Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

HIF-1 (hypoxia inducible factor 1) performs a crucial role in mediating the response to hypoxia. However, other transcription factors are also capable of regulating hypoxia-induced target-gene transcription. In a previous report, we demonstrated that the transcription factor ATF-2 (activating transcription factor 2) regulates hypoxia-induced gene transcription, along with HIF-1alpha. In the present study, we show that the protein stability of ATF-2 is induced by hypoxia and the hypoxia-mimic CoCl2 (cobalt chloride), and that ATF-2 induction enhances HIF-1alpha protein stability via direct protein interaction. The knockdown of ATF-2 using small interfering RNA and translation-inhibition experiments demonstrated that ATF-2 plays a key role in the maintenance of the expression level and transcriptional activity of HIF-1alpha. Furthermore, we determined that ATF-2 interacts directly with HIF-1alpha both in vivo and in vitro and competes with the tumour suppressor protein p53 for HIF-1alpha binding. Collectively, these results show that protein stabilization of ATF-2 under hypoxic conditions is required for the induction of the protein stability and transactivation activity of HIF-1alpha for efficient hypoxia-associated gene expression.
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PMID:Activating transcription factor 2 increases transactivation and protein stability of hypoxia-inducible factor 1alpha in hepatocytes. 1971 49

We sought to evaluate the molecular markers involved in breast tumorigenesis in a rat model that mimics many essential elements of human breast cancer. Female Sprague-Dawley rats were divided into two groups. Animals in group 1 were given a single dose of 7,12-dimethylbenz[a]anthracene (DMBA) (20 mg/rat) dissolved in 1 ml of sesame oil by intragastric intubation. Group 2 animals received basal diet and served as control. We analyzed DMBA-induced changes in the expression of CYP isoforms (CYP1A1 and 1B1) involved in DMBA metabolism, markers of oxidative stress (4HNE, HEL, and 8-OHdG), cell survival and proliferation (PCNA, NF-kappaB-p50, NF-kappaB-p65, GST-P, and p53), apoptosis (Bcl-2, Bax, caspases, Apaf-1, cytochrome C, and Fas), invasion (uPA, MMP-2, MMP-9, TIMP-2, and RECK), and angiogenesis (VEGF, VEGF-R1, HIF-1alpha, and PLGF) by immunohistochemical localization, Western blot, and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. The present study demonstrates increased carcinogen metabolism, oxidative stress, cell proliferation, together with apoptosis evasion, invasion, metastasis, and neovascularization that may confer a selective growth advantage to DMBA-induced mammary tumors. Aberrant expression of multiple molecules in key signaling pathways in Sprague-Dawley rat mammary tumors renders this model as an important tool for monitoring carcinogenic progression and chemointervention.
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PMID:Evaluation of molecular markers in a rat model of mammary carcinogenesis. 1972 28

Hypoxia-inducible factor-1 (HIF-1) plays crucial roles in tumor promotion by upregulating its target genes, which are involved in energy metabolism, angiogenesis, cell survival, invasion, metastasis, and drug resistance. The HIF-1alpha subunit, which is regulated by O2-dependent hydroxylation, ubiquitination, and degradation, has been identified as an important molecular target for cancer therapy. We have rationally designed G-rich oligodeoxynucleotides (ODNs) as inhibitors of HIF-1alpha for human cancer therapy. The lead compounds, JG243 and JG244, which form an intramolecular parallel G-quartet structure, selectively target HIF-1alpha and decreased levels of both HIF-1alpha and HIF-2alpha (IC50 < 2 micromol/l) and also inhibited the expression of HIF-1-regulated proteins [vascular endothelial growth factor (VEGF), Bcl-2, and Bcl-XL], but did not disrupt the expression of p300, Stat3, or p53. JG-ODNs induced proteasomal degradation of HIF-1alpha and HIF-2alpha that was dependent on the hydroxylase activity of prolyl-4-hydroxylase-2. JG243 and JG244 dramatically suppressed the growth of prostate, breast, and pancreatic tumor xenografts. Western blots from tumor tissues showed that JG-ODNs significantly decreased HIF-1alpha and HIF-2alpha levels and blocked the expression of VEGF. The JG-ODNs are novel anticancer agents that suppress tumor growth by inhibiting HIF-1.
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PMID:G-rich oligonucleotides inhibit HIF-1alpha and HIF-2alpha and block tumor growth. 1975 60

