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)

p53 has a key role in the negative regulation of cell proliferation, in the maintenance of genomic stability, and in the suppression of transformation and tumorigenesis. To identify novel regulators of p53, we undertook two functional screens to isolate genes which bypassed either p53-mediated growth arrest or apoptosis. In both screens, we isolated cDNAs encoding macrophage migration inhibitory factor (MIF), a cytokine that was shown previously to exert both local and systemic proinflammatory activities. Treatment with MIF overcame p53 activity in three different biological assays, and suppressed its activity as a transcriptional activator. The observation that a proinflammatory cytokine, MIF, is capable of functionally inactivating a tumor suppressor, p53, may provide a link between inflammation and tumorigenesis.
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PMID:A proinflammatory cytokine inhibits p53 tumor suppressor activity. 1056 11

The clinical histories of 10 women suffering from benign metastasizing leiomyoma (BML) after hysterectomy and information on lung lesions detected in these women are presented, together with corresponding data for 2 women with metastasizing leiomyosarcoma of the uterus for comparison: gross appearance, survival, and light microscopical, immunohistochemical and lectin-histochemical findings are reported. All patients with BML had undergone hysterectomy for uterus leiomyomatosus without any detection of sarcomatous lesions in the uterus wall. After a median period of 14.9 years intrapulmonary masses were detected by imaging techniques. On average, six nodules with a mean diameter of 1.8 cm were seen. Resection of the lesions was performed in all cases. The immunohistochemical and lectin-histochemical examination of the tumors included analysis of the proliferation-associated protein Ki-67, the p53 protein, estrogen and progesterone receptor, sarcolectin as an indicator of the presence of lymphokine macrophage migration inhibitory factor, antibodies and the labeled protein to assess galectin (galactoside-binding animal lectin)-dependent parameters, analysis of tumor vascularization (CD-34), and expression of bcl-2, vimentin, smooth muscle actin, desmin, and keratin. The lesions were characterized by low proliferation activity of 2.9% (measured with Ki-67), frequent hormone receptor expression (8 of the 10 cases presented hormone-specific receptors), low to moderate vascularization compared with metastases from the two uterine sarcomas, remarkable p53 overexpression and frequent expression of the lymphokine, the galectins and accessible binding sites. The median survival of the BML patients was 94 months after excision of the intrapulmonary lesions, and the maximum survival of the two sarcoma patients was 22 months. The results recorded in this patient sample with the methodology applied suggest that benign metastasizing leiomyomas are a slow-growing variant of leiomyosarcoma of the uterus, which becomes clinically apparent at a young age and progresses with low velocity.
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PMID:Benign metastasizing leiomyoma of the uterus: documentation of clinical, immunohistochemical and lectin-histochemical data of ten cases. 1103 49

The importance of the macrophage in innate immunity is underscored by its secretion of an array of powerful immunoregulatory and effector molecules. We report herein that macrophage migration inhibitory factor (MIF), a product of activated macrophages, sustains macrophage survival and function by suppressing activation-induced, p53-dependent apoptosis. Endotoxin administration to MIF(-/-) mice results in decreased macrophage viability, decreased proinflammatory function, and increased apoptosis when compared with wild-type controls. Moreover, inhibition of p53 in endotoxin-treated, MIF-deficient macrophages suppresses enhanced apoptosis and restores proinflammatory function. MIF inhibits p53 activity in macrophages via an autocrine regulatory pathway, resulting in a decrease in cellular p53 accumulation and subsequent function. Inhibition of p53 by MIF coincides with the induction of arachidonic acid metabolism and cyclooxygenase-2 (Cox-2) expression, which is required for MIF regulation of p53. MIF's effect on macrophage viability and survival provides a previously unrecognized mechanism to explain its critical proinflammatory action in conditions such as sepsis, and suggests new approaches for the modulation of innate immune responses.
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PMID:Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: regulatory role in the innate immune response. 1175 71

Over the past year, human studies have confirmed and expanded the involvement of macrophage migration inhibitory factor (MIF) in a number of diseases that had originally been studied in animals. In addition to sepsis, rheumatoid arthritis, glomerulonephritis and inflammatory lung disease, elevated MIF levels have been described in patients suffering from ulcerative colitis, inflammatory neurological diseases and cancer. Cellular studies indicate that in addition to macrophages, MIF affects the activities of CD4+ and CD8+ T cells, natural killer cells, fibroblasts and endothelial cells, actions that may explain the contribution of MIF to inflammatory diseases and cancer. Molecular studies have identified direct interactions between MIF and several intracellular regulatory proteins (Jab1, PAG and p53) that control cellular growth and proliferation; however, how interactions with these proteins fit into a general scheme to explain MIF's biological activity has not been elucidated. The three-dimensional structure of MIF has offered some surprising clues and if the potential enzymatic sites identified are involved with MIF-associated diseases, they may provide good targets for therapeutic intervention.
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PMID:Glucocorticoid counter regulation: macrophage migration inhibitory factor as a target for drug discovery. 1175 24

