Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia-inducible factor 1 (HIF-1) is a ubiquitously expressed transcriptional regulator involved in induction of numerous genes associated with angiogenesis and tumor growth. Kaposi's sarcoma, associated with increased angiogenesis, is a highly vascularized, endothelial cell-derived tumor. Previously, we have shown that the latency-associated nuclear antigen (LANA) encoded by Kaposi's sarcoma-associated herpesvirus (KSHV) targets the HIF-1alpha suppressors von Hippel-Lindau protein and p53 for degradation via its suppressor of cytokine signaling-box motif, which recruits the EC5S ubiquitin complex. Here we further show that HIF-1alpha was aberrantly accumulated in KSHV latently infected primary effusion lymphoma (PEL) cells, as well as HEK293 cells infected with KSHV, and also show that a potential alpha-helical amino-terminal domain of LANA was important for HIF-1alpha nuclear accumulation in normoxic conditions. Moreover, we have now determined that this association was dependent on the residues 46 to 89 of LANA and the oxygen-dependent degradation domain of HIF-1alpha. Introduction of specific small interfering RNA against LANA into PEL cells also resulted in a diminished nuclear accumulation of HIF-1alpha. Therefore, these data show that LANA can function not only as an inhibitor of HIF-1alpha suppressor proteins but can also induce nuclear accumulation of HIF-1alpha during KSHV latent infection.
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PMID:A potential alpha-helix motif in the amino terminus of LANA encoded by Kaposi's sarcoma-associated herpesvirus is critical for nuclear accumulation of HIF-1alpha in normoxia. 1763 30

An shRNA tumor suppressor panel was screened using reverse infection of an A549 tumorigenic cell line and exposing it to a predetermined concentration of paclitaxel, an anticancer drug. The shRNAs targeting a positive control gene, MDR1, were found to effectively decrease mRNA levels and cause cells to become more sensitive to the chemotherapeutic drug. A set of genes were identified in the screen of a panel of tumor suppressors which, when down-regulated, were found to increase or decrease cell sensitivity in regards to treatment with paclitaxel. In many cases, there were multiple clones to a single gene that provided a positive result. The shRNAs targeting SMAD4, LZTS2, ST14 and VHL all increased the cell's sensitivity to paclitaxel. The loss of other tumor suppressors such as GLTSCR2, LATS1, NF1, PTEN, TP53 and WT1 induced a protective effect in the cell, making it more resistant to the effect of the drug. Further investigation of VHL mRNA levels after down-regulation with shRNA show a direct correlation between gene expression levels and paclitaxel sensitivity. This study credits the identified genes with the potential to act as prognostic biomarkers for use in genetic profiling, or even as targets in pathways of tumorigenesis yet to be fully understood.
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PMID:A screen of shRNAs targeting tumor suppressor genes to identify factors involved in A549 paclitaxel sensitivity. 1798 36

The oncogene HDM2 has been implicated in the regulation of the transcription factor, hypoxia inducible factor (HIF). We show in von Hippel-Lindau (VHL)-defective renal carcinoma cells that express constitutively high levels of HIF-1 alpha and HIF-2 alpha that down-regulation of HDM2 by siRNA leads to decreased levels of both HIF-1 alpha and HIF-2 alpha protein levels. However, we show a differential regulation of HDM2 on the HIF angiogenic targets, vascular endothelial growth factor (VEGF), plasminogen activator inhibitor-1 (PAI-1), and endothelin-1 (ET-1): siRNA to HDM2 leads to increased expression of VEGF and PAI-1 proteins but decreased levels of ET-1. We show that HDM2-mediated regulation of these proteins is independent of VHL and p53 but dependent on a novel action of HDM2. Ablation of HDM2 leads to phosphorylation of extracellular-regulated kinase (ERK)1/2 in renal carcinoma cells. We show that regulation of these angiogenic factors is dependent on ERK1/2 phosphorylation, which can be reversed by addition of the MAP/ERK1/2 kinase inhibitors PD98059 and PD184352. This study identifies a novel role for the HDM2 oncoprotein in the regulation of angiogenic factors in renal cell carcinoma.
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PMID:Regulation of angiogenic factors by HDM2 in renal cell carcinoma. 1819 51

Germline von Hippel-Lindau tumour suppressor gene (VHL) mutations cause renal cell carcinomas, haemangioblastomas and phaeochromocytomas in humans. Mutations in VHL also occur in sporadic renal cell carcinomas. The protein encoded by VHL, VHL, is part of the ubiquitin ligase that downregulates the heterodimeric transcription factor Hif under well-oxygenated conditions. Here we show that acute VHL inactivation causes a senescent-like phenotype in vitro and in vivo. This phenotype was independent of p53 and Hif but dependent on the retinoblastoma protein (Rb) and the SWI2/SNF2 chromatin remodeller p400. Rb activation occurred through a decrease in Skp2 messenger RNA, which resulted in the upregulation of p27 in a Hif-independent fashion. Our results suggest that senescence induced by VHL inactivation is a tumour-suppressive mechanism that must be overcome to develop VHL-associated neoplasias.
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PMID:VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. 1829 59

