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 response to invading microorganisms, neutrophils produce large amounts of superoxide and other reactive oxygen intermediates (ROI) by assembly and activation of a multicomponent enzyme complex, the NADPH oxidase. While fulfilling a microbicidal role, ROI have also been postulated to serve as signaling molecules, because activation of the NADPH oxidase was found to be associated with increased tyrosine phosphorylation (Fialkow, L., Chan, C. K., Grinstein, S., and Downey, G.P. (1993) J. Biol. Chem. 268, 17131-17137). The mechanism whereby ROI induces phosphotyrosine accumulation was investigated using electroporated neutrophils stimulated with guanosine 5'-O-3-thiotriphosphate in order to bypass membrane receptors. In vitro immune complex assays and immunoblotting were used to identify five tyrosine kinases present in human neutrophils. Of these, p56/59hck, p72syk, and p77btk were activated during production of ROI. Interestingly, the in vitro autophosphorylation activities of p53/56lyn and p59fgr were found to decline with ROI production. The mode of regulation of p56/59hck was explored in detail. Oxidizing agents were unable to activate p56/59hck in vitro and, once activated in situ, reducing agents failed to inactivate it, suggesting that the effects of ROI are indirect. Tyrosine phosphorylation of p56/59hck paralleled its activation, and dephosphorylation in vitro reversed the stimulation. We therefore conclude that tyrosine phosphorylation is central to the regulation of p56/59hck and likely also of p72syk, which is similarly phosphorylated upon activation of the oxidase. Because ROI have been shown to reduce the activity of tyrosine phosphatases, we suggest that this inhibition allows constitutively active kinases to auto/transphosphorylate on stimulatory tyrosine residues, leading to an increase in their catalytic activity. Enhanced phosphotyrosine accumulation would then result from the combined effects of increased phosphorylation with decreased dephosphorylation.
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PMID:Endogenous reactive oxygen intermediates activate tyrosine kinases in human neutrophils. 857 38

We have analysed the cell-cycle arrests and cytotoxicity of the A2780 human ovarian cell line in response to geldanamycin, a benzoquinoid ansamycin that can inhibit tyrosine kinases. Geldanamycin causes a dose-dependent G2 arrest and reversible inhibition of entry into the S phase in A2780 cells. After a 3-h exposure to 0.1 microM geldanamycin, the cells show an increase in accumulation of p53 protein that is maximal at 24 h after drug exposure. Increased p53 levels can be induced in cells by DNA-damaging agents; however, using alkaline elution and sister chromatid exchange assays we detect no DNA damage induced by geldanamycin. Using dominant negative mutant TP53 transfectants of A2780 we have analysed the possible dependence of geldanamycin-induced cell-cycle arrests on the presence of functional p53. We observe no difference in cell-cycle arrests in mutant p53 transfectants known to have the p53-DNA damage-response pathway inactivated as compared with vector-alone controls. Similarly, we observe no difference in clonogenic resistance to the cytotoxicity of geldanamycin in these cells. These results suggest that geldanamycin can induce increased p53 protein by a mechanism not involving DNA damage. Furthermore, the cell-cycle arrests and cytotoxic effects of geldanamycin in these cells are not mediated by p53-dependent pathways.
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PMID:Cell-cycle arrest and p53 accumulation induced by geldanamycin in human ovarian tumour cells. 859 64

Protein tyrosine phosphorylation is one of the signals involved in stimulation of neutrophil (PMN) functions. We found that phorbol myristate acetate (PMA) activates the src family tyrosine kinases p58c-fgr and p53/56lyn in suspended PMNs. Moreover, we found that up to about 20% of p58c-fgr and p53/56lyn redistribute to a Triton X-100-insoluble fraction after PMA stimulation, and it is this fraction of the two kinases which diplays an increased activity. These changes of p58c-fgr and p53/56lyn distribution and activity correlate with tyrosine phosphorylation of endogenous substrates. In fact, in PMA-stimulated PMNs tyrosine phosphorylated proteins are mostly recovered in a Triton-insoluble cell fraction. To separate cytoskeletal from caveolar structures, which both display Triton X-100-insolubility, we used the detergent n-octyl beta-D-glucopyranoside (OGP) which solubilises components of caveolae. We found that the caveolae marker protein, caveolin, as well as the cytoskeletal protein alph-actinin and p58c-fgr and p53/56lyn, is insoluble in OGP. These findings suggest that PMA stimulation promotes the formation of multimolecular complexes containing cytoskeletal proteins, caveolin-containing structures and src family protein tyrosine kinases. Moreover, they show that p58c-fgr and p53/56lyn associated with this multimolecular complex display an enhanced kinase activity.
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PMID:Activation of SRC family kinases in human neutrophils. Evidence that p58C-FGR and p53/56LYN redistributed to a Triton X-100-insoluble cytoskeletal fraction, also enriched in the caveolar protein caveolin, display an enhanced kinase activity. 860 37

