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)

Many biological effects of taurine rely upon its cellular concentration, which is primarily controlled by taurine biosynthetic enzymes cysteine dioxygenase (CDO) and cysteine sulfinate decarboxylase (CSD) and taurine transporter (TauT). The cloning of CDO, CSD and TauT in various species provided first-hand information on these proteins, as well as molecular tools to investigate their regulations. CDO upregulation in hepatocytes in response to high sulfur amino acids appears clearly as the most spectacular among the regulations of the biosynthetic enzymes. Downregulation of TauT activity by activation of PKC appears particularly well documented. A unique serine residue could be identified as a phosphorylation site that leads to an inactive form of TauT. The previously revealed downregulation of TauT expression by taurine and hypertonicity-induced upregulation of TauT expression were shown to result from a modified transcription rate of TauT gene, but the precise molecular mechanisms are not yet formally established. Other regulations of taurine transporter expression were more recently reported, which involve glucose, tumor suppressor protein p53, tumor necrosis factor-alpha, and nitric oxide. This review reports the experimental models and data that support these various regulations but also points out the aspects that remain poorly understood or unknown concerning their molecular basis and physiological significance.
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PMID:Taurine biosynthetic enzymes and taurine transporter: molecular identification and regulations. 1499 66

Tumorigenesis is associated with enhanced cellular glucose uptake and increased metabolism. Because the p53 tumor suppressor is mutated in a large number of cancers, we evaluated whether p53 regulates expression of the GLUT1 and GLUT4 glucose transporter genes. Transient cotransfection of osteosarcoma-derived SaOS-2 cells, rhabdomyosarcoma-derived RD cells, and C2C12 myotubes with GLUT1-P-Luc or GLUT4-P-Luc promoter-reporter constructs and wild-type p53 expression vectors dose dependently decreased both GLUT1 and GLUT4 promoter activity to approximately 50% of their basal levels. PG(13)-Luc activity, which was used as a positive control for functional p53 expression, was increased up to approximately 250-fold by coexpression of wild-type p53. The inhibitory effect of wild-type p53 was greatly reduced or abolished when cells were transfected with p53 with mutations in amino acids 143, 248, or 273. A region spanning -66/+163 bp of the GLUT4 promoter was both necessary and sufficient to mediate the inhibitory effects of p53. Furthermore, in vitro translated p53 protein was found to bind directly to two sequences in that region. p53-DNA binding was completely abolished by excess unlabeled probe but not by nonspecific DNA and was super-shifted by the addition of an anti-p53 antibody. Taken together, our data strongly suggest that wild-type p53 represses GLUT1 and GLUT4 gene transcription in a tissue-specific manner. Mutations within the DNA-binding domain of p53, which are usually associated with malignancy, were found to impair the repressive effect of p53 on transcriptional activity of the GLUT1 and GLUT4 gene promoters, thereby resulting in increased glucose metabolism and cell energy supply. This, in turn, would be predicted to facilitate tumor growth.
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PMID:The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. 1505 20

The biological image of the transition element vanadium ferments a great deal of contradiction-from toxicity to essentiality. Importance of this element as micro-nutrient is yet to be unequivocally accepted by biologists and biomedical scientists. In spite of toxicity, it seems interesting to analyze the different biological roles of the element. Vanadium compounds have been proven to be associated with various implications in the pathogenesis of some human diseases and also in maintaining normal body functions. Salts of vanadium interfere with an essential array of enzymatic systems such as different ATPases, protein kinases, ribonucleases and phosphatases. While vanadium deficiency accounts for several physiological malfunctionings including thyroid, glucose and lipid metabolism, etc., several genes are regulated by this element or by its compounds, which include genes for tumor necrosis factor-alpha (TNF-alpha), Interleukin-8 (IL-8), activator protein-1 (AP-1), ras, c-raf-1, mitogen activated protein kinase (MAPK), p53, nuclear factors-kappaB, etc. All these seem to be not far from its recognition as an element of pharmacological and nutritional significance, which is revealed through its increasing therapeutic uses in diabetes. Vanadium is also emerging as a potent anti-carcinogenic agent. This review summarizes the developments related to vanadium biology as a whole by analyzing the general biochemical functions of vanadium.
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PMID:Vanadium--an element of atypical biological significance. 1509 69