Many oncolytic viruses are currently being tested as potential cancer therapeutic agents. To be effective, these viruses must replicate and propagate efficiently through the tumor mass. However, it is possible that the hypoxia that characterizes many tumors may be an obstacle to viral therapy because of its inhibition of viral replication and propagation. We, therefore, decided to test how oncolytic reovirus and its target cells respond to hypoxia. We found that reovirus infection suppresses hypoxia inducible factor (HIF)-1alpha protein levels (but not transcript abundance) in colon cancer HCT116 cells under CoCl(2) or hypoxia. Reovirus infection was able to reduce HIF-1alpha levels in both von Hippel Lindau (VHL)-/- renal carcinoma A498 and p53-/- HCT116 cells, indicating that the decrease of HIF-1alpha mediated by reovirus requires neither VHL nor p53 proteins. However, treatment with the inhibitor MG132 restored HIF-1alpha levels, suggesting that reovirus-induced HIF-1alpha decrease needs proteosomal activity. A498 VHL-/- cells with constitutive expression of HIF-1alpha were relatively resistant to reovirus-induced apoptosis when compared with A498 VHL+/+ cells. However, we found that the use of YC-1 to target HIF-1alpha promoted reovirus-induced apoptosis in A498 VHL-/- cells. Accordingly, we propose that reovirus may be used together with YC-1 as a potential therapeutic agent against chemoresistant or radioresistant tumors that are hypoxic and show increased levels of HIF-1alpha.
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PMID:Down-regulation of HIF-1alpha by oncolytic reovirus infection independently of VHL and p53. 2007 85

Radiation therapy is one of the effective curative treatments for uterine cervical cancer. However poor clinical results for the advanced stages require further improvement of the treatment. Intensive studies on basic and clinical research have been made to improve local control, primarily important for long term survival in radiation therapy. Regarding current advancement in radiation therapy for uterine cervical cancer, the following three major subjects are pointed out; technological development to improve dose distribution by image guided radiation therapy technology, the concomitant anticancer chemotherapy with combination of radiation therapy, and radiation biological assessment of the radiation resistance of tumors. The biological factors overviewed in this article include hypoxia relating factors of HIF-1alpha, SOD, cell cycle parameters of pMI, proliferation factors of Ki67, EGFR, cerbB2, COX-2, cycle regulation proteins p53, p21, apoptosis regulation proteins Bcl2 and Bax and so on. Especially, the variety of these radiation biological factors is important for the selection of an effective treatment method for each patient to maximize the treatment benefit.
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PMID:Current advancement in radiation therapy for uterine cervical cancer. 2017 13

Apurinic/apyrimidinic endonuclease/redox factor-1 (APE/Ref-1), as a type of multifunctional protein, plays an essential role in the base excision repair (BER) pathway, which is responsible for the repair of DNA caused by oxidative and alkylation damage. As importantly, APE/Ref-1 also functions as a redox factor maintaining transcription factors in an active reduced state. APE/Ref-1 stimulates the DNA-binding activity of numerous transcription factors that are involved in cancer promotion and progression, such as AP-1 (Fos/Jun), NF-kappaB, HIF-1alpha, p53, and others. Based on the structures and functions of APE1/Ref-1, we will provide an overview of its activities and explore the budding clinical use of this protein as a target in cancer treatment, and propose that APE/Ref-1 has a great potential for application in clinical research.
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PMID:Anticancer clinical utility of the apurinic/apyrimidinic endonuclease/redox factor-1 (APE/Ref-1). 2019 21

Tissue hypoxia commonly occurs in tumors. Hypoxia- inducible factor (HIF)-1 and HIF-2, which are essential mediators of cellular response to hypoxia, regulate gene expression for tumor angiogenesis, glucose metabolism, and resistance to oxidative stress. Their key regulatory subunits, HIF1A (HIF-1alpha) and endothelial PAS domain protein 1 (EPAS1; HIF-2alpha), are overexpressed and associated with patient prognosis in a variety of cancers. However, prognostic or molecular features of colon cancer with HIF expression remain uncertain. Among 731 colorectal cancers in two prospective cohort studies, 142 (19%) tumors showed HIF1A overexpression, and 322 (46%) showed EPAS1 overexpression by immunohistochemistry. HIF1A overexpression was significantly associated with higher colorectal cancer-specific mortality in Kaplan-Meier analysis (log-rank test, P < 0.0001), univariate Cox regression (hazard ratio = 1.84; 95% confidence interval, 1.37 to 2.47; P < 0.0001) and multivariate analysis (adjusted hazard ratio = 1.72; 95% confidence interval, 1.26 to 2.36; P = 0.0007) that adjusted for clinical and tumoral features, including microsatellite instability, TP53 (p53), PTGS2 (cyclooxygenase-2), CpG island methylator phenotype, and KRAS, BRAF, PIK3CA, and LINE-1 methylation. In contrast, EPAS1 expression was not significantly associated with patient survival. In addition, HIF1A expression was independently associated with PTGS2 expression (P = 0.0035), CpG island methylator phenotype-high (P = 0.013), and LINE-1 hypomethylation (P = 0.017). EPAS1 expression was inversely associated with high tumor grade (P = 0.0017) and obesity (body mass index > or = 30 kg/m2) (P = 0.039). In conclusion, HIF1A expression is independently associated with poor prognosis in colorectal cancer, suggesting HIF1A as a biomarker with potentially important therapeutic implications.
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PMID:HIF1A overexpression is associated with poor prognosis in a cohort of 731 colorectal cancers. 2036 10

