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)

Two isoforms of cyclooxygenase (COX) have been identified in eukaryotic cells: a constitutively expressed COX-1 and mitogen-inducible COX-2, which is selectively expressed in response to various inflammatory stimuli. Thus, COX-2 instead of COX-1 is implicated to produce prostanoids mediating inflammatory responses. Major efforts have been focused on identifying nonsteroidal anti-inflammatory drugs (NSAIDS) which can selectively inhibit the enzyme activity of COX-2. Such NSAIDS would be more desirable anti-inflammatory agents in comparison to NSAIDS which inhibit both COX-1 and COX-2. Other than glucocorticoids, pharmacological agents which can selectively suppress the expression of COX-2 without affecting that of COX-1 have not been identified. We report here that radicicol, a fungal antibiotic, is a potent protein tyrosine kinase inhibitor, and that it inhibits the expression of COX-2 without affecting COX-1 expression in lipopolysaccharide (LPS)-stimulated macrophages with the IC50 value of 27 nM. Radicicol inhibited tyrosine phosphorylation of p53/56lyn, a Src family tyrosine kinase and one of the major tyrosine-phosphorylated proteins in LPS-stimulated macrophages. Radicicol also inhibited COX-2 expression in vivo in glomeruli of rats with experimental glomerulonephritis induced by the anti-glomerular basement membrane antibodies, in which COX-2 expression is known to be enhanced. The enzyme activity of COX-1 or COX-2 was not affected by radicicol in macrophages. Radiciciol also suppressed the COX-2 expression induced by IL-1 beta in rat smooth muscle cells. Other protein tyrosine kinase inhibitors suppressed the LPS-induced COX-2 expression in macrophages but at much higher concentrations than needed for radicicol. Radicicol did not inhibit the COX-2 expression induced by phorbol 12-myristate 13-acetate in macrophages. These results suggest that the activation of tyrosine-specific protein kinases is the proximal obligatory step in the LPS-induced signal transduction pathway leading to the induction of COX-2 expression in macrophages. The magnitude of the inhibition of COX-2 protein synthesis by radicicol was much greater than that of the steady state levels of COX-2 mRNA. These results suggest that radicicol inhibits COX-2 expression mainly at post-transcriptional steps.
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PMID:Radicicol, a protein tyrosine kinase inhibitor, suppresses the expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide and in experimental glomerulonephritis. 789 Jun 56

Phagocytosis of pathogens and inert particles such as zymosan by macrophages, and related secretory functions require the combination of several intracellular signals and the reorganization of cytoskeleton. We recently reported that zymosan stimulated the tyrosine phosphorylations of several endogenous substrates in human monocytes. In this work, the relationship between zymosan-stimulated tyrosine phosphoproteins and detergent-insoluble material considered as cytoskeleton was investigated. Triton X-100-insoluble fraction contained two proteins of 53 and 56 kDa that were tyrosine phosphorylated after only 5 min of stimulation with zymosan and remained labeled for 30 min. Because 53- and 56-kDa phosphoproteins migrated, as did some components of the src tyrosine kinase family, namely p53-56lyn, we wondered if 53- and 56-kDa phosphoproteins were related to lyn kinase. First, the amount of immunoreactive p53-56lyn increased in Triton X-100-insoluble fraction as did zymosan-stimulated tyrosine phosphoproteins. This property of p53-56lyn was unique, as no other member of the src family was found in this fraction. Second, when the immunoblots were reprobed with anti-phosphotyrosine mAb, the m.w. of p53-56lyn and tyrosine-phosphorylated proteins were identical in apparent size. Third, p53-56lyn was probably activated after cell stimulation with zymosan, because the phosphorylation levels of a synthetic copolymer of glutamine-tyrosine were increased in Triton X-100-insoluble fraction. In addition, we studied the distribution of lyn kinase and tyrosine phosphoproteins in phagocytozing monocytes. By using immunofluorescence, we showed that lyn kinase was located preferentially in the periphagosomal region in a specific manner, as an src tyrosine kinase such as p59hck, which was not associated with cytoskeleton, was not concentrated around the vacuoles. Moreover, periphagosomal phosphoproteins were also detected and found to be colocalized with polymerized actin. Because zymosan interacts with human monocytes via beta 2 integrins, which are known to be cytoskeleton-associated, we suggest that p53-56lyn provides the molecular link between zymosan receptors and cytoskeleton, and directs the cytoskeletal reorganization in the periphagosomal area.
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PMID:Zymosan-triggered association of tyrosine phosphoproteins and lyn kinase with cytoskeleton in human monocytes. 789 29