Prostate cancer is the most common cancer in aged men. Although ras and p53 gene mutations have been detected in some prostate cancers, the major genetic alterations involved in its carcinogenesis are not well understood. Mutation of the APC gene is responsible for colorectal tumors in which ras and p53 mutations are also often involved. Using PCR-SSCP analysis and sequencing, we examined 31 human primary prostate cancers (three cases at stage A, 10 at stage B, five at stage C and 13 at stage D) and four cases of lymph node metastasis from the stage D cases, for mutations in the APC gene. A mutation was detected in only one of the 35 samples (3%). This mutation, present in a primary stage B cancer, had a T to C transition in exon 15 at the first position of codon 956, resulting in substitution of histidine for tyrosine. This study clarified that APC gene mutations are not largely involved in the development of clinical prostate cancer.
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PMID:APC gene mutations in human prostate cancer. 860 98

Src-family nonreceptor protein tyrosine kinases (NRPTK) are associated with cell surface receptors in large detergent-resistant complexes: in epithelial cells, yes is selectively located in vesicle structures containing caveolin ("caveolae"). These formations are typically also endowed with glycophosphatidylinositol (GPI)-anchored proteins. In the present study, we observed lck, lyn, src, hck, CD4, CD45, G proteins, and CD55 (decay-accelerating factor) expression in the buoyant low-density Triton-insoluble (LDTI) fraction of selected leukemic cell lines and granulocytes. We provide a detailed analysis of the two most highly expressed NRPTK, p53/p56lyn and p56lck, which are involved in the transduction of signals for proliferation and differentiation of monocytes/B lymphocytes and T lymphocytes, respectively. We show that lyn is selectively recovered in LDTI complexes isolated from human leukemic cell lines (promyelocytic [HL-60], erythroid [K562] and B-lymphoid [697]) and from normal human granulocytes, and that lck is recovered from LDTI fractions of leukemic T- and B-lymphoid cell lines (CEM, 697). In LDTI fractions of leukemic cells, lck and lyn are enriched 100-fold as compared with the total cell lysates. Analysis of these fractions by electron microscopy shows the presence of 70- to 200-nm vesicles: lyn and lck are homogenously distributed in the vesicles, as revealed by an immunogold labeling procedure. These novel results propose a role for these vesicles in signal transduction mechanisms of normal and neoplastic hematopoietic cells. In support of this hypothesis, we further observed that molecules participating in B- and T-cell receptor activation cofractionate in the LDTI fractions, CD45/lyn (B cells) and CD45/lck/CD4 (T cells).
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PMID:Signal transduction and glycophosphatidylinositol-linked proteins (lyn, lck, CD4, CD45, G proteins, and CD55) selectively localize in Triton-insoluble plasma membrane domains of human leukemic cell lines and normal granulocytes. 861 4

The nuclear matrix isolated from HeLa cells and Rat2 fibroblasts harbors tyrosine kinase and tyrosine phosphatase activities. Polypeptides of 53, 56 and 60 kDa, associated with this subnuclear structure, were phosphorylated at tyrosine in vivo. By immunoblot and immunolabelling experiments, we identified one of the nuclear-matrix-associated tyrosine kinases as Lyn, a Src family member. Lyn was distributed as foci throughout the matrix. The p56 and p53 isoforms of Lyn remained firmly associated with the nuclear matrix after a variety of matrix preparation procedures, and were not detectable in the chromatin fraction of the nucleus. The tyrosine kinase activity associated with the nuclear matrix showed cell-cycle-dependent changes, maximum activity being observed at the G1/S transition phase. Polyoma-virus-transformed rat fibroblast cells showed sixfold higher tyrosine kinase activity in the nuclear matrix preparations compared to that in untransformed cells. These observations are consistent with the suggestion that tyrosine kinase activity associated with the nuclear matrix may be an important determinant of cellular proliferation.
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PMID:Association of Lyn tyrosine kinase with the nuclear matrix and cell-cycle-dependent changes in matrix-associated tyrosine kinase activity. 861 2