Tumor hypoxia has been known to be associated with resistance to radiation and chemotherapy (CRT). Hypoxia-inducible factor-1alpha (HIF-1alpha), a transcription factor induced by hypoxic condition, plays a major role in the pleiotropic response observed under hypoxic conditions. It encodes proteins that play key roles in critical development and physiologic processes, including angiogenesis, glucose transport and erythropoiesis. On the other hand, cell cycle- and apoptosis-control genes p53 and p21 may play major roles in the tumor response to cytotoxic agents such as radiation and chemotherapy. Previous reports have suggested that the regulation of p53 and p21 is HIF-1-dependent. Our aim was to evaluate the expression of the HIF-1alpha, p53 and p21 proteins by immunohistochemistry in biopsy specimens of esophageal squamous cell carcinoma, which were obtained endoscopically from 65 patients before CRT, and then determine whether the levels of expression of these proteins predicted the clinical effectiveness of CRT in individual cancers. Also, to assess the relationship between expression of these proteins and cell death and cellular proliferation activity, we evaluated Ki67 expression and the apoptosis index (TUNEL). HIF-1alpha expression in esophageal cancer was significantly and negatively related to the response to CRT, independently of p53 and p21 expression. Interestingly, 44.4% (12/27) of the HIF-1alpha-negative group showed a complete response to therapy. There was no significant correlation between the expression of HIF-1alpha, p53 and p21 and proliferation and apoptosis. HIF-1alpha overexpression may predict resistance to CRT and may be a helpful guide in choosing between therapeutic strategies, such as intensive combined modality therapy vs. palliative therapy. Combined immunohistochemical evaluation of HIF-1alpha, p53 and p21 protein expression at the pretreatment biopsy is a very useful and powerful indicator of sensitivity to CRT in human esophageal cancer. Our data also indicate the importance of having a clear grasp of the degree of hypoxia (HIF-1alpha) of a tumor, rather than its cellular character (proliferation and apoptosis), to indicate the likely impact of CRT.
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PMID:Pretreatment evaluation of combined HIF-1alpha, p53 and p21 expression is a useful and sensitive indicator of response to radiation and chemotherapy in esophageal cancer. 1517 Jun 65

GRP78 is a stress-inducible chaperone protein with antiapoptotic properties that is overexpressed in transformed cells and cells under glucose starvation, acidosis, and hypoxic conditions that persist in poorly vascularized tumors. Previously we demonstrated that the Grp78 promoter is able to eradicate tumors using murine cells in immunocompetent models by driving expression of the HSV-tk suicide gene. Here, through the use of positron emission tomography (PET) imaging, we provide direct evidence of spontaneous in vivo activation of the HSV-tk suicide gene driven by the Grp78 promoter in growing tumors and its activation by photodynamic therapy (PDT) in a controlled manner. In this report, we evaluated whether this promoter can be applied to human cancer therapy. We observed that the Grp78 promoter, in the context of a retroviral vector, was highly activated by stress and PDT in three different types of human breast carcinomas independent of estrogen receptor and p53. Complete regression of sizable human tumors was observed after prodrug ganciclovir treatment of the xenografts in immunodeficient mice. In addition, the Grp78 promoter-driven suicide gene is strongly expressed in a variety of human tumors, including human osteosarcoma. In contrast, the activity of the murine leukemia virus (MuLV) long-terminal repeat (LTR) promoter varied greatly in different human breast carcinoma cell lines, and in some cases, stress resulted in partial suppression of the LTR promoter activity. In transgenic mouse models, the Grp78 promoter-driven transgene is largely quiescent in major adult organs but highly active in cancer cells and cancer-associated macrophages, which can diffuse to tumor necrotic sites devoid of vascular supply and facilitate cell-based therapy. Thus, transcriptional control through the use of the Grp78 promoter offers multiple novel approaches for human cancer gene therapy.
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PMID:Spontaneous and controllable activation of suicide gene expression driven by the stress-inducible grp78 promoter resulting in eradication of sizable human tumors. 1521 14