The pro-inflammatory mediator macrophage migration inhibitory factor (MIF) is produced by immune and endocrine cells and inhibits the antiinflammatory activities of glucocorticoids. MIF also catalyzes the tautomerization of the non-naturally occurring D-isomer of dopachrome, phenylpyruvate, and certain catecholamines, suggesting that MIF might exert its biological effects via enzymatic action on a substrate. However, no physiologically relevant substrate for MIF has been identified. Site-directed mutagenesis studies have not consistently supported a requirement for an intact, functional catalytic site as a prerequisite for MIF bioactivity. We hypothesized that the catalytically active site, but not the enzymatic activity per se, nevertheless plays a critical role in MIF pro-inflammatory activity. Accordingly, we designed small druglike molecules that bind at the catalytically active tautomerase site of MIF and tested the complex for MIF bioactivity. We describe herein the rational design and synthesis of a class of imine conjugates produced by coupling amino acids to a range of benzaldehyde derivatives that inhibit MIF tautomerase and biological activities. We found that aromatic amino acid Schiff bases were better inhibitors of MIF enzymatic and bioactivities compared to the aliphatic ones. For instance, the IC(50) inhibition of MIF tautomerase activity by aromatic amino acid Schiff base methyl esters was achieved at a concentration between 1.65 and 50 microM, suggesting a critical role for the additional binding of the aromatic residues within the vicinity of the active site. The most potent inhibitor of MIF tautomerase activity was 2-[(4-hydroxybenzylidene)amino]-3-(1H-indol-3-yl)propionic acid methyl ester (8), with an IC(50) of 1.65 microM. We found that compound 8 binding to MIF active site resulted in the inhibition of MIF bioactivity in three established bioassays: ERK-1/2 MAP kinase activation, p53-dependent apoptosis, and proliferation of serum-starved cells. Compound 8 inhibited MIF interaction with its as yet unidentified cognate cell surface receptor as shown by flow cytometry, concluding a critical role for the tautomerase active site in receptor binding. Thus the inhibitory effect of compound 8 on MIF bioactivities strongly correlated with the inhibition of MIF tautomerase activity, a connection not made previously through use of small-molecule MIF inhibitors. The inhibitory activity of amino acid-benzaldehyde Schiff base-type MIF antagonists is the first step toward a meaningful structure/function analysis of inhibitors of MIF cellular bioactivities.
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PMID:Inhibition of MIF bioactivity by rational design of pharmacological inhibitors of MIF tautomerase activity. 1203 50

Macrophage migration inhibitory factor (MIF) is known to be a proinflammatory cytokine, glucocorticoid-induced immunomodulator. MIF is abundantly expressed in various cancer cells, and is considered to contribute to cell growth and differentiation. MIF inactivates the functions of wild-type p53. Consequently, if MIF expression in cancer cells can be suppressed, the functions of p53 and p21 will be restored and an anti-tumor effect can be expected due to the inducement of cell cycle arrest. In the p21 promoter there are three DNA binding sites of STAT-1, and p21 is induced without p53. In the present study, an investigation was made of associations between p53-p21 and STAT-1-p21 signal transmission by the introduction of antisense MIF plasmid and cell cycle. Two groups, namely a transfected antisense MIF plasmid group (antisense MIF group) and a transfected PBK group (PBK group, as a control), in a DLD-1 cell line were created and used in these experiments. The cell cycle, apoptosis, inhibition of growth by subcutaneous tumor, p21 promoter activity, p21 protein, p53 cis enhancer activity and STAT-1 protein were observed. In the antisense MIF group, a shift from the S phase to the G1 phase and an inhibition of growth was noted. Scarcely any apoptotic cells were noted in either group. In terms of p21 promoter, p53 cis enhancer and STAT-1 activity, an increase in activity was found in the anti-sense MIF group. In cancer cells with MIF expression, cell arrest via p21 began due to the inhibition of MIF expression, and increases in p53 transcription activity and in STAT-1 intervention at this time were confirmed.
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PMID:Induction of cell arrest by transfection of macrophage migration inhibitory factor antisense plasmid. 1223 94