There has been an explosive increase in information relevant to the pathways that determine growth signal transduction, regulation of the cell cycle, mechanism of action of oncogenes and tumor suppressors, and mechanisms of programmed cell death (apoptosis). Additional information is needed to determine the targets for anticancer therapy that are most likely to lead to cancer cell death and/or growth cessation. Current experimental clinical approaches are directed toward killing cells with unique cancer-related phenotypes, such as cell surface antigens or growth factor receptors, or altering the host immune system to attack cancer cells. The following major therapeutic targets were identified during the course of this conference: 1) Reduce activity of gene products associated with stimulation of cell growth and increase activity of gene products that inhibit growth. The major principle here is that genes known to be sufficient for malignant transformation (such as Ras, Raf, and Bcr-Abl) and genes whose expression is necessary, but not sufficient, for malignant transformation (such as some cyclins) both may be important targets for anticancer drugs. The reason genes necessary but not sufficient for cell growth are targets is that progression through the cell cycle is based on a series of "on-off" switches whose activation depends on critical levels of specific kinases and phosphatases. Subtle differences in concentration or activity of these regulators, as may be found in cancer cells, could profoundly influence the position of the switch. There are many ways to affect activity of gene products, including use of anti-sense or ribozyme targeting of mRNAs; manipulation of regulatory controls (i.e., state of phosphorylation of Raf and p53; effect of SOS and GAP on Ras, etc.); alteration of essential covalent modifications (i.e., farnesylation of Ras which is essential for its association with the plasma membrane); and various forms of gene therapy to introduce genes (i.e., addition of wild-type p53) or to reduce activity of genes essential for growth (i.e., dominant negative receptor mutants). 2) Interfere with protein-protein or DNA-protein interactions that are needed for the activity of oncogenes and/or growth factors or the transcription factors essential for cell growth. This approach has been demonstrated to work in vitro to interfere with SH2-tyrosine phosphate interactions (i.e., Grb-2 and EGF receptor) and Ras-Raf interactions using specific peptides (J. Downward), but to be useful therapeutically it must be possible to introduce stable low-molecular-weight drugs into cells to affect these interactions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Report of a meeting: molecular basis of cancer therapy. 791 37

The introduction of the techniques of molecular biology as tools to study skin carcinogenesis has provided more precise localization of biochemical pathways that regulate the tumor phenotype. This approach has identified genetic changes that are characteristic of each of the specific stages of squamous cancer pathogenesis: initiation, exogenous promotion, premalignant progression, and malignant conversion. Initiation can result from mutations in a single gene, and the Harvey allele of the ras gene family has been identified as a frequent site for initiating mutations. Heterozygous activating mutations in c-rasHa are dominant, and affected keratinocytes hyperproliferate and are resistant to signals for terminal differentiation. An important pathway impacted by c-rasHa activation is the protein kinase C (PKC) pathway, a major regulator of keratinocyte differentiation. Increased activity of PKC alpha and suppression of PKC delta by tyrosine phosphorylation contribute to the phenotypic consequences of rasHa gene activation in keratinocytes. Tumor promoters disturb epidermal homeostasis and cause selective clonal expansion of initiated cells to produce multiple benign squamous papillomas. Resistance to differentiation and enhanced growth rate of initiated cells impart a growth advantage when the epidermis is exposed to promoters. The frequency of premalignant progression varies among papillomas, and subpopulations at high risk for progression have been identified. These high-risk papillomas overexpress the alpha 6 beta 4 integrin and are deficient in transforming growth factor beta 1 and beta 2 peptides, two changes associated with a very high proliferation rate in this subset of tumors. The introduction of an oncogenic rasHa gene into epidermal cells derived from transgenic mice with a null mutation in the TGF beta 1 gene have an accelerated rate of malignant progression when examined in vivo. Thus members of the TGF beta gene family contribute a tumor-suppressor function in carcinogenesis. Accelerated malignant progression is also found with v-rasHa transduced keratinocytes from skin of mice with a null mutation in the p53 gene. The similarities in risk for malignant conversion by initiated keratinocytes from TG beta 1 and p53 null geneotypes suggest that a common, growth-related pathway may underly the tumor-suppressive functions of these proteins in the skin carcinogenesis model.
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PMID:Role of oncogenes and tumor suppressor genes in multistage carcinogenesis. 796 91

