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)

Hepatocyte growth factor/scatter factor (HGF/SF) can elicit a wide variety of effects upon cells expressing its receptor, the tyrosine kinase proto-oncogene product Met, including mitogenicity, motility, and morphogenesis. Normally, met expression is restricted to epithelial cells and is activated in a paracrine fashion by HGF/SF secreted from cells of mesenchymal origin. In this chapter, we review data showing that: (i) met over-expression in HGF/SF-expressing NIH/3T3 fibroblasts leads to sarcomagenesis and metastasis via an autocrine mechanism; (ii) Met-HGF/SF autocrine signalling occurs to a low level in normal fibroblasts and to a much greater extent in human sarcomas and sarcoma cell lines; (iii) met expression is enhanced as p53-deficient fibroblasts are passaged in vitro and (iv) met and HGF/SF over-expression are selected for during tumorigenesis of p53-deficient late-passage fibroblasts. Thus, loss of p53 predisposes a mesenchymal cell to over-express met and high level Met-HGF/SF autocrine signaling in mesenchymal cells promotes both sarcomagenesis and metastasis through inappropriate induction of the pleiotropic responses to Met-HGF/SF stimulation.
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PMID:The Met-HGF/SF autocrine signaling mechanism is involved in sarcomagenesis. 852 3

The transformation of the normal fully differentiated thyroid follicular cell to the rapidly growing undifferentiated anaplastic thyroid carcinoma cell involves a number of stages which have been defined morphologically and are now being related to various growth pathways and to molecular biological defects. The two main factors involved in this transformation are growth stimulation and mutagenesis. Growth stimulation alone, through elevated TSH, can lead to the development of thyroid tumours, usually benign, and retaining TSH dependency in some cases. Mutagens alone, if growth is suppressed, do not produce tumours, the combination of mutagens and increased growth is a potent carcinogenic regime. Non-genotoxic carcinogenesis in the thyroid involves growth, without mutagenesis the agent often causes this through affecting one component of thyroid hormone synthesis or metabolism, leading to a fall in thyroid hormone levels and a rise in TSH. Growth stimulation increases the rate of cell division, and therefore increases the chance of a mutation. Continued growth increases the change of subsequent events, in particular loss of heterozygosity in a tumour suppressor gene. The main oncogenes involved in human thyroid carcinogens are ras in the follicular tumour pathway, and ret in the papillary carcinoma pathway. p53 is involved in the progression of either papillary or follicular adenoma to an undifferentiated carcinoma. In experimental thyroid carcinogenesis, ras is again involved, with a link between the mutagenic agent used and the type of ras gene showing mutation. Analysis of the involvement of different growth factors and oncogenes in thyroid carcinogenesis suggests that genes related to the two receptors concerned with normal TSH stimulated growth, TSH receptor and the IGF1 receptor may be involved in the progression of thyroid tumours of follicular pathology. Several tyrosine kinase receptors with unknown ligands or of uncertain physiological function are linked to papillary carcinoma. The recent large increase in papillary carcinoma of the thyroid in children exposed to fallout from the Chernobyl nuclear accident underlines the importance of understanding the pathobiology of thyroid neoplasia.
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PMID:Mechanisms and pathogenesis of thyroid cancer in animals and man. 853 19

Infection with Herpesvirus saimiri, a T lymphotropic virus of non-human primates, immortalizes human T cells in vitro. The cells show a mature activated phenotype and retain their antigen specificity. We have previously shown that in H. saimiri transformed cells a viral gene product termed tyrosine kinase interacting protein (Tip) associates with the T cell-specific tyrosine kinase p56lck and becomes phosphorylated by the enzyme on tyrosine residues. Here we show that p56lck is activated by recombinant and native Tip in cell-free systems. A dramatic increase of Lck activity was also observed in T cell lines transfected with Tip. p60fyn and p53/56lyn, the other Src-related kinases expressed in H. saimiri transformed T cells, did not phosphorylate Tip, and they were not activated by the protein. The selective activation of p56lck by Tip could contribute to the transformed phenotype of H. saimiri infected cells, and it might explain the T cell selectivity of the transformation event.
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PMID:Selective activation of T cell kinase p56lck by Herpesvirus saimiri protein tip. 855 95

Juvenile polyps (JP) are the most common colonic tumor in children. Although considered benign, malignant transformation has been reported in JP. Ornithine decarboxylase (ODC) and tyrosine kinase (TyK) enzymes are markers for a rapid cell proliferation index. DNA aneuploidy score and p53 gene expression are late malignant changes seen in patients with colon cancer. In this study, we investigated ODC and TyK activities as well as DNA aneuploidy score and p53 expression in juvenile polyps compared with the adjacent normal colonic mucosa. Results showed that ODC was significantly increased in JP compared with the adjacent normal colonic mucosa. TyK activity was increased in 3/5 polyps and decreased in 2/5 polyps compared with the mucosa. Mean TyK activity was higher in JP compared with normal mucosa but did not reach significance (707 and 632 pmol/mg pmol, respectively). Moreover, changes in phosphorylization of TyK proteins was also observed in JP but not in normal mucosa. JP had a normal DNA aneuploidy score and showed no expression of p53 gene. We conclude that JP do not express p53 gene and aneuploidy but had higher activity of ODC and TyK enzymes, suggesting a higher stage of cell proliferation.
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PMID:Ornithine decarboxylase and tyrosine kinase activity in juvenile polyps of childhood. 855 12