Macrophage migration inhibitory factor (MIF) is a peptide released upon hypothalamo-pituitary stimulation that acts as a potent endogenous antagonist of the glucocorticoid inhibition of acute inflammatory response and subsequent antigen-specific response. MIF also sustains tumour growth as it promotes angiogenesis, overcomes p53-mediated cell growth arrest and inhibits tumour-specific immune responses. Using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry, we studied MIF expression in 35 human glioblastomas and two normal brains. We compared these results with the expression of vascular endothelial growth factor (VEGF), the most potent angiogenic factor in glioblastomas. We detected MIF in normal cortical neurons and glial cells. All glioblastomas were positive for MIF mRNA with expression levels similar to or higher than those of normal brain. MIF immunoreactivity was seen mainly in tumour cells and less frequently in hyperplastic endothelial cells. The expressions of MIF and VEGF mRNA were strongly correlated (P < 0.0001). Our results demonstrate the expression of MIF in human glioblastomas, and indicate a close relationship with VEGF expression. This is of particular interest given the potential modulation of MIF by glucocorticosteroids.
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PMID:Macrophage migration inhibitory factor (MIF) expression in human glioblastomas correlates with vascular endothelial growth factor (VEGF) expression. 1244 61

Glioblastoma multiforme (GBM) is the most malignant variant of human glial tumors. A prominent feature of this tumor is the occurrence of necrosis and vascular proliferation. The regulation of glial neovascularization is still poorly understood and the characterization of factors involved in this process is of major clinical interest. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine released by leukocytes and by a variety of cells outside of the immune system. Recent work has shown that MIF may function to regulate cellular differentiation and proliferation in normal and tumor-derived cell lines, and may also contribute to the neovascularization of tumors. Our immunohistological analysis of MIF distribution in GBM tissues revealed the strong MIF protein accumulation in close association with necrotic areas and in tumor cells surrounding blood vessels. In addition, MIF expression was frequently associated with the presence of the tumor-suppressor gene p53. To substantiate the concept that MIF might be involved in the regulation of angiogenesis in GBM, we analyzed the MIF gene and protein expression under hypoxic and hypoglycemic stress conditions in vitro. Northern blot analysis showed a clear increase of MIF mRNA after hypoxia and hypoglycemia. We could also demonstrate that the increase of MIF transcripts on hypoxic stress can be explained by a profound transcriptional activation of the MIF gene. In parallel to the increase of MIF transcripts, we observed a significant rise in extracellular MIF protein on angiogenic stimulation. The data of our preliminary study suggest that the up-regulation of MIF expression during hypoxic and hypoglycemic stress might play a critical role for the neovascularization of glial tumors.
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PMID:Up-regulation of macrophage migration inhibitory factor gene and protein expression in glial tumor cells during hypoxic and hypoglycemic stress indicates a critical role for angiogenesis in glioblastoma multiforme. 1250 85

Macrophage migration inhibitory factor (MIF) has been shown to functionally inactivate the p53 tumor suppressor and to inhibit p53-responsive gene expression and apoptosis. To better understand the role of MIF in cell growth and tumor biology, we evaluated MIF-null embryonic fibroblasts with respect to their immortalization and transformation properties. Although minor deviations in the growth characteristics of MIF(-/-) fibroblasts were observed under normal culture conditions, MIF-deficient cells were growth-impaired following the introduction of immortalizing oncogenes. The growth retardation by the immortalized MIF(-/-) cultures correlated with their reduced susceptibility to Ras-mediated transformation. Our results identify E2F as part of the restraining mechanism that is activated in response to oncogenic signaling and show that the biological consequences of E2F induction in MIF(-/-) fibroblasts vary depending on the p53 status, inducing predominantly G(1) arrest or apoptosis in p53-positive cells. This E2F activity is independent of Rb binding, but contingent on binding DNA. Resistance to oncogenic transformation by MIF(-/-) cells could be overcome by concomitant interference with p53- and E2F-responsive transcriptional control. Our results demonstrate that MIF plays a role in an E2F/p53 pathway that operates downstream of Rb regulation and implicate MIF as a mediator of normal and malignant cell growth.
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PMID:Macrophage migration inhibitory factor deficiency is associated with altered cell growth and reduced susceptibility to Ras-mediated transformation. 1253 81

Macrophage migration inhibitory factor (MIF) is a ubiquitous protein that is found in virtually all cells. Its precise function in the majority of cells is not known, but studies performed over the last decade indicate that it is a critical upstream regulator of the innate and acquired immune response. MIF is released under a variety of circumstances, regulates cytokine secretion and the expression of receptors that are involved in innate immunity, inhibits p53 function, and activates components of the mitogen-activated protein kinase and Jun-activation domain-binding protein-1 (Jab-1) pathways. Compelling in vitro and in vivo evidence has focused attention on this protein as a new therapeutic target for inflammatory and autoimmune diseases. Unique structural features, including an intrinsic catalytic activity, offer attractive opportunities for the discovery and design of therapeutic MIF inhibitors.
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PMID:Macrophage migration inhibitory factor. 1266 94


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