The surface immunoglobulin M (sIgM)-associated src family protein tyrosine kinases (PTKs) p55blk, p59fyn, and p53/56lyn become activated in B cells within seconds following sIgM cross-linking. Studies using protein tyrosine kinase (PTK) inhibitors have demonstrated that PTK activity is crucial for downstream events such as calcium flux, inositol phospholipid hydrolysis, and cell cycle entry. The roles that the individual src family PTKs play in sIgM signaling are largely unknown, however. In order to determine whether p59fyn plays a distinct role in sIgM signal transduction, the signaling capabilities of B cells isolated from fyn "knockout" mice were evaluated. We observed that in the absence of p59fyn, there was no demonstrable compromise of the sIgM-coupled signaling events measured (tyrosine phosphorylation, inositol phospholipid hydrolysis, and Ca2+ flux). We propose that either p59fyn is not involved in coupling sIgM to these specific signaling pathways or that other PTKs are able to compensate for the absence of p59fyn, indicating redundancy in the sIgM signaling pathways.
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PMID:Surface IgM-stimulated proliferation, inositol phospholipid hydrolysis, Ca2+ flux, and tyrosine phosphorylation are not altered in B cells from p59fyn-1- mice. 799 57

We recently described culture conditions that allow proliferation of metastatic human breast cancer cells from biopsy specimens of certain patient samples. These conditions resulted in the development of an immortalized cell strain designated SUM-44PE. These same culture conditions were used to isolate a human breast cancer cell strain from a metastatic lymph node of a separate breast cancer patient. The SUM-16LN human breast cancer cells isolated from this specimen were cultured either in serum-free medium or serum-containing medium supplemented with insulin and hydrocortisone. Unlike the SUM-44PE cells that have proliferated in culture continuously for over two years, SUM-16LN cells proliferated in culture for approximately 200 days and underwent 15 to 20 population doublings before undergoing cell senescence. No cells of this strain proliferated beyond passage 8. SUM-16LN cells were keratin-19 positive and had an aneuploid karyotype. These cells overexpressed p53 protein and had an amplified epidermal growth factor (EGF) receptor gene that resulted in high level expression of tyrosine phosphorylated EGF receptor protein. Despite the presence of high levels of tyrosine phosphorylated EGF receptor in these cells, they proliferated in serum-free, EGF-free medium and did not secrete detectable levels of EGF-like mitogenic growth factor. In addition, these cells were potently growth inhibited by all concentrations of exogenous EGF tested and by the neutralizing EGF receptor antibody Mab 425. These results suggest that the high level of tyrosine phosphorylated EGF receptor present in these cells is the direct result of receptor overexpression and not the result of the presence of a stimulatory ligand. Thus, SUM-16LN represents a human breast cancer cell strain that exhibited genetic and cellular characteristics of advanced human breast cancer cells. Nevertheless, these cells exhibited a finite proliferative lifespan in culture, suggesting that cellular immortalization is not a phenotype expressed by all human breast cancer cells.
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PMID:Finite proliferative lifespan in vitro of a human breast cancer cell strain isolated from a metastatic lymph node. 801 55

The monoclonal antibody AA4 (mAb AA4) recognizes novel alpha-galactosyl derivatives of GD1b on rat basophilic leukemia (RBL-2H3) cells. The binding of mAb AA4 induced protein tyrosine phosphorylations without histamine release. Several of the same proteins including Fc epsilon RI beta, Fc epsilon RI gamma, p72syk, and phospholipase C-gamma 1 were tyrosine-phosphorylated by mAb AA4 binding and by the activation of the high affinity IgE receptor, Fc epsilon RI. There was also activation of the p53/56lyn and p72syk protein-tyrosine kinases, but compared to direct Fc epsilon RI activation, mAb AA4 did not result in increased tyrosine phosphorylation of pp105-115 or pp125FAK, and the receptor subunits (Fc epsilon RI beta and Fc epsilon RI gamma) were more heavily phosphorylated. Furthermore, the time course of the phosphorylations with mAb AA4 was slower than that induced by Fc epsilon RI aggregation. By immunofluorescence, the tyrosine-phosphorylated proteins after mAb AA4 stimulation were localized in patches at the cell membrane and in areas of cell-cell contact, whereas after Fc epsilon RI activation, there was a reticular cytoplasmic pattern. There were no protein tyrosine phosphorylations either when Fc epsilon RI was saturated with IgE or when F(ab')2 fragments of mAb AA4 were used, although the F(ab')2 fragments still induced morphological changes. There was also coprecipitation of the beta and gamma subunits of Fc epsilon RI with the anti-ganglioside antibody. These data strongly suggest the involvement of Fc epsilon RI in the antiganglioside-induced protein tyrosine phosphorylations. Moreover, phosphorylations of these proteins including the beta and gamma chains of Fc epsilon RI and activation of p53/56lyn and p72syk did not result in histamine release.
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PMID:The anti-ganglioside monoclonal antibody AA4 induces protein tyrosine phosphorylations, but not degranulation, in rat basophilic leukemia cells. 803 15

