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)

The ability to locomote and migrate is fundamental to the acquisition of invasive and metastatic properties by tumor cells. Autocrine motility factor (AMF) is a 55 kD cytokine produced by various tumor cells which stimulates their in vitro motility and in vivo lung colonizing ability. AMF stimulates cell motility via a receptor-mediated signalling pathway. Signal transduction following binding of AMF to its receptor, a cell surface glycoprotein of 78 kD (gp78) homologous to p53, is mediated by a pertussis toxin sensitive G protein, inositol phosphate production and the phosphorylation of gp78. Cell surface gp78 is localized to the leading and trailing edges of motile cells but following cell permeabilization is found within an extended network of intracellular tubulovesicles. Gp78 tubulovesicles colocalize with microtubules and extension of the tubulovesicular network to the cell periphery is dependent on the presence of intact microtubules. Gp78 labeled vesicles can be induced to translocate between the cell center and periphery by altering intracellular pH as previously described for tubulovesicles labeled by fluid phase uptake. Anti-gp78 mAb added to viable motile cells is localized to large multivesicular bodies which, with time, relocate to the leading edge. Binding of AMF to its receptor induces signal transduction, similar to chemotactic stimulation of neutrophil mobility, as well as the internalization and transport of its receptor to the leading edge stimulating pseudopodial protrusion and cell motility.
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PMID:Autocrine motility factor and its receptor: role in cell locomotion and metastasis. 132 4

A high frequency of lymphoma in human immunodeficiency virus-infected individuals has been reported since the outbreak of the acquired immunodeficiency syndrome (AIDS) epidemic in 1982. In the vast majority of cases, these lymphomas are highly aggressive B-cell, non-Hodgkin's lymphoma of intermediate or high grade of malignancy. AIDS-associated non-Hodgkin's lymphoma are histologically classified as small noncleaved cell lymphoma, large cell immunoblastic plasmacytoid lymphoma, or large noncleaved cell lymphoma. Host factors predisposing to lymphoma development in AIDS patients include decreased immunosurveillance as well as human immunodeficiency virus-induced chronic perturbation of the immune system leading to cytokine overproduction and increased B-cell stimulation. These alterations are associated with the development of multiple oligoclonal B-cell expansions, which are characterized by persistent generalized lymphadenopathy. The presence of Epstein-Barr virus within a persistent generalized lymphadenopathy clone further increases the risk of its neoplastic transformation. The appearance of non-Hodgkin's lymphoma is characterized by the presence of a monoclonal B-cell population displaying several genetic lesions, including monoclonal Epstein-Barr virus infection, c-myc rearrangements, Ras mutations, and p53 inactivation. The number and type of lesions varies among the different types of AIDS-non-Hodgkin's lymphoma, defining multiple alternative molecular pathways in AIDS-associated lymphomagenesis.
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PMID:Biologic aspects of human immunodeficiency virus-related lymphoma. 145 5

We have investigated the mechanism of action of IL 1 on T cell activation. For this purpose, we analyzed the content of specific messenger RNA for lymphokines and other genes that are associated with T cell activation in the murine IL 1-dependent T cell lymphoma LBRM33-1A5. Using cloned genes for IL 2, IL 3, TGF-beta, TY5, IL 2 receptor, Ly-1, c-myc, and p53 as probes in the S1 nuclease protection assay, we compared the amount of specific transcripts among total RNA prepared from unstimulated cells, IL 1 alpha or PHA-stimulated cells, and PHA plus IL 1 alpha-stimulated cells. IL 1 alpha augmented the PHA-induced accumulation of IL 2 mRNA with a magnitude comparable to the amount of IL 2 produced, suggesting that IL 1 alpha modulates IL 2 gene expression at the RNA level. Similar results were obtained with IL 3. We also observed that Ly-1 mRNA appears after PHA treatment and its accumulation was augmented by IL 1 alpha addition. On the basis of the effects of IL 1 alpha and/or PHA treatments on gene expression, we classified these genes into four groups. In all cases, IL 1 alpha seemed to affect mRNA levels quantitatively. These observations support previously described characteristics of this cytokine as a co-stimulator of T cell activation.
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PMID:Interleukin 1 modulates messenger RNA levels of lymphokines and of other molecules associated with T cell activation in the T cell lymphoma LBRM33-1A5. 349 73