Chemotherapeutic drugs that inhibit the synthesis of DNA precursor thymidine triphosphate cause apoptosis, although the mechanism underlying this process remains rather unknown. Here, we describe thymineless death of human myeloid leukemia U937 cells treated with the thymidylate-synthase inhibitor 5'-fluoro- 2'-deoxyuridine (FUdR). This apoptotic process was shown to be independent of p53, reactive oxygen species generation and CD95 activation. Caspases were activated downstream of cytochrome c but upstream of mitochondrial depolarization. Furthermore, FUdR-induced apoptosis required the presence of glucose in the culture medium at a step upstream of the release of cytochrome c from mitochondria.
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PMID:Thymidylate synthase inhibition triggers glucose-dependent apoptosis in p53-negative leukemic cells. 1525 65

An 8-amino-acid peptide, NAPVSIPQ (NAP), was identified as the smallest active element of activity-dependent neuroprotective protein that exhibits potent neuroprotective action. Potential signal transduction pathways include cGMP production and interference with inflammatory mechanisms, tumor necrosis factor-alpha, and MAC1-related changes. Because of its intrinsic structure, NAP might interact with extracellular proteins and also transverse membranes. NAP-associated protection against oxidative stress, glucose deprivation, and apoptotic mechanisms suggests interference with fundamental processes. This paper identifies p53, a key regulator of cellular apoptosis, as an intracellular target for NAP's activity.
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PMID:NAP mechanisms of neuroprotection. 1531 52

Maternal diabetes increases the risk for neural tube, and other, structural defects. The mother may have either type 1 or type 2 diabetes, but the diabetes must be existing at the earliest stages of pregnancy, during which organogenesis occurs. Abnormally high glucose levels in maternal blood, which leads to increased glucose transport to the embryo, is responsible for the teratogenic effects of maternal diabetes. Consequently, expression of genes that control essential developmental processes is disturbed. In this review, some of the biochemical pathways by which excess glucose metabolism disturbs neural tube formation are discussed. Research from the author's laboratory has shown that expression of Pax3, a gene required for neural tube closure, is significantly reduced by maternal diabetes, and this is associated with significantly increased neural tube defects (NTD). Pax3 encodes a transcription factor that has recently been shown to inhibit p53-dependent apoptosis. Evidence in support of this model, in which excess glucose metabolism inhibits expression of Pax3, thereby derepressing p53-dependent apoptosis of neuroepithelium and leading to NTD will be discussed.
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PMID:Current perspectives on the causes of neural tube defects resulting from diabetic pregnancy. 1580 Aug 53

Replicative cell division is an energetically demanding process that can be executed only if cells have sufficient metabolic resources to support a doubling of cell mass. Here we show that proliferating mammalian cells have a cell-cycle checkpoint that responds to glucose availability. The glucose-dependent checkpoint occurs at the G(1)/S boundary and is regulated by AMP-activated protein kinase (AMPK). This cell-cycle arrest occurs despite continued amino acid availability and active mTOR. AMPK activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate AMPK-dependent cell-cycle arrest. AMPK-induced p53 activation promotes cellular survival in response to glucose deprivation, and cells that have undergone a p53-dependent metabolic arrest can rapidly reenter the cell cycle upon glucose restoration. However, persistent activation of AMPK leads to accelerated p53-dependent cellular senescence. Thus, AMPK is a cell-intrinsic regulator of the cell cycle that coordinates cellular proliferation with carbon source availability.
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PMID:AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. 1605 73

Cell growth and proliferation requires an intricate coordination between the stimulatory signals arising from nutrients and growth factors and the inhibitory signals arising from intracellular and extracellular stresses. Alteration of the coordination often causes cancer. In mammals, the mTOR (mammalian target of rapamycin) protein kinase is the central node in nutrient and growth factor signaling, and p53 plays a critical role in sensing genotoxic and other stresses. The results presented here demonstrate that activation of p53 inhibits mTOR activity and regulates its downstream targets, including autophagy, a tumor suppression process. Moreover, the mechanisms by which p53 regulates mTOR involves AMP kinase activation and requires the tuberous sclerosis (TSC) 1/TSC2 complex, both of which respond to energy deprivation in cells. In addition, glucose starvation not only signals to shut down mTOR, but also results in the transient phosphorylation of the p53 protein. Thus, p53 and mTOR signaling machineries can cross-talk and coordinately regulate cell growth, proliferation, and death.
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PMID:The coordinate regulation of the p53 and mTOR pathways in cells. 1592 81


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