The mitochondria are unique cellular organelles that contain their own genome and, in conjunction with the nucleus, are able to transcribe and translate genes encoding components of the electron transport chain (ETC). To do so, the mitochondria must communicate with the nucleus via the production of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2), which are produced as a byproduct of aerobic respiration within the mitochondria. Mitochondrial signaling is proposed to be altered in cancer cells, where the mitochondria are frequently found to harbor mutations within their genome and display altered functional characteristics leading to increased glycolysis. As signaling molecules, ROS oxidize and inhibit MAPK phosphatases resulting in enhanced proliferation and survival, an effect particularly advantageous to cancer cells. In terms of transcriptional regulation, ROS affect the phosphorylation, activation, oxidation, and DNA binding of transcription factors such as AP-1, NF-kappaB, p53, and HIF-1alpha, leading to changes in target gene expression. Increased ROS production by defective cancer cell mitochondria also results in the upregulation of the transcription factor Ets-1, a factor that has been increasingly associated with aggressive cancers.
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PMID:Mechanisms associated with mitochondrial-generated reactive oxygen species in cancer. 2039 86

Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor that is composed of a hypoxia-inducible alpha subunit (HIF-1alpha and HIF-2alpha) and a constitutively expressed beta subunit (HIF-1beta). HIF mediates the adaptation of cells and tissues to low oxygen concentrations. It also plays an important role in tumorigenesis and constitutes an important therapeutic target in anti-tumor therapy. We have screened a number of reported HIF inhibitors for their effects on HIF-transcriptional activity and found that the DNA damage inducing agents camptothecin and mitomycin C produced the most robust effects. Camptothecin is a reported inhibitor of HIF-1alpha translation, while mitomycin C has been reported to induce p53-dependent HIF-1alpha degradation. In this study we demonstrate that the inhibitory effect of mitomycin C on HIF-1alpha protein expression is not dependent on p53 and protein degradation, but also involves HIF-1alpha translational regulation. Initiation of a DNA damage response with the small molecule p53 activator NSC-652287 (RITA) has been reported to inhibit HIF-1alpha protein synthesis by increasing the phosphorylation of eIF2alpha. However, we show here that even when eIF2alpha phosphorylation is prevented, the DNA damage inducing drugs mitomycin C, camptothecin and NSC-652287 still inhibit HIF-1alpha protein synthesis to the same extent. The inhibitory effects of camptothecin on HIF-1alpha expression but not that of mitomycin C and NSC-652287 were dependent on cyclin-dependent kinase activity. In conclusion, specific types of DNA damage can bring about selective inhibition of HIF-1alpha protein synthesis. Further characterization of the involved mechanisms may reveal important novel therapeutic targets.
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PMID:Inhibition of hypoxia-inducible factor-1alpha (HIF-1alpha) protein synthesis by DNA damage inducing agents. 2047 87

The von Hippel-Lindau tumour suppressor gene encodes a protein with 213 amino acids, which is known to be part of an E3-ubiquitin ligase targeting the HIF-1alpha transcription factor as well as to form a complex with p53. The VHL protein can be phosphorylated by protein kinase CK2 at serines 33, 38 and 43. However, the role of VHL phosphorylation in the context of p53 and HIF-1alpha regulation remained so far unknown. In the present study we investigated whether phosphorylation of VHL by CK2 might affect the function of p53 and HIF-1alpha. By using 4,5,6,7-tetrabromobenzotriazole (TBB), a CK2-specific inhibitor, as well as a mutant VHL where serines 33, 38 and 43 were replaced by alanines we found that CK2 phosphorylation affected the VHL protein half-life and increased VHL protein stability. Further, we found that inhibition of VHL phosphorylation by CK2 reduced p53 function. In addition, the enhanced levels of VHL due to CK2 inhibition contributed to the down-regulation of HIF-activity and degradation of HIF-1alpha. Thus, these results demonstrate that phosphorylation of VHL by CK2 plays an important role in the regulation of VHL protein stability and may contribute to the survival of tumour cells.
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PMID:Phosphorylation of the von Hippel-Lindau protein (VHL) by protein kinase CK2 reduces its protein stability and affects p53 and HIF-1alpha mediated transcription. 2063 92


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