Exposure of a wide variety of cells to ionizing (X- or gamma-) irradiation results in a division delay which may have several components including a G1 block, a G2 arrest or an S phase delay. The G1 arrest is absent in many cell lines, and the S phase delay is typically seen following relatively high doses (> 5 Gy). In contrast, the G2 arrest is seen in virtually all eukaryotic cells and occurs following high and low doses, even under 1 Gy. The mechanism underlying the G2 arrest may involve suppression of cyclin B1 mRNA and/or protein in some cell lines and tyrosine phosphorylation of p34cdc2 in others. Similar mechanisms are likely to be operative in the G2 arrest induced by various chemotherapeutic agents including nitrogen mustard and etoposide. The upstream signal transduction pathways involved in the G2 arrest following ionizing radiation remain obscure in mammalian cells; however, in the budding yeast the rad9 gene and in the fission yeast the chk1/rad27 gene are involved. There is evidence indicating that shortening of the G2 arrest results in decreased survival which has led to the hypothesis that during this block, cells repair damaged DNA following exposure to genotoxic agents. In cell lines examined to date, wildtype p53 is required for the G1 arrest following ionizing radiation. The gadd45 gene may also have a role in this arrest. Elimination of the G1 arrest leads to no change in survival following radiation in some cell lines and increased radioresistance in others. It has been suggested that this induction of radioresistance in certain cell lines is due to loss of the ability to undergo apoptosis. Relatively little is known about the mechanism underlying the S phase delay. This delay is due to a depression in the rate of DNA synthesis and has both a slow and a fast component. In some cells the S phase delay can be abolished by staurosporine, suggesting involvement of a protein kinase. Understanding the molecular mechanisms behind these delays may lead to improvement in the efficacy of radiotherapy and/or chemotherapy if they can be exploited to decrease repair or increase apoptosis following exposure to those agents.
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PMID:The molecular basis for cell cycle delays following ionizing radiation: a review. 804 94

The tumor suppressor gene p53 is the most frequently mutated gene in human cancer. We have used polymerase chain reaction-single-strand conformation polymorphism analysis and sequencing to examine the status of the p53 gene in human testicular cancers of various histologies. We were unable to find in 40 samples and four cell lines any mutations in the regions of this gene (exons 5 through 8) that are usually mutated in other cancers. Northern blot analysis showed expression of this gene in most of the samples analyzed, as well as in four human testicular tumor cell lines. The MDM-2 gene is amplified and overexpressed in sarcomas; it binds and functionally inactivates p53. The 44 testicular tumor samples and cell lines were examined for amplification of MDM-2 by dot-blot analysis; none was found. The proto-oncogene c-kit probably plays an important role in normal testicular development. Mutation of the tyrosine phosphorylation site of a closely related member of this family of tyrosine kinase receptors (c-fms) is associated with cellular transformation and cancer. Codon 936 is the analogous tyrosine of c-kit; using polymerase chain reaction-single-strand conformation polymorphism analyses, we were unable to detect mutations at this site in our 44 testicular cancer samples. We conclude from our studies that mutations in the most conserved region of the p53 gene, as well as at codon 936 of the c-kit gene and amplification of MDM-2, are extremely rare in human testicular cancers.
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PMID:Mutations of the p53 gene are not detectable in human testicular tumors. 806 72

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.
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PMID:Signaling properties of anti-immunoglobulin--resistant variants of WEHI-231 B lymphoma cells. 808 19


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