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)

Nitric oxide (NO) is a potent bioactive molecule produced in the presence of NO synthase (NOS) enzymes, which mediates numerous physiological functions under constitutive conditions. Sustained overproduction of NO (and NO-reaction products), typically under inductive conditions, can lead to cell cycle arrest and cellular apoptosis. Furthermore, carcinogenesis may result from mutational events following NO-mediated DNA damage and hindrance to DNA repair (e.g., mutation of tumour-suppressor gene p53). In a majority of human and experimental tumours, tumour-derived NO appears to stimulate tumour progression; however, for a minority of tumours, the opposite has been reported. This apparent discrepancy may be explained by differential susceptibility of tumour cells to NO-mediated cytostasis or apoptosis, and the emergence of NO-resistant and NO-dependent clones. NO-resistance may be mediated by p53 inactivation, and upregulation of cyclo-oxygenase-2 and heat shock protein 70 (HSP70). In a murine mammary tumour model, tumour-derived NO promoted tumour growth and metastasis by enhancing invasive, angiogenic, and migratory capacities of tumour cells. Invasion stimulation followed the altered balance of matrix metalloproteases and their inhibitors; migration stimulation followed activation of guanylate cyclase and MAP kinase pathways. Selective NOS inhibitors may have a therapeutic role in certain cancers.
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PMID:Role of nitric oxide in tumour progression with special reference to a murine breast cancer model. 1193 55

Oncogenic activation of the mitogen-activated protein (MAP) kinase cascade in murine fibroblasts initiates a senescence-like cell cycle arrest that depends on the ARF/p53 tumor suppressor pathway. To investigate whether p53 is sufficient to induce senescence, we introduced a conditional murine p53 allele (p53(val135)) into p53-null mouse embryonic fibroblasts and examined cell proliferation and senescence in cells expressing p53, oncogenic Ras, or both gene products. Conditional p53 activation efficiently induced a reversible cell cycle arrest but was unable to induce features of senescence. In contrast, coexpression of oncogenic ras or activated mek1 with p53 enhanced both p53 levels and activity relative to that observed for p53 alone and produced an irreversible cell cycle arrest that displayed features of cellular senescence. p19(ARF) was required for this effect, since p53(-/-) ARF(-/-) double-null cells were unable to undergo senescence following coexpression of oncogenic Ras and p53. Although the levels of exogenous p53 achieved in ARF-null cells were relatively low, the stabilizing effects of p19(ARF) on p53 could not explain the cooperation between oncogenic Ras and p53 in promoting senescence. Hence, enforced p53 expression without oncogenic ras in p53(-/-) mdm2(-/-) double-null cells produced extremely high p53 levels but did not induce senescence. Taken together, our results indicate that oncogenic activation of the MAP kinase pathway in murine fibroblasts converts p53 into a senescence inducer through both quantitative and qualitative mechanisms.
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PMID:Oncogenic ras and p53 cooperate to induce cellular senescence. 1197 80

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

Reactive oxygen species such as superoxide and hydroxyl radicals have been implicated in the pathogenic growth of various cell types. The molecular mechanisms involved in redox-sensitive cell growth control are poorly understood. Stimulation of cultured vascular smooth muscle cells (VSMC) with xanthin/xanthin oxidase (X/XO) increases proliferation, whereas stimulation with hydrogen peroxide and Fe3+NTA (H-Fe) causes growth arrest of VSMC. Differential Display led to the identification of two novel, differentially regulated redox-sensitive genes. The dominant negative helix-loop-helix protein Id3 is induced by X/XO and down-regulated by H-Fe. The transcription factor gut-enriched Kruppel-like factor (GKLF) is induced by H-Fe but not by X/XO. Induction of GKLF and inhibition of Id3 via transfection experiments leads to growth arrest, whereas overexpression of Id3 and inhibition of GKLF cause cell growth. Id3 down-regulation is induced via binding of GKLF to the Id3 promotor and concomitantly reduced Id3 gene transcription rate. GKLF induction by H-Fe is mediated through hydroxyl radicals, p38MAP kinase-, calcium-, and protein synthesis-dependent pathways. Id3 is induced by X/XO via superoxide, calcium, p38, and p42/44 MAP kinase. GKLF induces and Id3 depresses expression of p21WAF1/Cip1, p27KIP1, p53. Induction of Id3 is accomplished by angiotensin II via superoxide release. A vascular injury mouse model revealed that Id3 is overexpressed in proliferating vascular tissue in vivo. These findings reveal novel mechanisms of redox-controlled cellular proliferation involving GKLF and Id3 that may have general implications for our understanding of vascular and nonvascular growth control.
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PMID:Redox-sensitive vascular smooth muscle cell proliferation is mediated by GKLF and Id3 in vitro and in vivo. 1208 69

