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 genetic components required for glucocorticoid induction of apoptosis were studied by using somatic cell hybridization. Intertypic whole-cell hybrids were generated by crossing the glucocorticoid-resistant rat liver cell line Fado-2 with the glucocorticoid-sensitive mouse thymoma cell line BW5147.3. Morphological and biochemical criteria were used to assess sensitivity or resistance to glucocorticoid-induced cell death. Both phenotypes were observed, and all of the hybrids retained a functional glucocorticoid receptor as judged by their abilities to induce the metallothionein gene in response to dexamethasone (Dex). Sensitivity to apoptosis did not correlate with morphological phenotype in that not all suspension cells were sensitive. The effect of glucocorticoids on the expression of apoptosis-linked genes was analyzed in a subset of Dex-sensitive and Dex-resistant hybrids. p53 and c-myc mRNAs were present in parental cells as well as sensitive and resistant hybrid cells, and their levels were not affected by glucocorticoid treatment. bcl-2 expression was restricted to the thymoma cell line and was also not affected by glucocorticoids. We did not detect any bcl-2 mRNA in the hepatoma cell line and the hybrids, suggesting that, as with most tissue-specific genes, bcl-2 is regulated in trans. Furthermore, while the majority of hybrids analyzed retained a full complement of mouse chromosomes, sensitive hybrids were missing some rat chromosomes (preferentially chromosomes 16 and 19), indicating that apoptosis is subject to trans repression. Resistant cells thus appear to repress the activity or synthesis of a nuclear factor that interacts with a glucocorticoid-dependent gene(s) to activate the cell death pathway.
 ...
PMID:Evidence for trans regulation of apoptosis in intertypic somatic cell hybrids. 806 45

Stimulation of the B cell antigen receptor (BCR) of the murine immature WEHI-231 B lymphoma with anti-immunoglobulin antibodies leads to irreversible growth arrest and apoptosis. As in normal B cells, membrane immunoglobulin (mIg) ligation in WEHI-231 cells triggers a series of signaling cascades from the BCR to intracellular compartments. In order to address the role of early signals in mediating the growth arrest of WEHI-231 cells, we have generated two variants resistant to the anti-Ig-mediated inhibitory effect. Some of the properties of these variants have been recently described in terms of bcl-2 and c-myc gene regulation. We report here that these variants can be further distinguished from the wild type on the basis of significant alterations in the early biochemical events which follow mIg ligation. Both Ca2+ signals and patterns of protein tyrosine phosphorylation were affected in these variants, suggesting that alterations in the early signal transduction machinery may have profound effects on the fate of B cells. In addition, we found that expression of the p75HS1 substrate of p53/56lyn was strikingly reduced in both variants as compared to the wild type. These findings support the view that p75HS1 may play a critical role in BCR-dependent signaling cascades.
 ...
PMID:Signaling properties of anti-immunoglobulin--resistant variants of WEHI-231 B lymphoma cells. 808 19

Paired samples of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and the subsequent diffuse large cell lymphoma (DLL) of six cases of Richter's syndrome were investigated to establish the clonal relationship between the CLL/SLL and the DLL components and to define the oncogene and/or tumor-suppressor gene alterations involved in the morphologic transformation of CLL/SLL. Southern blot hybridization analysis showed identical clonal immunoglobulin (Ig) gene-rearrangement patterns in the CLL/SLL and DLL components in four cases and different Ig gene-rearrangement patterns in two cases. Polymerase chain reaction (PCR) amplification, cloning, and DNA sequencing of complementary determinant region 3 (CDR3) of the Ig-heavy chain gene of one of the two cases in which the Ig gene-rearrangement patterns were different showed nonidentical sequences in the CLL/SLL and DLL components. In the other case, monomorphic Epstein-Barr virus (EBV) genome integration was detected in the DLL but not in the CLL, suggesting that the CLL and DLL components in this case of Richter's syndrome also represent unrelated clones. Single-strand conformation polymorphism (SSCP) analysis and sequencing of exons 5 through 9 of the p53 tumor-suppressor gene showed a mutation in codon 176 of the DLL but not in the CLL/SLL component in one case where the CLL/SLL and DLL represented different clones. The p53 mutation probably played a role in the development of the lymphoma rather than morphologic transformation of the CLL/SLL in this case. SSCP analysis and sequencing also showed identical mutations in codon 282 in both the CLL/SLL and DLL components in a case where the CLL and DLL represented identical clones. Thus, this p53 gene mutation was present both before and after morphologic transformation, and therefore, probably did not play a primary role in this process. Southern blot hybridization analysis failed to show evidence of bcl-1, bcl-2, c-myc proto-oncogene or retinoblastoma (Rb) tumor-suppressor gene rearrangements in these six cases of Richter's syndrome. In conclusion, the original CLL/SLL and the subsequent DLL in Richter's syndrome may or may not be derived from identical clones, and the well-known proto-oncogenes and tumor-suppressor genes do not appear to play an obvious and consistent role in the morphologic transformation of CLL/SLL to DLL.
 ...
PMID:Molecular genetic demonstration of the diverse evolution of Richter's syndrome (chronic lymphocytic leukemia and subsequent large cell lymphoma). 811 38

