Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 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

The murine B-cell hybridoma B9 requires interleukin-6 (IL-6) for its survival and proliferation in vitro. We show here that withdrawal of IL-6 from B9 cultures results in programmed death, concomitant with arrest of the cells in the G1 phase of the cell cycle. Unlike several other systems that undergo programmed cell death, no induction of transcripts corresponding to the testosterone-repressed message-2 or transglutaminase genes is observed during this process. Upon readdition of IL-6 to G1-arrested B9 cells, viability is maintained and entry into S phase occurs after a lag period of 10 to 12 hr. Northern blot analysis showed that the immediate-early mRNAs normally induced shortly after growth factor stimulation in quiescent fibroblasts (c-fos, c-jun, Egr-1, c-myc, JE, and KC), and other growth-related genes (2F1, c-Ha-ras, and p53), are either not induced or remain unchanged during G1 to S phase progression. A correlation was found, however, between the temporal pattern of expression of several G1/S phase genes (dihydrofolate reductase, thymidine kinase, transferrin receptor, and histone H3) and DNA synthesis. These results demonstrate that IL-6-induced viability and growth of hybridoma (and, presumably, plasmacytoma) cells is mediated via novel signal transduction pathways.
 ...
PMID:Suppression of programmed death and G1 arrest in B-cell hybridomas by interleukin-6 is not accompanied by altered expression of immediate early response genes. 170 72

Wild-type p53 protein has many properties consistent with its being the product of a tumour suppressor gene. Although the normal roles of tumour suppressor genes are still largely unknown, it seems that they could be involved in promoting cell differentiation as well as in mediating growth arrest by growth-inhibitory cytokines. Hence, the abrogation of wild-type p53 expression, which is a common feature of many tumours, could eliminate these activities. We have now tested this notion by restoring the expression of p53 in a murine myeloid leukaemic cell line that normally lacks p53. The use of a temperature-sensitive p53 mutant allowed us to analyse cells in which the introduced p53 had either wild-type or mutant properties. Although there seemed to be no effect on differentiation, the introduction of wild-type p53 resulted in rapid loss of cell viability in a way characteristic of apoptosis (programmed cell death). The effect of wild-type p53 was counteracted by interleukin-6. Thus products of tumour suppressor genes could be involved in restricting precursor cell populations by mediating apoptosis.
 ...
PMID:Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. 185 10

The ability of p53 species (wild-type and mutant) to modulate the "differentiated" response of human hepatoma cell lines Hep3B and HepG2 to interleukin-6 (IL-6) was investigated. Transient transfection experiments were carried out in Hep3B and HepG2 cell cultures in which IL-6 was used to activate a beta-fibrinogen (beta Fib) enhancer/reporter construct containing two copies of the 36-base pair IL-6-response element (IL-6RE) (p beta FibCAT). Cotransfection with constitutive expression vectors for wild-type (wt) human or murine p53 inhibited the activation of the p beta FibCAT reporter by IL-6 in both Hep3B and HepG2 cells. Several mutant p53 species either did not inhibit the activation of p beta FibCAT or up-regulated the response. Hepatoma cell lines stably expressing the Val-135 temperature-sensitive mutant of murine p53 (wt-like at 32.5 degrees C and mutant-like at 37 degrees C) were derived from Hep3B cells and tested for the temperature-sensitive phenotype of their ability to synthesize and secrete fibrinogen and alpha 1-antichymotrypsin in response to IL-6. In an experimental protocol in which the parental Hep3B cells did not show a significant difference in plasma protein secretion at the two temperatures, hepatoma line 3 (p53Val-135+) had a greater response to IL-6 at 37 degrees C than parental Hep3B cells, while line 3 cells had a reduced response to IL-6 at 32.5 degrees C. Similarly, hepatoma lines 1 and 2 (both p53Val-135+) had reduced IL-6 responsiveness at 32.5 degrees C, whereas line 22 (transfected with pSVneo alone) and the parental Hep3B cells did not. These data indicate that mutations in p53 contained in tumor cells can modulate the "differentiated" response of these cells to cytokines.
 ...
PMID:Modulation of interleukin-6-induced plasma protein secretion in hepatoma cells by p53 species. 755 62

