HeLa cell proliferation by functional interference with cell cycle checkpoint regulators. 1035 27

Mantle cell lymphomas (MCLs) are characterized by 11q13 chromosomal translocations and cyclin D1 overexpression. The secondary genetic and molecular events involved in the progression of these tumors are not well known. In this study, we have analyzed 45 MCLs (32 typical and 13 blastoid variants) by comparative genomic hybridization (CGH). To identify the possible genes included in the abnormal chromosome regions, selected cases were analyzed for P53, P16(INK4a), RB, C-MYC, N-MYC, BCL2, BCL6, CDK4, and BMI-1 gene alterations. The most frequent imbalances detected by CGH were gains of chromosomes 3q (49%), 7p (27%), 8q (22%), 12q (20%), 18q (18%), and 9q34 (16%) and losses of chromosomes 13 (44%), 6q (27%), 1p (24%), 11q14-q23 (22%), 10p14-p15 (18%), 17p (16%), and 9p (16%). High-level DNA amplifications were identified in 11 different regions of the genome, predominantly in 3q27-q29 (13%), 18q23 (9%), and Xq28 (7%). The CGH analysis allowed the identification of regional consensus areas in most of the frequently involved chromosomes. Chromosome gains (P =. 02) and losses (P =.01) and DNA amplifications (P =.015) were significantly higher in blastoid variants. The significant differences between blastoid and typical tumors were gains of 3q, 7p, and 12q, and losses of 17p. CGH losses of 17p correlated with P53 gene deletions and mutations. Similarly, gains of 12q and high-level DNA amplifications of 10p12-p13 were associated with CDK4 and BMI-1 gene amplifications, respectively. One of 2 cases with 8q24 amplification showed C-MYC amplification by Southern blot. Alterations in 2p, 3q, 13, and 18q were not associated with N-MYC, BCL6, RB, or BCL2 alterations, respectively, suggesting that other genes may be the targets of these genetic abnormalities in MCLs. Increased number of gains (0 v 1-4 v >4 gains per case) (P =.002), gains of 3q (P =.02), gains of 12q (P =.03), and losses of 9p (P =. 003) were significantly associated with a shorter survival of the patients. These results indicate that an increased number of chromosome imbalances are associated with blastoid variants of MCLs and may have prognostic significance.
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PMID:Increased number of chromosomal imbalances and high-level DNA amplifications in mantle cell lymphoma are associated with blastoid variants. 1036 Nov 35

Expression of c-Myc sensitizes cells to a wide range of pro-apoptotic stimuli. We here show that this pro-apoptotic effect is mediated through release of mitochondrial holocytochrome c into the cytosol. First, activation of c-Myc triggers release of cytochrome c from mitochondria. This release is caspase-independent and blocked by the survival factor IGF-1. Second, c-Myc-induced apoptosis is blocked by microinjection of anticytochrome c antibody. In addition, we show that microinjection of holocytochrome c mimics the effect of c-Myc activation, sensitizing cells to DNA damage and to the CD95 pathway. Both p53 and CD95/Fas signaling have been implicated in c-Myc-induced apoptosis but neither was required for c-Myc-induced cytochrome c release. Nonetheless, inhibition of CD95 signaling in fibroblasts did prevent c-Myc-induced apoptosis, apparently by obstructing the ability of cytosolic cytochrome c to activate caspases. We conclude that c-Myc promotes apoptosis by causing the release of cytochrome c, but the ability of cytochrome c to activate apoptosis is critically dependent upon other signals.
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PMID:c-Myc-induced sensitization to apoptosis is mediated through cytochrome c release. 1036 55

p27Kip1, a cyclin-dependent kinase inhibitor, is a negative regulator of the cell cycle, and apoptosis is a genetically encoded program of cell death. To clarify the relationship between the cell cycle and apoptosis, we investigated expression of p27, cyclin D1 and apoptosis-related proteins (p53, Bax, Bcl-2 and c-Myc) in 60 cases of oral and oropharyngeal squamous-cell carcinoma (SCC) using an immuno-histochemical approach, and evaluated spontaneous apoptosis in vivo. Our most notable finding was that spontaneous apoptosis in the p27-positive group was significantly higher than that in the p27-negative group (p = 0.028). In addition, the percentage of p27-positive cells was clearly correlated with that of Bax-positive cells (gamma = 0.288, p = 0.028) and with that of cyclin D1-positive cells (gamma = 0.416, p = 0.002). Expression of p27 was inversely associated with the clinical stage of total tumor progression (p = 0.027). However, no correlation was found between p27 expression and the following parameters: gender, tumor size, lymph node metastasis, overall survival and disease-free survival. Our results give evidence that the action of the cell-cycle regulator p27 is closely linked with apoptosis in clinical samples from patients and indicate that over-expression of p27 might induce apoptosis in cancer cells through elevation of Bax expression, thereby acting on tumor progression.
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PMID:Expression of p27 is associated with Bax expression and spontaneous apoptosis in oral and oropharyngeal carcinoma. 1037 53

Deregulated expression of c-Myc has been shown to induce or enhance apoptosis in various different cell types. c-Myc requires p53 for apoptosis in some but not all the cell types, indicating heterogeneous mechanisms for c-Myc-induced apoptosis. In B lymphoma line WEHI-231, stable expression of c-Myc has been demonstrated to protect cells from BCR-mediated apoptosis. However, stable expression of c-Myc carrying pro-apoptotic functions may generate variant cells resistant to apoptosis. By utilizing an inducible system for c-Myc, we demonstrated here that deregulated expression of c-Myc induced apoptosis of WEHI-231 by itself, indicating that c-Myc induces apoptosis in WEHI-231 as is the case for other cell types. When transactivation of p53 was inactivated, WEHI-231 cells overexpressing c-Myc no longer underwent apoptosis in the absence of other stimuli, but showed markedly enhanced apoptosis in the presence of BCR ligation. These results indicate that deregulated c-Myc expression enhances apoptosis by a p53-independent pathway in the presence of BCR signaling but requires p53 for apoptosis in the absence of BCR crosslinking in WEHI-231. BCR ligation may thus activate a p53-independent pathway of c-Myc-induced apoptosis.
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PMID:Signaling through the antigen receptor of B lymphocytes activates a p53-independent pathway of c-Myc-induced apoptosis. 1043 90

Polyomavirus middle T antigen does not overcome p53-mediated G(1) arrest in mouse embryo fibroblasts. Middle T antigen still associates with the signaling molecules phosphatidylinositol 3-kinase and SHC and activates the transcriptional activity of c-Myc and AP1 in p53-arrested cells. Examination of cell cycle regulatory proteins indicated that p53 does not interfere with these mitogenic signals but acts later in the G(1) phase of the cell cycle.
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PMID:Middle T antigen activation of signal transduction pathways does not overcome p53-mediated growth arrest. 1043 85


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