Apoptotic cell death is physiological. Malignant cells often escape programmed cell death. Many genes that promote (p53) or antagonize (bcl-2, fes) apoptosis have been recognized. Apoptosis promoter genes can be activated by growth factor or hormone withdrawal in growth factor- or hormone-dependent tumor cells. Malignant cells acquiring apoptosis-resistance, still can be killed by cytotoxic lymphocytes releasing lymphotoxins. This phenomenon gives further support to the therapeutic use of activated and expanded lymphocyte populations and/or apoptosis-inducing cytokines. Chemotherapeutic agents (esp. topoisomerase inhibitors) frequently kill tumor cells by activating programmed cell death (PCD). Biologicals and chemotherapeutics may synergize in evoking apoptosis. We propose the cloning of apoptotic genes and their transfer by transfection in vivo into tumor cells. While transfection of genes into tumor cells in vitro is widely practiced, the lack of proper technology for transfection in vivo and the unknown aspects of apoptotic cell death are recognized.
 ...
PMID:Apoptosis by genetic engineering. 815 15

Apoptosis is an active mechanism for cell death that is characterized by unique biochemical processes, including nuclear condensation, cytoplasmic compaction and breaking up of the cells into a number of membrane-bound fragments called apoptotic bodies. Many physiological cell death is known to proceed by apoptosis, and importance of cell death in a variety of biological phenomena is now well recognized. Eukaryotic molecular biology resulted in the identification of several genes with an ability to modulate apoptosis. Some genes induce and the others inhibit apoptotic cell death. These include oncogenes (bcl-2, myc etc), anti-oncogenes (p53) and cell surface antigen genes (Fas, TNF receptor etc). Genetical approach to dissect programmed cell death, majority of which proceed by apoptosis resulted in the identification of several crucial genes involved in cell death processes (ced 3, ced 4, ced 9 etc. in C. elegans). In this chapter, I will overview genes involved in cell death, and show where we are now standing toward complete understanding of apoptosis in biochemical terms.
 ...
PMID:[Molecular biology of cell death]. 815 83

Apoptosis is a kind of programmed cell death, that is, intrinsically programmed "cell suicide process". Mammalian thymic lymphocytes, thymocytes, show a typical apoptosis immediately after a low dose irradiation. Apoptosis appears also during radiotherapy of tumor, especially of thymoma. Tumor suppressor gene such as p53 and oncogene such as bcl-2 are found to be closely related to apoptotic processes in a cell. Possible mechanisms underlying interrelationship between expression of these genes, apoptosis and carcinogenesis were discussed.
 ...
PMID:[Radiation and apoptosis]. 815 85

Apoptosis is a distinct mode of cell death that is responsible for deletion of cells in normal tissues; it also occurs in specific pathologic contexts. Morphologically, it involves rapid condensation and budding of the cell, with the formation of membrane-enclosed apoptotic bodies containing well-preserved organelles, which are phagocytosed and digested by nearby resident cells. There is no associated inflammation. A characteristic biochemical feature of the process is double-strand cleavage of nuclear DNA at the linker regions between nucleosomes leading to the production of oligonucleosomal fragments. In many, although not all of the circumstances in which apoptosis occurs, it is suppressed by inhibitors of messenger RNA and protein synthesis. Apoptosis occurs spontaneously in malignant tumors, often markedly retarding their growth, and it is increased in tumors responding to irradiation, cytotoxic chemotherapy, heating and hormone ablation. However, much of the current interest in the process stems from the discovery that it can be regulated by certain proto-oncogenes and the p53 tumor suppressor gene. Thus, c-myc expression has been shown to be involved in the initiation of apoptosis in some situations, and bcl-2 has emerged as a new type of proto-oncogene that inhibits apoptosis, rather than stimulating mitosis. In p53-negative tumor-derived cell lines transfected with wild-type p53, induction of the gene has, in rare cases, been found to cause extensive apoptosis, instead of growth arrest. Finally, the demonstration that antibodies against a cell-surface protein designated APO-1 or Fas can enhance apoptosis in some human lymphoid cell lines may have therapeutic implications.
 ...
PMID:Apoptosis. Its significance in cancer and cancer therapy. 815 6