IL-7 was identified originally as a specific pre-B cell growth factor. We have investigated its signal transduction mechanism by using the human pre-B cell line Nalm-6, and have found that it stimulates tyrosine phosphorylation of various proteins: pp27, pp43, pp54, pp64, pp78, pp90, pp105, and pp120. Antiphosphotyrosine immunoprecipitates from IL-7-stimulated Nalm-6 showed two major proteins of M(r) = 60,000 and 55,000, capable of autophosphorylation. Autophosphorylation was maximal 10 min after the cells were challenged with the cytokine. Antiphosphotyrosine immunoprecipitates from IL-7-stimulated cells also increased tyrosine phosphorylation of the exogenously added substrate histone H2B. Furthermore, by using a polyclonal anti-IL-7 receptor (IL-7R) Ab in Western blotting analysis, we observed that antiphosphotyrosine immunoprecipitates were associated with the IL-7R in a transient manner. These data indicate that the IL-7R associates with tyrosine-phosphorylated proteins as its amino acid sequence is devoid of a putative site of tyrosine phosphorylation. These results were confirmed as several 32P-labeled proteins were visualized after immunoprecipitation by using anti-IL-7R Ab. Anti-IL-7R immunoprecipitates from IL-7-stimulated cells revealed a unique band of M(r) = 60,000 associated with the receptor able to autophosphorylate in the presence of ATP and Mn2+. Hence, we identified p59fyn and p53/56lyn to be stimulated by IL-7. In contrast to p53/56lyn, p59fyn was found to be associated constitutively with the cloned IL-7R. These data emphasize the role of the src family in hematopoiesis.
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PMID:Activation of src family kinases in human pre-B cells by IL-7. 751 33

Induction of differentiation in M1 myeloid leukemic cells by the hematopoietic cytokines interleukin 6 and granulocyte-colony stimulating factor, or by the glucocorticoid dexamethasone, was associated with down-regulation of the apoptosis inhibiting gene bcl-2. The cytokine treated leukemic cells showed an increased sensitivity to induction of apoptotic cell death by the cancer chemotherapy compounds Adriamycin and cytosine arabinoside and by heat shock and cycloheximide. Dibutyryl cyclic AMP neither induced differentiation nor down-regulated bcl-2 expression, but it sensitized the cells to induction of apoptosis by some of these agents. Although dexamethasone induced differentiation and down-regulated bcl-2 expression, it did not sensitize the cells to induction of apoptosis and inhibited the apoptosis sensitizing effect of the cytokines and dibutyryl cyclic AMP. Dexamethasone did not inhibit induction of apoptosis by wild-type p53 or viability factor withdrawal. The apoptosis sensitizing effect of the cytokines and dibutyryl cyclic AMP was reversible upon their withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Control of sensitivity to induction of apoptosis in myeloid leukemic cells by differentiation and bcl-2 dependent and independent pathways. 751 74

Nitric oxide (NO) is a diffusible messenger involved in several patho-physiological processes including immune-mediated cytotoxicity and neural cell killing. NO or the products of its redox chemistry can cause DNA damage and activate subsequent lethal reactions including energy depletion and cell necrosis. However, regardless of whether it is endogenously produced in response to cytokines, or generated by chemical breakdown of donor molecules, NO can also induce apoptosis in different systems. Here, we report that NO generation in response to a cytokine induced NO-synthase or by NO donors stimulates the expression of the tumor suppressor gene, p53, in RAW 264.7 macrophages or pancreatic RINm5F cells prior to apoptosis. NO-synthase inhibitors such as NG-monomethyl-L-arginine prevent the inducible NO generation as well as p53 expression and apoptosis. Since p53 expression is linked to apoptosis in some cells exposed to DNA damaging agents, we suggest that NO-induced apoptosis in these cell systems is the consequence of DNA damage and subsequent expression of this tumor suppressor gene.
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PMID:p53 expression in nitric oxide-induced apoptosis. 752 58