In this work we intended to determine whether p53 and/or retinoblastoma (Rb) tumor suppressor genes are involved at specific stages in the process of in vitro human peripheral stem cell hematopoiesis. Mononuclear peripheral blood cells were depleted of adherent cells and T lymphocytes (A-T-PMCs). Cells were then cultured in semisolid medium, under conditions that favor the growth of specific progenitor cell types. A-T-PMCs were exposed to p53 and/or Rb sense, scrambled DNA and antisense oligodeoxynucleotides. p53 and/or Rb antisenses (but not their senses or scrambled DNA) treatment of A-T-PMCs resulted in a significantly increase in the number of granulocyte/macrophage colony-forming units (CFU-GM) in the presence of interleukin-3 (IL-3) and/or granulocyte/macrophage colony-stimulating factor (GM-CSF). After antisense treatment, blast forming units/erythroblasts (BFU-E) derived from A-T-PMCs cultured in the presence of IL-3 + erythropoietin (Epo) were also increased whereas colony forming units/erythroblasts (CFU-E) were not markedly affected in the presence of Epo only. Megakaryocytic colony (CFU-Meg) formation from A-T-PMCs in the presence of interleukin-6 (IL-6) + IL-3 + Epo was also increased after antisense oligodeoxynucleotide treatment. These results are consistent with the hypothesis that p53 and Rb tumor suppressor gene products are involved in the control of distinct signal pathways in different peripheral progenitor cells.
 ...
PMID:In vitro p53 and/or Rb antisense oligonucleotide treatment in association with growth factors induces the proliferation of peripheral hematopoietic progenitors. 762 11

A replication-defective recombinant retrovirus containing the human papilloma virus E6/E7 genes (LXSN-16 E6E7) was used to immortalize stromal cells from human marrow. The E6/E7 gene products interfere with the function of tumor-suppressor proteins p53 and Rb, respectively, thereby preventing cell cycle arrest without causing significant transformation. Twenty-seven immortalized clones designated HS-1 to HS-27 were isolated, four of which are characterized in this report. Two cell lines, HS-5 and HS-21, appear to be fibroblastoid and secrete significant levels of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage-CSF (GM-CSF), macrophage-CSF (M-CSF), Kit ligand (KL), macrophage-inhibitory protein-1 alpha, interleukin-6 (IL-6), IL-8, and IL-11. However, only HS-5 supports proliferation of hematopoietic progenitor cells when cocultured in serum-deprived media with no exogenous factors. Conditioned media (CM) from HS-5 promotes growth of myeloid colonies to significantly greater extent than a cocktail of recombinant factors containing 10 ng/mL of IL-1, IL-3, IL-6, G-CSF, GM-CSF, and KL and 3 U of erythropoietin (Epo). Two additional clones, HS-23 and HS-27, resemble "blanket" cells, with an epithelioid morphology, and are much larger, broader, and flatter when compared with HS-5 and HS-21. These lines secrete low levels of growth factors and do not support proliferation of isolated progenitor cells in cocultures. CM from HS-23 and HS-27 also fail to support growth of myeloid colonies. Both HS-23 and HS-27 express relatively high levels of VCAM-1, yet HS-27 is the only line that supports the formation of "cobblestone" areas by isolated CD34+38lo cells. We hypothesize that HS-5, HS-21, HS-23, and HS-27 represent functionally distinct components of the marrow microenvironment.
 ...
PMID:Functionally distinct human marrow stromal cell lines immortalized by transduction with the human papilloma virus E6/E7 genes. 784 21

The development of clinically frank malignant melanomas in humans is thought to evolve over decades in a stepwise process of progression. By analogy with certain other adult cancers, eg, colorectal carcinomas, alterations in expression or function of a number of different suppressor genes might be expected to be involved in this process. This could lead to loss of expression of a number of different negative growth controls. Evidence is reviewed implicating the presence of putative suppressor genes for the melanocytic lineage located on chromosomes 9p21, 6q, and 1p. In addition, there is evidence suggesting a contribution for the p53 and NF1 tumor-suppressor genes, and the nm23 metastasis-suppressor gene, in melanoma development or progression. Additional possible suppressor genes include those encoding manganese superoxide dismutase, and possibly c-kit. An accumulation of such alterations may be responsible for the progressive loss of responsiveness to several independent growth inhibitors for melanocytes or early stage melanomas, including interleukin-6, transforming growth factor-beta, and oncostatin M. They may also be responsible for some aspects of the production of direct acting autocrine growth factors or production of angiogenesis stimulating factors, or both, by melanoma cells. The acquisition of resistance to several growth inhibitors and the multiplicity of putative suppressor gene alterations (combined with the production of multiple autocrine and paracrine growth factors) may be necessary for the evolution of nondividing single melanocytes resident in the epidermis into highly proliferative and metastatic melanomas capable of growing multicellularly in ectopic organ sites.
 ...
PMID:Cytokines, growth factors and the loss of negative growth controls in the progression of human cutaneous malignant melanoma. 801 99

