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)

The aim of this study was to determine the mechanisms responsible for the growth inhibitory effect of hyperthermia and verapamil in human colon cancer cell line HT-29. Apoptotic cell death was verified by flow cytometry analysis. The effect of treatment with hyperthermia and verapamil on the expression of apoptosis-associated proteins including Bcl-2, p53, bax, and c-Myc was studied by Western blot analysis. Changes in intracellular calcium homeostasis was analysed by fluorescence microscopy. The combination of 42 degrees C hyperthermia and verapamil caused a significant delay of human colon cancer cell proliferation as a result of apoptosis. Administration of these agents alone did not cause any cell inhibitory effect. Our experiments have shown that HT-29 cells constitutively express apoptosis-promoting proteins, such as Bax and c-Myc, while they fail to produce Bcl-2. Therefore, we hypothesize that HT-29 cells must have Bcl-2 independent pathways to protect cells against death-inducing signals. Also, apoptosis of HT-29 cells produced by hyperthermia in the presence of verapamil is a p53-independent process. Verapamil, when it did not act as a calcium channel blocker or inhibitor of release from intracellular storages under hyperthermic conditions, accelerated the increase of [Ca2+]i in HT-29 cells which resulted in programmed cell death (apoptosis).
 ...
PMID:Apoptosis induced by hyperthermia and verapamil in vitro in a human colon cancer cell line. 935 39

Studies have indicated that deregulated oncogene expression can result in either programmed cell death or proliferation, depending on the cellular microenvironment. However, little is known about whether oncogenic signals in themselves are able to activate a cellular apoptotic program. We have tested the hypothesis that oncogenic signals in the absence of gene expression are sufficient to induce cell death, which would indicate that constitutive expression of antiapoptotic genes is necessary for maintenance of the transformed state. Using two highly specific RNA polymerase (RNAP) II inhibitors, 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) and alpha-amanitin, which inhibit RNAP II function by two distinct mechanisms, we found that inhibition of gene expression substantially increased apoptosis in a time- and dose-dependent manner in p53+/+- and p53(-/-)-transformed mouse embryonic fibroblasts and in HeLa cells, demonstrating that this type of apoptosis does not require wild-type p53. Engineered expression of an alpha-amanitin resistance RNAP II gene rendered cells resistant to induction of apoptosis by alpha-amanitin without affecting their sensitivity to DRB, indicating that alpha-amanitin induces apoptosis solely by inhibiting RNAP II function and not by a nonspecific mechanism. DRB-induced apoptosis was independent of the cell cycle or ongoing DNA replication, since DRB induced similar levels of apoptosis in asynchronous cells and cells synchronized by collection at mitosis. Inhibition of RNAP II in untransformed cells like Rat-1 or human AG1522 fibroblasts resulted not in apoptosis but in growth arrest. In contrast, deregulated expression of c-Myc in Rat-1 cells dramatically increased their sensitivity to DRB, directly demonstrating that apoptosis following inhibition of RNAP II function is greatly enhanced by oncogenic expression. The requirement for RNAP II function to prevent oncogene-induced apoptosis implies the need for the constitutive expression of an antiapoptotic gene(s) to maintain the transformed state. The differential sensitivities of untransformed and transformed cells to induction of apoptosis by transcriptional inhibition, coupled with the finding that this type of apoptosis is independent of p53 status, suggest that inhibition of RNAP II may be exploited therapeutically for the design of successful antitumor agents.
 ...
PMID:Transformed cells require continuous activity of RNA polymerase II to resist oncogene-induced apoptosis. 937 62

The ras proto-oncogene is frequently mutated in human tumors and functions to chronically stimulate signal transduction cascades resulting in the synthesis or activation of specific transcription factors, including Ets, c-Myc, c-Jun, and nuclear factor kappa B (NF-kappaB). These Ras-responsive transcription factors are required for transformation, but the mechanisms by which these proteins facilitate oncogenesis have not been fully established. Oncogenic Ras was shown to initiate a p53-independent apoptotic response that was suppressed through the activation of NF-kappaB. These results provide an explanation for the requirement of NF-kappaB for Ras-mediated oncogenesis and provide evidence that Ras-transformed cells are susceptible to apoptosis even if they do not express the p53 tumor-suppressor gene product.
 ...
PMID:Requirement of NF-kappaB activation to suppress p53-independent apoptosis induced by oncogenic Ras. 938 87