TNF-alpha is a pleiotropic cytokine with stimulatory as well as inhibitory effects on hematopoiesis. We have previously demonstrated that TNF-alpha directly inhibits CSF-induced proliferation of primitive murine lineage-negative bone marrow progenitors (Lin-) and stem cell antigen-1 hematopoietic progenitors through the 75-kDa TNF receptor (TNF-R2), whereas TNF-alpha-induced inhibition of more committed Lin- progenitors is mediated through the 55-kDa TNF-R (TNF-R1), indicating a differential role of the two TNF-Rs in hematopoiesis. Numerous studies have demonstrated the ability of stem cell factor (SCF), a key regulator of hematopoiesis signaling through c-kit, to synergize with other hematopoietic growth factors, but little is known about cytokines capable of inhibiting hematopoiesis induced by SCF. While TNF-alpha has been demonstrated to enhance SCF-induced proliferation of myeloid leukemia blasts, the present report demonstrates that TNF-alpha, by signaling through TNF-R2, inhibits SCF-induced proliferation of normal murine Lin- and stem cell antigen-1 hematopoietic progenitors. SCF-stimulated proliferation of the hematopoietic cell line FDC-P1 was also potently inhibited by TNF-alpha and was accompanied by down-regulation of c-kit cell surface expression as well as c-kit mRNA levels. Finally, treatment of the FDC-P1 cell line with TNF-alpha resulted in increased levels of the tumor suppressor p53 mRNA, suggesting another mechanism by which hematopoietic effects of TNF-alpha may be mediated.
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PMID:Inhibition of stem cell factor-induced proliferation of primitive murine hematopoietic progenitor cells signaled through the 75-kilodalton tumor necrosis factor receptor. Regulation of c-kit and p53 expression. 753 12

Hormonal treatment of advanced prostatic cancer patients generally results in an initially beneficial response, but the treated patients develop hormonally resistant disease in which no curative therapy is currently available. Recent studies have revealed that interleukin 6 (IL-6) is a growth factor for myeloma, renal cell carcinoma, and certain T-cell lymphomas. Further, IL-6 has been shown to block apoptosis induced by p53, transforming growth factor beta, and certain cancer chemotherapeutic compounds. The objective of the present study was to determine whether IL-6 is a growth factor for two human prostate cancer lines and whether it protects the tumor cells from drug-induced cell death. Two hormone-independent prostate cell lines were used in this study, namely PC-3 and DU145, and these have been shown to be relatively resistant to cis-diamminedichloroplatinum (CDDP), etoposide (VP-16), and adriamycin (ADR). Both cell lines express IL-6 mRNA and secrete IL-6 constitutively. The addition of anti-IL-6 antiserum to the cell lines resulted in a significant inhibition of cell growth up to day 2, and when additional antibody was added at day 2 the inhibition persisted for 4 days. The coaddition of anti-IL-6 antiserum and CDDP or VP-16 resulted in synergy in cytotoxicity in both cell lines, whereas the combination of antibody and ADR or suramin resulted only in additive effects. Sequential treatment revealed that anti-IL-6 antibody was required to achieve synergy, whereas either sequence of pretreatment resulted in synergy with anti-IL-6 and CDDP but not with VP-16. CDDP treatment of tumor cells down-regulated IL-6 mRNA expression and IL-6 secretion. The present findings demonstrate that IL-6 is an autocrine/paracrine growth factor for DU145 and PC-3 prostate lines. Additionally, the secretion of this cytokine protects the tumor cells against the cytotoxic effect of CDDP and VP-16 and its neutralization sensitizes the cells to cytotoxicity. Overall, the studies suggest that agents that can down-regulate or inhibit protective factors in tumors may overcome drug resistance.
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PMID:Endogenous interleukin 6 is a resistance factor for cis-diamminedichloroplatinum and etoposide-mediated cytotoxicity of human prostate carcinoma cell lines. 755 41