Drm/Gremlin, a member of the Dan family of BMP antagonists, is known to function in early embryonic development, but is also expressed in a tissue-specific fashion in adults and is significantly downregulated in transformed cells. In this report, we demonstrate that overexpression of Drm in the tumor-derived cell lines Daoy (primitive neuroectodermal) and Saos-2 (osteoblastic), either under ecdysone-inducible or constitutive promoters, significantly inhibits tumorigenesis. Furthermore, Drm overexpression in these cells increases the level of p21(Cip1) protein and reduces the level of phosphorylated p42/44 MAP kinase. Finally, our data indicate that Drm can induce p21(Cip1) transcriptionally via a novel pathway that is independent of p53 and the p38 and p42/44 MAP kinases. These results provide evidence that Drm can function as a novel transformation suppressor and suggest that this may occur through its affect on the levels of p21(Cip1) and phosphorylated p42/44 MAPK.
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PMID:Drm/Gremlin transcriptionally activates p21(Cip1) via a novel mechanism and inhibits neoplastic transformation. 1213 12

The human disease neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene, and is characterized by the formation of benign and malignant tumors of the peripheral nervous system. We have shown previously that aberrant expression of the epidermal growth factor receptor (EGFR) is a common feature of human NF1-related tumor development in humans and in NF1 animal models. One recent approach taken to investigate the changes associated with NF1 tumor formation is the development of the Nf1:p53 mouse tumor model. Here, we examined a series of tumor cell lines derived from Nf1:p53 mice for their expression of EGFR family members. Immunoblotting analyses revealed that 23 of the 24 cell lines examined express the EGFR, and 24 of 24 express the related tyrosine kinase erbB2, whereas erbB3 was detected in only 6 of 24. All of the cell lines expressing EGFR responded to epidermal growth factor (EGF) by activation of the downstream signaling pathways, mitogen-activated protein (MAP)/extracellular signal-regulated kinase kinase/MAP kinase, and phosphatidylinositol 3'-kinase (PI3k)/AKT. Growth of the cell lines was greatly stimulated by EGF in vitro and could be blocked by an antagonist of the EGFR. In addition, inhibition of the PI3k pathway potently inhibited the EGF-dependent growth of these cell lines, whereas inhibition of the MAP/extracellular signal-regulated kinase kinase/MAP kinase pathway had more limited effects. We conclude that EGFR expression is a common feature of the Nf1:p53 tumor cell lines and that inhibition of this molecule or its downstream target PI3k, may be useful in the treatment of NF1-related malignancies.
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PMID:Epidermal growth factor receptor signaling pathways are associated with tumorigenesis in the Nf1:p53 mouse tumor model. 1215 62

Mammalian cells have a remarkable diverse repertoire of response to genotoxic stress that damage DNA. Cellular responses to DNA damaging agents will initially exhibit gene induction, which is regulated by complex mechanism(s) and probably involves multiple signaling pathways. In this paper, we demonstrate that induction of ATF3 protein, a member of the ATF/CREB family of transcription factors, by ionizing radiation (IR) requires normal cellular p53 function. In contrast, induction of ATF3 after UV radiation (UV) or Methyl methanesulphonate (MMS) is independent of p53 status. Induction of ATF3 by DNA damage is rapid, transient, and through a transcriptional mechanism. The ATF3 promoter is induced by UV and MMS, but not by IR. In addition, ATF3 promoter can be activated by MEKK1, an upstream activator of the ERK and JNK kinase pathway, but not induced following p53 expression. Those results indicate that regulation of ATF3 induction after DNA damage utilizes both the p53-dependent and -independent pathways, and may also involve MAP kinase signaling pathways. Using the tetracycline-inducible system (tet-off), we have found that over-expression of ATF3 protein moderately suppresses cell growth. Interestingly, over-expression of ATF3 protein is able to slow down progression of cells from G1 to S phase, indicating that ATF3 protein might play a negative role in the control of cell cycle progression.
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PMID:ATF3 induction following DNA damage is regulated by distinct signaling pathways and over-expression of ATF3 protein suppresses cells growth. 1238 11

p53 has a role in many cellular processes through the transcriptional regulation of target genes. PAC1 (phosphatase of activated cells 1; also known as dual specificity phosphatase 2, DUSP2) is a dual threonine/tyrosine phosphatase that specifically dephosphorylates and inactivates mitogen-activated protein (MAP) kinases. Here we show that during apoptosis, p53 activates transcription of PAC1 by binding to a palindromic site in the PAC1 promoter. PAC1 transcription is induced in response to serum deprivation and oxidative stress, which results in p53-dependent apoptosis, but not in response to gamma-irradiation, which causes cell cycle arrest. Reduction of PAC1 transcription using small interfering RNA inhibits p53-mediated apoptosis, whereas overexpression of PAC1 increases susceptibility to apoptosis and suppresses tumour formation. Moreover, activation of p53 significantly inhibits MAP kinase activity. We conclude that, under specific stress conditions, p53 regulates transcription of PAC1 through a new p53-binding site, and that PAC1 is necessary and sufficient for p53-mediated apoptosis. Identification of a palindromic motif as a p53-binding site may reveal a novel mechanism whereby p53 regulates its target genes.
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PMID:PAC1 phosphatase is a transcription target of p53 in signalling apoptosis and growth suppression. 1267 51