Normal fibroblasts are resistant to the cytotoxic action of tumor necrosis factor (TNF), but are rendered TNF-sensitive upon deregulation of c-Myc. To assess if oncoproteins induce the cytotoxic TNF activity by modulating TNF signaling, we investigated the TNF-elicited signaling responses in fibroblasts containing a conditionally active c-Myc protein. In association with cell death, c-Myc impaired TNF-induced activation of phospholipase A2, JNK protein kinase and cell survival-signaling-associated NF-kappaB transcription factor complex. The TNF-induced death of mouse primary fibroblasts expressing deregulated c-Myc was inhibited by transient overexpression of the p65 subunit of NF-kappaB, which increased NF-kappaB activity in the cells. Unlike other TNF-induced signals, TNF-induced accumulation of the wild-type p53 mRNA and protein was not inhibited by c-Myc. TNF, with c-Myc, induced apoptosis in mouse primary fibroblasts but only weakly in p53-deficient primary fibroblasts. The C-terminal domain of p53, which is a transacting dominant inhibitor of wild-type p53, failed to inhibit apoptosis by c-Myc and TNF, suggesting that the cell death was not dependent on the transcription-activating function of p53. Taken together, the present findings show that the cytotoxic activity of TNF towards oncoprotein-expressing cells involves p53 and an impaired signaling for survival in such cells.
 ...
PMID:Induction of TNF-sensitive cellular phenotype by c-Myc involves p53 and impaired NF-kappaB activation. 940 67

The lactate dehydrogenase A (LDH-A) gene, whose product participates in normal anaerobic glycolysis and is frequently increased in human cancers, has been identified as a c-Myc-responsive gene. It was of interest, therefore, to compare the effect of glucose deprivation in c-Myc-transformed and nontransformed cells. We observed that glucose deprivation or treatment with the glucose antimetabolite 2-deoxyglucose caused nontransformed cells to arrest in the G0/G1 phase of the cell cycle. In contrast, c-Myc-transformed fibroblasts, lymphoblastoid, or lung carcinoma cells underwent extensive apoptosis. Ectopic expression of LDH-A alone in Rat1a fibroblasts was sufficient to induce apoptosis with glucose deprivation but not with serum withdrawal, suggesting that LDH-A mediates the unique apoptotic effect of c-Myc when glycolysis is blocked. The apoptosis caused by glucose deprivation was blocked by Bcl-2 expression but appeared to be independent of wild-type p53 activity. These studies provide insights on the coupling of glucose metabolism and the cell cycle in c-Myc-transformed cells and may in the future be exploited for cancer therapeutics.
 ...
PMID:A unique glucose-dependent apoptotic pathway induced by c-Myc. 946 46

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.
 ...
PMID:Involvement of CPP32/Caspase-3 in c-Myc-induced apoptosis. 946 64

Previously we have shown that nitric oxide (NO) donors induced apoptosis in vascular smooth muscle cells (VSMCs). However, the mechanisms by which NO induced apoptosis in VSMCs are entirely unknown. In the present study, we intended to identify the mechanism by which NO donors induce apoptosis in VSMCs. First, we evaluated the expression of c-Myc, P53, and Bcl-2 proteins in VSMCs treated by NO donors. c-Myc and P53 protein expression increased after VSMCs were incubated with NO donors for 6 hr and reached a maximum level at 24 hr, while Bcl-2 protein decreased after 12 hr incubation. Next we investigated to see whether the CPP32 protease activation was involved in NO donors-induced apoptosis. In VSMCs treated by NO donors, the increase of CPP32 protease activity was observed and specific inhibition of CPP32 activity significantly prevented apoptosis induced by NO donors in a dose-dependent manner. These results suggest that NO donors induced apoptosis through proto-oncoprotein expression and CPP32-like protease activation.
 ...
PMID:No induced apoptosis accompanying the change of oncoprotein expression and the activation of CPP32 protease. 948 2