Murine erythroleukemia cells that lack endogenous p53 expression were transfected with a temperature-sensitive p53 allele. The temperature-sensitive p53 protein behaves as a mutant polypeptide at 37 degrees C and as a wild-type polypeptide at 32 degrees C. Three independent clones expressing the temperature-sensitive p53 protein were characterized with respect to p53-mediated G1 cell cycle arrest, apoptosis, and differentiation. Clone ts5.203 responded to p53 activation at 32 degrees C by undergoing G1 arrest, apoptosis, and differentiation. Apoptosis was seen in cells representative of all phases of the cell cycle and was not restricted to cells arrested in G1. The addition of a cytokine (erythropoietin, c-kit ligand, or interleukin-3) to the culture medium of ts5.203 cells blocked p53-mediated apoptosis and differentiation but not p53-mediated G1 arrest. These observations indicate that apoptosis and G1 arrest can be effectively uncoupled through the action of cytokines acting as survival factors and are consistent with the idea that apoptosis and G1 arrest represent separate functions of p53. Clones ts15.15 and tsCB3.4 responded to p53 activation at 32 degrees C by undergoing G1 arrest but not apoptosis. We demonstrate that tsCB3.4 secretes a factor with erythropoietin-like activity and that ts15.15 secretes a factor with interleukin-3 activity and suggest that autocrine secretion of these cytokines blocks p53-mediated apoptosis. These data provide a framework in which to understand the variable responses of cells to p53 overexpression.
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PMID:Cytokines inhibit p53-mediated apoptosis but not p53-mediated G1 arrest. 756 57

Biologic responses to cytokines are mediated by intracellular pathways involving induction of signaling and metabolic cascades. Interferon (IFN) regulatory factor-1 (IRF-1) is a major transcription factor induced not only by IFN-gamma but also by other cytokines including tumor necrosis factor-alpha (TNF-alpha). Possible IRF-1 binding sequence elements have been located in the promoter regions of several genes, including p53, inducible nitric oxide synthase, and cyclin D1. IFN-gamma and TNF-alpha can inhibit hematopoiesis in vitro and have been implicated in the pathophysiology of bone marrow (BM) failure. We investigated whether the inhibitory effects of these cytokines were intracellularly mediated through the expression of IRF-1 or -2 in target cells. In total BM cells, IRF-1 mRNA expression increased after stimulation with IFN-gamma and TNF-alpha; the stronger effect was observed with IFN-gamma. In contrast, IRF-2 mRNA expression was constitutive and not altered by cytokine stimulation. By gene amplification, low levels of IRF-1 mRNA were present in unstimulated, highly purified CD34+ cells; on exposure to IFN-gamma and TNF-alpha, amplified IRF-1 mRNA showed a much stronger signal than control. When CD34+ cells were treated with IFN-gamma and TNF-alpha, IRF-1 antisense oligodeoxynucleotide (ODN) partially reversed the suppressive effects on CD34+ cell-derived colony formation by IFN-gamma but not those by TNF-alpha. In parallel experiments, IRF-1 antisense ODN decreased both IRF-1 protein and mRNA expression. The effects of ODN were sequence-specific and concentration-dependent. These results suggest that the inhibitory hematopoietic effects of IFN-gamma and TNF-alpha are mediated by different pathways. For IFN-gamma, IRF-1 is involved in the activation of cellular genes responsible for IFN-gamma suppressive effects.
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PMID:Hematopoietic inhibition by interferon-gamma is partially mediated through interferon regulatory factor-1. 757 40


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