One event that accompanies glioma progression is the upregulation of angiogenesis. Low-grade gliomas are moderately vascularized tumors whereas high-grade gliomas show prominent microvascular proliferations and areas of high vascular density. To analyze the molecular mechanisms underlying glioma angiogenesis, we studied the expression of vascular endothelial growth factor (VEGF) and its tyrosine kinase receptors VEGFR-1 and VEGFR-2 during normal brain development and glioma-induced angiogenesis. Our results suggest a paracrine control of angiogenesis and endothelial cell proliferation that is tightly regulated and transient in the embryonic brain, switched off in the normal adult brain, and turned on in tumor cells (VEGF) and the host vasculature (VEGFR-1 and -2) during tumor progression. It is unknown how VEGF and VEGF receptors are upregulated during glioma angiogenesis, but there is recent evidence that VEGF as well as endogenous inhibitors of angiogenesis could be under control of the tumor suppressor genes p53 and VHL.
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PMID:Angiogenesis in malignant gliomas. 858 68

c-Abl is a non-receptor protein-tyrosine kinase lacking a clear physiological role. A clue to its normal function is suggested by overexpression of Abl in fibroblasts, which leads to inhibition of cell growth. This effect requires tyrosine kinase activity and the Abl C-terminus. c-Abl is localized to the cell nucleus, where it can bind DNA, and interacts with the retinoblastoma protein, a potential mediator of the growth-inhibitory effect. Nuclear localization of Abl can be directed by a pentalysine nuclear localization signal in the Abl C-terminus. Here, we have identified two additional basic motifs in the Abl C-terminus, either of which can function independently of the pentalysine signal to localize Abl to the nucleus. Using a quantitative transfection assay, we show that both c-Abl and transforming Abl proteins inhibit entry into S phase and this effect is absolutely dependent on nuclear localization. Further, we demonstrate that the Abl cytostatic effect requires both the Rb and p53 tumor suppressor gene products. These results indicate that Abl inhibits cell proliferation by interacting with central elements of the cell cycle control apparatus in the nucleus, and suggest a direct connection between p53 and Rb in this growth-inhibitory pathway.
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PMID:The cytostatic function of c-Abl is controlled by multiple nuclear localization signals and requires the p53 and Rb tumor suppressor gene products. 861 82

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

Degenerate PCR was employed to identify novel tyrosine kinase genes from an enriched population of human umbilical cord blood hematopoietic stem/progenitor cells. One novel tyrosine kinase gene, designated Tnk1, was cloned. The sequence of the complete Tnk1 coding region predicts a 72 kD protein. Comparison of Tnk1 to available sequences in protein databases reveals that it is most homologous to Ack, an intracellular tyrosine kinase which associates with the GTP-bound form of p21cdc42Hs. Like Ack, Tnk1 consists of an N-terminal kinase domain, a putative SH3 domain immediately C-terminal to the kinase domain, and a proline-rich C-terminal region. Analysis of Tnk1 mRNA expression demonstrates that Tnk1 is expressed in all cord blood, bone marrow and adult blood sub-populations, as well as in most of the leukemia cell lines examined (16 of 20). Hybridization to fetal multi-tissue Northern blots detected several different Tnk1 transcripts in all fetal tissues examined. In contrast, a single Tnk1 transcript was detected in only five of 16 adult tissues examined (prostate, testis, ovary, small intestine and colon). Fluorescence in situ hybridization (FISH) analysis of metaphase chromosomes localized the Tnk1 gene to the short arm of chromosome 17 (17p13.1), near the p53 locus. Thus, Tnk1 is a novel tyrosine kinase that may be involved in signalling pathways utilized broadly during fetal development, more selectively in adult tissues and in cell of the lymphohematopoietic system.
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PMID:Tnk1: a novel intracellular tyrosine kinase gene isolated from human umbilical cord blood CD34+/Lin-/CD38- stem/progenitor cells. 863 13

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

Chronic myeloid leukaemia (CML) is characterized cytogenetically by a t(9;22)(q34;ql1) reciprocal translocation which gives origin to a hybrid BCR-ABL gene, encoding a p2lO(BCR-ABL) fusion protein with elevated tyrosine kinase activity and transforming abilities. The t(9;22) was suggested to be associated with genomic imprinting of centromeric regions of chromosomes 9 and 22, but the genes directly affected by the translocation, ABL and BCR, were shown not to be imprinted. For most diagnostic and research purposes the BCR-ABL gene can be efficiently identified by reverse-transcription and polymerase chain reaction (RT/PCR) amplification of its fusion transcripts, which can be quantified by competitive PCR and similar assays for assessment of residual disease in the follow-up of therapy. In the great majority of CML patients the BCR-ABL transcripts exhibit a b2a2 and/or a b3a2 junction; in rare cases, the only detectable BCR-ABL transcripts have unusual junctions, such as b2a3, b3a3, e1a2 or e6a2. There is a recent suggestion that the BCR-ABL gene may not be always 'functional', since extremely low levels of BCR-ABL transcripts can be found in leucocytes from normal individuals and, conversely, it appears that no BCR-ABL transcription can be detected in a proportion of Ph-positive haematopoietic progenitors from some CML patients. The role, if any, of the reciprocal ABL-BCR hybrid gene in CML is unknown. Although its mRNA message is in frame, no ABL-BCR fusion protein has yet been identified in CML patients. The blast crisis of CML has been variably associated with abnormalities of proto-oncogenes, such as RAS and MYC, or of tumour suppressor genes, in particular RB, p53 and p16, or with the generation of chimeric transcription factors, as in the AML1-EVI1 gene fusion. It is likely, therefore, that multiple and alternative molecular defects, as opposed to a single universal mechanism, underlie the acute transformation of the disease.
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PMID:The molecular biology of chronic myeloid leukaemia. 865 67


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