Intact nuclei derived from murine metastatic large-cell lymphoma and human chronic myelogenous leukemia cells were digested to discrete subchromatin deoxyribonucleoprotein/ribonucleoprotein precursor complexes by treatment with Msp-I. The resultant complexes were composed of nucleoproteins (NPs) that were isolated and purified by two-dimensional isoelectric focusing/sodium dodecylsulfate polyacrylamide gel electrophoresis (2D-SDS-PAGE), electroelution from the gel, and removal of SDS by extractigel chromatography. Various NPs purified by 2D-SDS-PAGE were examined for the presence of oncogenes and tissue-specific genes using a dot-blot hybridization technique. The RNA polymerase products of NPs were labeled, purified, and subsequently used in a back-hybridization assay to identify transcripts for particular genes. By utilizing a 2D-SDS-PAGE Southwestern technique in parallel with the dot-blot and RNA back-hybridization assays, we assessed whether it is possible to "track" a gene and its associations in particular NPs. In patients with chronic myelogenous leukemia, we screened approximately 1000 NPs for bcl-2 sequences and found them present in a single NP of apparent M(r) approximately 19,000, pI approximately 5.5. In murine RAW117-H10 cells transformed by the abl oncogene, we found by Western analysis that an antigen cross-reacting with abl antigen was localized to a p53 gene-containing NP of apparent M(r) approximately 22,000, pI approximately 7.2. A coincident Southwestern experiment using the same blot showed that the abl gene was bound by the same NP. The techniques described present the basis for "tracking" a particular gene to individual NPs and studying its relationship to other genes, their respective gene products, and its binding properties with particular NPs.
 ...
PMID:Nucleoprotein complexes from metastatic cells containing oncogenes and tissue-specific genes: a novel method to track genes associated with specific nucleoproteins. 816 4

bcl-2 and p53 gene products have been both linked to programmed cell death pathways. We have analyzed several human breast cancer cell lines for the expression of bcl-2 and p53. We found an inverse correlation between the expression of the two proteins. The result suggested that mutant p53 could substitute for bcl-2 function in breast cancer cells and that could also down-regulate bcl-2 expression. We found, indeed, that overexpression of a mutant p53 (mut 175) in MCF-7 cells could induce down-regulation of bcl-2 both at protein and mRNA level. However, the promoter region of the human bcl-2 gene does not contain the negative regulatory element responsible for the down-regulation. If this mechanism will be proved also for the wild-type p53 allele, it may disclose a possible mechanism for p53-induced apoptosis: down-regulation of bcl-2.
 ...
PMID:Down-regulation of bcl-2 by p53 in breast cancer cells. 817 12

Recently, both Bcl-2, which promotes cell survival, and Bax, which promotes cell death, have been implicated as major players in the control of apoptotic pathways, and it has been suggested that the ratio of Bcl-2 and Bax protein controls the relative susceptibility of cells to death stimuli. We have used M1 myeloid leukemia cells and genetically engineered M1 variants as a model system to study apoptosis induced by two distinct apoptotic stimuli. This includes apoptosis induced by activation of wild type p53 function of a temperature sensitive p53 transgene expressed in M1 cells, which do not express endogenous p53, and apoptosis induced by TGF beta 1. It is shown that the kinetics of apoptosis induced by p53 is more rapid than apoptosis induced by TGF beta 1. It is also shown that ectopic expression of Bcl-2, at levels which blocked TGF beta 1-induced apoptosis of M1 cells, delayed, but did not block, p53-induced apoptosis. Both p53 and TGF beta 1 down-regulated endogenous Bcl-2 expression, but only p53 up-regulated Bax expression, where bax has been identified as a p53 immediate early response gene. Thus, the p53-mediated up-regulation of Bax may provide at least a partial explanation for the more rapid rate of apoptosis induced by p53 compared to by TGF beta 1, as well as for the ineffectiveness of ectopoic Bcl-2 to abrogate p53-mediated apoptosis. These findings provide first insights to the molecular mechanisms which mediate p53-induced apoptosis, identifying bax and bcl-2 as p53 regulated genes, and serve as a paradigm of how the intracellular balance of Bcl-2 to Bax is differentially altered by distinct death stimuli.
 ...
PMID:Immediate early up-regulation of bax expression by p53 but not TGF beta 1: a paradigm for distinct apoptotic pathways. 818 78


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