A chicken B cell line DT40 and its syk-negative or lyn-negative mutants were used to investigate the roles of protein-tyrosine kinases in oxidant stress signaling. The data presented here for wild-type cells demonstrate that hydrogen peroxide stimulates p53/56lyn-dependent tyrosine phosphorylation and activation of p72syk, and induces a rapid and prolonged elevation of intracellular calcium, which consists of calcium release from intracellular stores and influx from the extracellular space. Hydrogen-peroxide-triggered calcium mobilization was impaired in both syk-negative and lyn-negative cells, which was mainly due to the loss of calcium release from intracellular stores. Further studies indicated that inositol trisphosphate production was also abolished in both syk-negative and lyn-negative cells, which is consistent with the loss of calcium release. Taken together, these observations suggest that the defect of p72syk or p53/56lyn was responsible for the abnormality of calcium mobilization in both lyn-negative and syk-negative cells, and that both p72syk and p53/56lyn might regulate calcium mobilization through the phosphatidylinositol pathway in B cell oxidant stress signaling.
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PMID:Cooperation of tyrosine kinases p72syk and p53/56lyn regulates calcium mobilization in chicken B cell oxidant stress signaling. 861 14

To identify novel signal transducers involved in signaling mediated by the Src-family protein tyrosine kinases (PTKs), we used a yeast two-hybrid system with a probe corresponding to the regulatory region of p56lyn, a member of Src-family PTKs. One of the isolated clones contained the COOH-terminal 470 amino acid residues of p120c-cbl, the product of the cellular homologue of the v-cbl retroviral oncogene. p120c-cbl is a cytoplasmic protein with nuclear protein-like motifs. Here we show in vivo association of p120c-cbl with p53/56lyn. After stimulation of the B cell antigen receptor (BCR), p120c-cbl was rapidly tyrosine phosphorylated. Studies with lyn- or syk-negative chicken B cells demonstrated that p53/56lyn, but not p72syk, was crucial for tyrosine phosphorylation of p120c-cbl upon stimulation of the BCR. We also show the importance of p59fyn in tyrosine phosphorylation of p120c-cbl in the T-cell receptor-mediated signaling using fyn-overexpressing T cell hybridomas and splenic T cells from fyn-deficient mice. These results suggest that p120c-cbl is an important substrate of Src-family PTKs in the intracellular signaling mediated by the antigen receptors
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PMID:Physical and functional association of the cbl protooncogen product with an src-family protein tyrosine kinase, p53/56lyn, in the B cell antigen receptor-mediated signaling. 862 81

The B-lymphocyte-restricted adhesion protein CD22 mediates sialic acid-dependent cell-cell interactions. Engagement of CD22 on B lymphocytes with a CD22 monoclonal antibody (MoAb) HB22.7 that blocks the binding of CD22 to its ligand(s) directly stimulated B-cell proliferation. In addition, the HB22.7 MoAb costimulated B-cell proliferation with either anti-IgM, interleukin-2 (IL-2), IL-4, or CD40 and triggered predominantly B-cell IgG secretion with IL-2. Even more striking levels of B-cell proliferation occurred with HB22.7 MoAb under culture conditions that enhanced B-B-cell interactions. In contrast, a nonblocking CD22 MoAb (CD22.5) poorly costimulated in similar experiments. The functional differences between the two antibodies likely result from differing abilities to trigger downstream signaling events as significant differences in CD22 tyrosine phosphorylation and the recruitment of the tyrosine kinase p53/56lyn and the tyrosine phosphatase SH-PTP1C were found. Besides their role in B-cell stimulation, CD22/CD22L interactions may also assist in regulating T-cell proliferation because inhibition of CD22-CD22L engagement with the HB22.7 MoAb impaired T-cell proliferation in a costimulatory assay. Thus, CD22/CD22L interactions result in stimulatory signals for both B and T lymphocytes.
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PMID:Engagement of the adhesion receptor CD22 triggers a potent stimulatory signal for B cells and blocking CD22/CD22L interactions impairs T-cell proliferation. 863 42

CD22 is a B lymphocyte-specific membrane protein that functions as an adhesion molecule via its interactions with a subset of alpha 2-6-linked sialic acid-containing glycoproteins. Engagement of CD22 with a monoclonal antibody (HB22.23) that blocks the binding of CD22 to its ligands results in rapid CD22 tyrosine phosphorylation and in increased association of CD22 with p53/56lyn kinase, p85 phosphatidyl inositol-3 kinase, and p72syk kinase. Synthetic peptides that span various regions of the intracellular portion of CD22 were used to map potential kinase binding sites. All three kinases associated with a tyrosine-phosphorylated peptide that spans tyrosine amino acid residues 822 and 842, implicating this as an important region in mediating CD22 signal transduction. In addition, purified p56lyn directly bound to the same peptide. Engagement of CD22 with HB22.23 was sufficient to stimulate normal B cell proliferation. This study further substantiates the importance of CD22 as a B lymphocyte signaling molecule and begins to unravel the mechanisms by which CD22 cross-linking can alter B cell function.
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PMID:Involvement of p72syk kinase, p53/56lyn kinase and phosphatidyl inositol-3 kinase in signal transduction via the human B lymphocyte antigen CD22. 864


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