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)

Okadaic acid, a phosphatase inhibitor from a marine organism, mimics tumor necrosis factor/interleukin-1 (TNF/IL-1) in inducing changes in early cellular protein phosphorylation. A total of approximately 116 proteins exhibit significant and concordant changes in phosphorylation or dephosphorylation within 15 min in human fibroblasts activated by either okadaic acid, TNF, or IL-1. The fidelity of this mimicry by okadaic acid extends to the phosphorylation of the 27 hsp complex, stathmin, eIF-4E, myosin light chain, nucleolin, epidermal growth factor receptor, and other cdc2-kinase substrates (c-abl, RB, and p53). The okadaic acid-induced pattern of protein phosphorylation is distinct from that observed in cells treated with phorbol 12-myristate 13-acetate or with ligands like epidermal growth factor, cyclic AMP agonists, bradykinin, or interferons. Like TNF, okadaic acid also induces the transcription of immediate early response genes like c-jun and Egr-1 as well as the interleukin-6 genes. The overall early effects of okadaic acid uniquely parallel those of TNF/IL-1 and not those of other cytokines or ligands. Regulation of protein phosphatase inhibition is discussed as a mechanism for TNF/IL-1 signal transduction.
 ...
PMID:Okadaic acid mimics multiple changes in early protein phosphorylation and gene expression induced by tumor necrosis factor or interleukin-1. 137 Apr 82

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.
 ...
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

Transcripts coding for transcription factors (RB, P53, FOS, MYC, MYB, ERBA, REL), growth factors (FGF1, FGF2, INT2, TGFA, TGFB, PDGF, IGF1, IGF2), interleukins, (IL1, IL2, IL3, IL4, IL6, TNF), growth-factor receptors or cytosolic protein kinases (RAF, PIM, FES, MET, SRC, ROS, TRK, KIT, CSFR, IGFR, PDGFR, EGFR, NEU) were quantified in cultured human mammary fibroblasts from normal tissues, benign tumours, carcinomas and post-radiation fibrosis lesions by slot-blot autoradiography and image analysis. The effects of a differentiating agent (cholera toxin) and of a tumour promoter (12-O-tetradecanoyl-phorbol-13-acetate) were also examined. The drugs modulated the levels of the anti-oncogene transcripts (RB, P53) and of ERBA, REL, RAF, MET, ROS, TRK, CSFR, EGFR, NEU, FGF1, INT2, IGF1, IL1, IL2, IL4 and IL6. Apart from this variation, there were multiple differences in gene expression among normal and pathological cells (concerning all but P53, TGFB and interleukin transcripts) and between sub-types defined by the presence of alpha-sm-actin (myofibroblasts) or EDB-fibronectin (RAF, ROS, FES, KIT, IGFR, NEU, INT2, TGFB, PDGF, IGFs, ILs). It appears, therefore, that mammary stroma progress irreversibly along with the epithelium during tumoral development, and that breast cancer is not only a multi-gene but also a multi-tissue phenotype.
 ...
PMID:Quantitative variation of proto-oncogene and cytokine gene expression in isolated breast fibroblasts. 776 44

Fanconi anemia belongs to a group of human genetic diseases characterized by chromosomal instability, sensitivity to genotoxic agents associated to impaired processing of DNA lesions, cell cycle anomalies and cancer predisposition. We recently added to this list of distinctive features reduced production of interleukin 6 and overproduction of tumor necrosis factor alpha. Since growth factor deprivation, TNF alpha treatment or DNA damage can trigger apoptosis, we monitored the apoptotic response of FA cell lines. We show here that, although the spontaneous rate of apoptosis is slightly more elevated in FA than in normal cell cultures, the apoptosis induced by gamma-irradiation is drastically reduced in FA. Since the induction of apoptosis by radiation is a p53-dependent mechanism, the induction of this protein in FA cells was also examined. We found that the p53 protein is not radio-induced in FA cells belonging to the two genetic complementation groups examined (C and D), in contrast to normal cells. Moreover, the same impairment in p53 induction is observed after exposure to mitomycin C, a chemical agent for which FA cells demonstrate a specific cellular and chromosomal hypersensitivity, as well as after u.v.-B irradiation, an agent known to cause oxidative stress. These observations are in line with recent reports showing that at least certain cell lines from other chromosome breakage syndromes, such as ataxia telangiectasia and Bloom syndrome, may be also defective for radiation-induced increase of p53 protein. As the p53 tumor suppressor gene encodes a transcriptional activator whose targets include genes that regulate genomic stability, cellular response to DNA damage and cell cycle progression, we suggest that altered expression of p53 may be relevant to the FA phenotype.
 ...
PMID:p53-dependent pathway of radio-induced apoptosis is altered in Fanconi anemia. 782 83