The human egr-1 gene encodes a zinc finger transcription factor induced by endogenous and exogenous stimuli such as growth factors, cytokines, and mitogens. Egr-1 regulates other genes involved in growth and differentiation. The present study investigated the influence of genotoxic agents, such as chemotherapy drugs and other DNA damaging agents, on egr-1 expression in normal and neoplastic cells. A transcriptional fusion between the human egr-1 promoter and the enhanced green fluorescent protein (EGFP) gene was used for direct visualization of intracellular Egr-1 regulation. The transcriptional activity of the egr-1 promoter in this reporter system faithfully reflects intrinsic egr-1 expression and induction, as demonstrated by FACS analysis of fluorescence and by RT-PCR for egr-1. EGFP was expressed under the control of the egr-1 promoter in stably transfected immortalized cell lines, such as HEK293, T98G, LNZ308, and 9L, which were then treated with genotoxic agents.A multitude of DNA damaging agents and therapeutic drugs caused significant upregulation of egr-1 transcription. Furthermore, cytotoxic compounds without a direct DNA damaging effect, such as resveratrol and vincristine, which interfere with DNA replication and cell division, were also able to activate egr-1 transcription. This suggests that cell cycle arrest rather than DNA damage seems to be the condition triggering egr-1 transcription. Moreover, treatment with the MAP kinase (MAPK) inhibitor SB203580, which specifically blocks the stress inducible p38/SAPK2 pathway, did not alter egr-1 induction. On the other hand, treatment with the inhibitor PD98059, which specifically blocks the MAPK/ERK pathway, partially suppressed the induction effect. In addition, the egr-1 induction effect caused by genotoxic stress was found to be at least in part independent from the cellular p53 status, as it was observed in p53-deficient as well as in wild type p53 cell lines. These results suggest that induction of egr-1, a gene to which until now no relation to DNA repair has been assigned, may belong to the fundamental cellular responses elicited by genotoxic and mitotic stress in normal as well as in neoplastic cells, and that enhanced levels of Egr-1 protein may be needed to regulate genes involved in DNA repair, cell survival, and apoptosis.
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PMID:The egr-1 gene is induced by DNA-damaging agents and non-genotoxic drugs in both normal and neoplastic human cells. 1270 85

There are over 1 million cases of skin cancer diagnosed yearly in the United States. The majority of these are nonmelanoma (NMSCs) and are associated with chronic exposure to ultraviolet light (UV). Actinic keratosis (AK) has been identified as a precursor for SCC, but not for BCC. AKs are far more common than SCC, making them excellent targets for chemoprevention. Cancer chemoprevention can prevent or delay the occurrence of cancer in high-risk populations using dietary or chemical interventions. We have developed strategies that have rational mechanisms of action and demonstrate activity in preclinical models of skin cancer. Promising agents proceed to phase I-III trials in subjects at high risk of skin cancer. UV light induces molecular signaling pathways and results in specific genetic alterations (i.e., mutation of p53) that are likely critical to skin cancer development. UVB-induced changes serve as a basis for the development of novel agents. Targets include inhibition of polyamine or prostaglandin synthesis, specific retinoid receptors, and components of the Ras and MAP kinase signaling pathways. Agents under study include: epigallocatechin gallate (EGCG), a green tea catechin with antioxidant and sunscreen activity, as well as UVB signal transduction blocking activity; perillyl alcohol, a monoterpene derived from citrus peel that inhibits Ras farnesylation; difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase and polyamines; retinoids that target retinoid X receptors and AP-1 activity; and nonsteroidal anti-inflammatory agents that inhibit cylooxygenase and prostaglandin synthesis. We performed a series of Phase I-II trials in subjects with multiple AK. For example, a phase II randomized trial of topical DFMO reduced AK number, suppressed polyamines, and reduced p53 protein. Our goal is to develop agents for use in combination and/or incorporation into sunscreens to improve chemoprevention efficacy and reduce skin cancer incidence.
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PMID:Skin cancer chemoprevention: strategies to save our skin. 1290 51


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