Tumor necrosis factor-alpha (TNF-alpha) is a macrophage-derived multifunctional cytokine that acts as a cytostatic or cytotoxic agent in many tumor cells. However, the molecular mechanisms by which tumor cells become sensitive to the cytotoxic action of TNF-alpha are not clear. In this study we demonstrated that the cytotoxicity of TNF-alpha markedly increased in c-Myc overexpressing tumor cells. The stomach cancer cell line, SNU-16, in which c-Myc expression is high due to gene amplification, showed programmed cell death detected by DNA fragmentation and morphological changes. An antisense c-myc S-oligonucleotide specifically inhibited the TNF-alpha-induced apoptosis of SNU-16 cells, provided that the oligonucleotide was added 4 h prior to TNF-alpha treatment. Western immunoblot analysis of p53 and Bax showed that in this cell line, TNF-alpha increased the level of these proteins in a time-dependent manner and that this effect lasted for 12 h. Taken together these data indicate that the deregulation of c-Myc plays an important role in sensitizing tumor cells to TNF-alpha. Furthermore, TNF-alpha-induced apoptosis in the SNU-16 cell line showed increased expression of p53 and Bax protein levels following TNF-alpha treatment. Therefore, we suggest that TNF-alpha-induced apoptosis, which is cytotoxic to tumor cells, is coupled with a p53 and Bax apoptotic pathway.
 ...
PMID:Increased susceptibility of the c-Myc overexpressing cell line, SNU-16, to TNF-alpha. 956 90

We found that over-expression of PU.1, a member of the ets family of transcription factors, induces apoptotic cell death along with differentiation of DMSO stimulation in murine erythroleukemia (MEL) cells. To elucidate the molecular mechanisms of apoptosis, cell-cycle distribution and expression of several genes encoding apoptosis-promoting and -inhibiting factors were analyzed during the process of PU.1-induced apoptosis. FACS analysis revealed that cells were accumulated in the G0/G1 phase of the cell cycle before apoptosis. Morphological analysis of PI-stained nuclei of the apoptotic cells sorted by a FACScan showed 22.6% in G0/G1, 35.8% in S and 8.5% in G2/M phase by fluorescent microscopy after cell sorting, suggesting that PU.1-induced apoptosis in MEL cells occurs in G0/G1 through S phases. Semi-quantitative RT-PCR revealed that expression of c-myc and bcl-2 genes was reduced during the apoptotic process, while expression of bax and bcl-X(L) genes was not changed. Expression of the p53 gene was reduced rather than enhanced, suggesting that PU.1-induced apoptosis in MEL cells is p53-independent. Apoptosis was inhibited by adding 30% serum in culture, while no reduction of c-myc and bcl-2 gene expression was observed. Forced expression of the c-myc, bcl-2 and bcl-X(L) genes protected MEL cells from apoptosis. Our results suggest that a reduction of at least 2 important apoptosis-inhibiting factors, c-Myc and Bcl-2, is involved in PU.1-induced apoptosis in MEL cells.
 ...
PMID:Down-regulation of c-myc and bcl-2 gene expression in PU.1-induced apoptosis in murine erythroleukemia cells. 959 Jan 29

We studied overexpression of p53, Bcl-2, Bcl-6, c-Myc and Mdm2 proteins by immunohistochemistry for a total of 27 primary central nervous system B cell lymphomas (CNS lymphomas) in immunocompetent patients and one CNS lymphoma in an AIDS patient. The expression of Epstein-Barr (EB) virus-encoded small RNA-1 (EBER-1) was also analysed using in situ hybridisation. Overexpression (more than 20% of cells stained) of p53 protein was detected in 8 of 27 immunocompetent cases (30%); 6 cases showed a nuclear stain and 2 cases showed cytoplasmic stain (nuclear exclusion). Strong Bcl-2 or Bcl-6 immunoreactivity suggestive of overexpression was seen, respectively, in 5 (19%) and 6 (22%) cases; 2 cases were positive for both immunoreactivities. Interestingly, overexpression of Bcl-2 or Bcl-6 was not seen in the cases which showed p53 overexpression (P < 0.03; chi-square test). EBER-1 expression was not detected in any of the 27 immunocompetent cases, but was found in the AIDS-related CNS lymphoma, which also showed an overexpression of Bcl-6, but not Bcl-2. None of the cases showed c-Myc or Mdm2 overexpression. Taken together, it is suggested that CNS lymphoma in immunocompetent hosts is a distinct disease that has a different molecular profile from those of systemic lymphoma and/or AIDS-related CNS lymphoma.
 ...
PMID:Expression of oncogenic molecules in primary central nervous system lymphomas in immunocompetent patients. 960 May 97


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>