In a search for specific serum markers with prognostic impact, we evaluated the clinical significance of IL-4, IL-7, and IL-8 as well as TNF receptor levels and soluble p53 in the serum of patients with untreated Hodgkin's lymphoma (HD). No elevations were observed for IL-4, while IL-7 and IL-8 were elevated in 15/52 (29%) and 21/78 (27%) patients, respectively. Soluble TNF receptors were detected in 16/29 patients (55%), and were significantly elevated in 6 (21%). P53 was detected in 21/33 (64%) patients. While IL-7 levels, detectable sTNF receptors, and p53 were not correlated with other obvious parameters, elevated IL-8 levels were associated with the presence of B symptoms (p < 0.002) and occurred more often in the nodular sclerosis form than in other histological subtypes (p < 0.02). Further investigations that correlate these serum parameters with the situation at the cellular level of an involved tissue will help to elucidate the enigmatic biology of HD.
 ...
PMID:Interleukin-7, interleukin-8, soluble TNF receptor, and p53 protein levels are elevated in the serum of patients with Hodgkin's disease. 817 27

Topical steroid treatment is a common therapy for psoriasis. Steroids are known to bind to specific cytoplasmic receptors and to influence gene expression. We investigated the effects of the novel steroid derivative mometasone furoate on the expression of putative target genes in normal human epidermal cells (KC). Gene expression was measured by semiquantitative mRNA-PCR. In addition, cytokine receptor characteristics were assessed by ligand binding studies. We found a dose-dependent downregulation of proinflammatory mediators (IL-8, TNF alpha). Genes involved in growth regulation (HER-2, p53) were also modulated. IL-8 binding to KC was inhibited. We conclude that modulation of the expression of cytokine, cytokine receptor and growth factor genes may contribute to the antipsoriatic action of steroids.
 ...
PMID:Novel steroid derivative modulates gene expression of cytokines and growth regulators. 852 52

The p53 protein directly regulates the expression of the WAF1 (wild-type p53-activated fragment 1) protein which is a cyclin-dependent kinase inhibitor (CDK1). DNA damaging agents such as ionizing or UV radiation, and some chemical agents induce WAF1 in wild-type p53 containing cells, thereby halting cell cycle progression. WAF1 expression is also induced through a p53-independent pathway. Tumor necrosis factor alpha (TNF alpha) is a cytotoxic/cytostatic compound for some human cancer cells. We examined a series of myeloid leukemic cell lines that expressed either no p53 (HL-60, K562) or mutant inactive p53 (KG-1, KCL22,THP-1, U937). The KG-1, HL-60, K562, and KCL22 myeloid leukemic cells increased their levels of WAF1 mRNA in the presence of TNF alpha. We focused on KG-1 cells to determine how TNF alpha modulated WAF1 expression. WAF1 mRNA increased in a dose-dependent manner in the cells after exposure to increasing concentrations of TNF alpha, and this increase occurred in the absence of new protein synthesis. An increase of WAF1 protein and a concominant decrease of cyclin-dependent kinase 2 activity also was found in KG-1 cells. Flow cytometry using 5-bromo-2'-deoxyuridine showed an increase in the proportion of TNF alpha- treated KG-1 cells in the G0/G1 phase of the cell cycle. TNF alpha enhanced the rate of WAF1 transcription only 1.4 fold in TNF alpha-treated KG-1 cells as compared to untreated cells. Notably, however, the half-life (t 1/2) of WAF1 mRNA in TNF alpha-treated cells was 2.5 hours as compared to 0.5 hours in untreated cells. These results indicate that TNF alpha increases WAF1 levels at least in part via a postttranscriptional stabilization of the mRNA; and TNF alpha may mediate its cytostatic effects through WAF1 in some cell types.
 ...
PMID:Tumor necrosis factor alpha: posttranscriptional stabilization of WAF1 mRNA in p53-deficient human leukemic cells. 860 Jan 60