Stable transfection of M1 myeloid leukemia cells with a temperature-sensitive mutant of p53 results in two phenomena that are manifested exclusively at the permissive temperature. On one hand, activation of wild-type p53 by the temperature shift induced an apoptotic type of cell death which could be inhibited by interleukin-6 (IL-6) (E. Yonish-Rouach, D. Resnitzky, J. Lotem, L. Sachs, A. Kimchi, and M. Oren, Nature 352:345-347, 1991). On the other hand, as reported in this work, activated p53 complemented the antiproliferative effects of IL-6 in M1 cells. A shift to the permissive temperature concomitant with or early after IL-6 treatment imposed a novel pattern of cell cycle arrest in which about 95% of the cells were retained within a G0-like quiescent state. This phase was characterized by 2N DNA content and low RNA and protein content. On the molecular level, activation of wild-type p53 transrepressed the c-myc gene but not the cyclin A, D1, or D2 gene, which are all independently suppressed by IL-6 in M1 cells. To further analyze whether c-myc inhibition mediates or complements p53 effects, the p53-transfected M1 cells were infected with a retroviral vector expressing deregulated c-myc, refractory to p53 or IL-6 action. It was found that the process of cell death was not interrupted at all in these M1 c-myc-p53 double transfectants, suggesting that the transrepression of c-myc is not a major obligatory event mediating p53-induced cell death. In addition, some of the antiproliferative effects of activated p53, manifested in the presence of IL-6, could still be transmitted in the background of constitutive c-myc. Yet the context of deregulated c-myc interfered with the final accumulation of cells within a G0-like phase, suggesting complementary interactions between the outcome of p53 activation and of c-myc suppression in the control of cell cycle arrest.
 ...
PMID:Complementation by wild-type p53 of interleukin-6 effects on M1 cells: induction of cell cycle exit and cooperativity with c-myc suppression. 824 9

The p53 mutant Val135 is widely considered to have a wild-type (wt) phenotype at 32.5 degrees C, but not at 37 degrees C. The ability of wt murine p53 and its Val135 mutant to modulate transcription from the muscle-specific creatine kinase promoter (-3.3 kb pMCK), from a reporter construct containing two copies of the p53-binding DNA element from within MCK (p50-2), and from the interleukin-6 (IL-6) promoter (pIC225) was evaluated in transient transfection experiments in CV1 and HeLa cells. In CV1 cells, wt p53 was confirmed to activate the pMCK and p50-2 reporters, but to repress the IL-6 promoter. However, although in these cells p53 Val135 had the expected wt-like phenotype with respect to activation of the p50-2 reporter at 32.5 degrees C (32.5 degrees C > 37 degrees C), this mutant had little effect on expression from pMCK at either temperature, and activated rather than repressed the IL-6 promoter at 32.5 degrees C. In HeLa cells, although wt p53 activated p50-2 but repressed the MCK and IL-6 promoters, p53 Val135 activated all three reporters. Unexpectedly, in these cells the upregulation of p50-2 and pIC225 was basically temperature-independent, and that of pMCK was inversely ts (37 degrees C > 32.5 degrees C). The novel ts properties of p53 Val135 show that this mutant is not always wt-like at 32.5 degrees C but exhibits strong cell-type and promoter-dependent differences in its ts phenotype for transcriptional modulation.
 ...
PMID:Cell-type- and promoter-dependent ts phenotype of p53 Val135. 824 45

Constitutive up-regulation of interleukin-6 (IL-6) gene expression is observed in many neoplastic cell lines. The contribution of mutations in p53 to the up-regulation of the IL-6 promoter was evaluated in transient transfection experiments. In HeLa cells, wild-type (wt) human or murine p53 preferentially repressed the IL-6 promoter. The p53 mutants Val-135 and Phe-132 up-regulated IL-6 promoter activity in these cells at both 32.5 and 37 degrees C. The temperature-sensitive Val-135 mutant was not only not inhibitory or "wt-like" at the lower temperature, but had gained a transcriptional activator phenotype which was temperature-independent in HeLa cells. The functional DNA target for transcriptional modulation of the IL-6 promoter by p53 species included the multiple cytokine- and second messenger-response element (-173 to -145); point mutations in the transcription factor C/EBP beta-binding site within the second messenger-response element largely blocked the ability of p53 mutants Val-135 and Phe-132 to up-regulate this promoter. The up-regulation of IL-6 promoter constructs by co-transfection into HeLa cells of a C/EBP beta constitutive expression vector was blocked in a dominant negative manner by wt p53. In contrast, the p53 mutants Val-135 and Phe-132 further enhanced C/EBP beta-mediated up-regulation of IL-6 promoter constructs. The modulation of C/EBP beta function by p53 species provides a basis for the involvement of p53 not only in the regulation of cytokine synthesis but also in the altered responsiveness of tumor cells to cytokines.
 ...
PMID:Modulation of the human interleukin-6 promoter (IL-6) and transcription factor C/EBP beta (NF-IL6) activity by p53 species. 832 85


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