Recent studies have shown that experimental tumors could be treated more efficiently with ionizing radiation if genetic material was transfered into tumor cells. Several approaches have been reported, and among them, the first one consisted of increasing the apoptotic response to radiation by modulating genes involved in the regulation of the apoptotic pathway. Indeed the modulation of p53 and bcl-2 gene expression has recently been used successfully in several experimental models to increase the apoptotic death after radiation. A second approach consisted of taking advantage of the conditional expression of some genes after exposure to ionizing radiation. Indeed, some genes exhibit a radio-inducible promoter which can be combined to a gene, able to enhance or decrease the biological effect of radiation. The irradiation of such a transgene under the control of a radio-inducible promoter can lead to a second biological effect, concomitant to the irradiation, as reported for the TNF alpha under the control of the EGR (early growth response) promoter. A third approach consisted of enhancing the effect of radiation induced tumor cell death by the expression of a suicide gene in these cells, as suggested recently for the HSV-tk (herpes virus thymidine kinase gene). These preliminary results obtained in experimental models appear to be very promising and might improve the efficacy and specificity of radiation therapy in a not too distant future.
 ...
PMID:[Gene transfer and radiotherapy]. 865 4

Homeostasis of cell numbers in tissues is maintained by a critical balance between cell proliferation and programmed cell death or apoptosis. Many human viruses are able to develop suitable strategies for modifying apoptosis in virus-infected cells and in virus-primed T cells. Apoptosis is characterized by the fragmentation of nuclear DNA into 180-200 bp apoptotic bodies and can be analysed microscopically or by flow cytometry using staining with various dyes. Moreover DNA cleavage can be identified by electrophoresis and by specific labeling using in situ nucleotidyltransferase assay (ISNT), terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling technique (Tunel), or by Elisa. Adenovirus E1A induces expression of protooncogenes c-myc and c-fos which sensitize cells to apoptosis; EBV EBNA-5, and adenovirus E1A, HPV E7, and polyomavirus large T act in the same way by displacing pRB-bound E2F. EBV EBNA-5, HPV E6, Adenovirus E1B 55 kDa inactivate the tumor suppressor protein p53 and engage the cells in the transformation process. EBV LMP-1, HHV6, and HTLV1 tax induce the antiapoptotic bcl-2 protein. EBV BHRF1 encodes proteins with homology to bcl-2 and Adenovirus E1B 19 kDa encodes proteins that have protective functions similar to bcl-2. Activated lymphocytes responding to viral infections express high levels of fas and are susceptible to apoptosis. TNF alpha can down- or up-regulate fas and down-regulates TNF-R. Adenovirus E1B 19 kDa blocks the proapoptotic activity of TNF alpha. Inversly, Cytomegalovirus, hepatitis C virus and Myxoviruses up-regulate fas antigen prior to undergoing apoptosis. In HIV-infected patients, CD4+ T-cell apoptosis is mediated by the cytopathic effect of the virus and the cell surface expression of gp 120-env protein. Moreover, an accelerated T-cell apoptosis in HIV-infected individuals is characterized by (i) HIV gp120-CD4+ cross-linking and subsequent aberrant signaling of T-cells, (ii) involvement of TNF alpha-fas/Apo-1 (TNF-R) binding, (iii) involvement of accessory cells as an apoptosis inducer and as a result of defective antigen presentation, (iv) possible superantigen activity induced by HIV products and cofactors. Many viruses also encode proteins with protease activity which could induce apoptosis. The induction of apoptosis may result in virus clearance, in contrast the inhibition of apoptosis may result in virus cell transformation and viral persistence. Indirectly, the apoptosis of infected cells may be induced by CTLs, NK cells and cytokines. In addition, apoptosis-mediated physiological depletion of T lymphocytes in the course of viral infection can silence the immune response and can induce immunodeficiency.
 ...
PMID:[Apoptosis and human viral infections]. 886 58

A good prognosis is often achieved in patients who have undergone treatment for human papillary carcinoma of the thyroid. On the assumption that this may be partly attributable to an apoptotic tendency of this special type of tumor, we measured DNA fragmentation, cell death by enzyme-linked immunosorbent assay (ELISA), and the expression of apoptosis-related genes. DNA fragmentation occurred more extensively in malignant tumor cells than in benign thyroid tumors or normal thyroid tissue, as examined by agarose gel electrophoresis and confirmed by the quantitative method using an ELISA kit. Although only expression of the tumor suppressor gene, p53, was increased in the tumor tissue, no expression of other genes, such as Fas, TNF, c-myc, c-fos or bcl-2, was observed in the normal, benign, or malignant tumor tissues, indicating that the roles of these gene functions, if any, were minimal in these tissues. Since p53 is closely related to cellular apoptosis and no point mutation was observed in the transcripts expressed by malignant cells, apoptosis and/or the production of an angiogenesis inhibitor induced by wild-type p53 molecules may be related to the favorable prognosis of patients treated for papillary carcinoma of the thyroid.
 ...
PMID:Expression of wild-type p53 tumor suppressor gene and its possible involvement in the apoptosis of thyroid tumors. 906 3


1 2 3 4 5 6 7 8 9 10 Next >>