The VHL (von Hippel-Lindau) tumour-suppressor gene is inactivated in VHL disease and in sporadic cases of CCRCC [clear-cell RCC (renal cell carcinoma)]. pVHL (VHL protein) functions as part of an E3 ubiquitin ligase complex that targets proteins for proteasomal degradation. The best-characterized substrate is HIF-alpha (hypoxia-inducible factor-alpha). Loss of pVHL and subsequent up-regulation of HIF target genes has been attributed to the highly vascular nature of these neoplasms. However, pVHL does not just function as the executioner of HIF-alpha. Additional functions of pVHL that may be important in preventing CCRCC tumorigenesis have been identified, including primary cilium maintenance, assembly of the extracellular matrix and roles in the stabilization of p53 and Jade-1 (gene for apoptosis and differentiation in epithelia). Current evidence indicates that pVHL probably requires additional co-operating signalling pathways for CCRCC initiation and tumorigenesis.
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PMID:Role of the VHL (von Hippel-Lindau) gene in renal cancer: a multifunctional tumour suppressor. 1848 84

In present study, we investigated the mechanism of regulating HIF-1alpha expression by hydroxysafflor yellow A (HSYA) in Eahy 926 cell line under 1% O2 hypoxia. Eahy 926 cells were incubated with HSYA (100, 10 and 1 micromol x L(-1)) under hypoxia for the indicated time after treatment. Cell proliferation rate was detected using MTT assays. VHL and p53 location and protein expression were analyzed by immunocytochemical stain. HIF-1alpha, VHL and p53 mRNA expression were detected by RT-PCR. Protein expression of HIF-1alpha, VHL and p53 were assayed by Western blotting method. HSYA at 100 micromol x L(-1) increased Eahy 926 cells proliferation rate under hypoxia. HIF-1alpha mRNA and protein expression were up-regulated in the presence of HSYA. VHL, p53 mRNA and protein expression decreased significantly after 8 hours of treatment under hypoxia. HSYA protected Eahy 926 cells from hypoxia, and up-regulated HIF-1alpha expression partially via its inhibition of VHL and p53 expression.
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PMID:[Hydroxysafflor yellow A up-regulates HIF-1alpha via inhibition of VHL and p53 in Eahy 926 cell line exposed to hypoxia]. 1871 35

Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) and is characterized by widespread tubular and microvascular damage. The tumor suppressor p53 is upregulated after IRI and contributes to renal injury in part by promoting apoptosis. Acute, short-term inhibition of p53 with pifithrin-alpha conveys significant protection after IRI. The hypoxia-inducible factor-1 (HIF-1) pathway is also activated after IRI and has opposing effects to those promoted by p53. The balance between the HIF-1 and p53 responses can determine the outcome of IRI. In this manuscript, we investigate whether p53 regulates the HIF-1 pathway in a rodent model of IRI. HIF-1alpha is principally expressed in the collecting tubules (CT) and thick ascending limbs (TAL) under physiological conditions. However, inhibition of p53 with pifithrin-alpha increases the faint expression of HIF-1alpha in proximal tubules (PT) under physiological conditions. Twenty-four hours after IRI, HIF-1alpha expression is decreased in both CT and TAL. HIF-1alpha expression in the PT is not significantly altered after IRI. Acute inhibition of p53 significantly increases HIF-1alpha expression in the PT after IRI. Additionally, pifithrin-alpha prevents the IRI-induced decrease in HIF-1alpha in the CT and TAL. Parallel changes are observed in the HIF-1alpha transcriptive target, carbonic anhydrase-9. Finally, inhibition of p53 prevents the dramatic changes in Von Hippel-Lindau protein morphology and expression after IRI. We conclude that activation of p53 after IRI mitigates the concomitant activation of the protective HIF-1 pathway. Modulating the interactions between the p53 and HIF-1 pathway can provide novel options in the treatment of AKI.
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PMID:p53 regulates renal expression of HIF-1{alpha} and pVHL under physiological conditions and after ischemia-reperfusion injury. 1881 19

Colorectal carcinomas are the third most common malignant tumours worldwide with an incidence of 570,000 per year. According to their molecular mechanisms, sporadic colorectal carcinomas can be divided into two different phenotypes. The genetic phenotype, 50 to 70 % of all sporadic colorectal carcinomas, is characterised by a chromosomal instability (CIN) with the classical adenoma-carcinoma sequence due to alteration of the APC-betacatenin pathway with p53 mutations, SMAD alterations and LOH (loss of heterozygositiy) of 5q, 17 p 18q. On the other, the CpG island methylator phenotype (CIMP+) was described with an epigenetic inactivation of tumour suppressor genes that are typically inactivated by germline mutations in familiar cancer syndromes, e. g., Rb, VHL, hMLH1, p16 or BRCA. Colorectal carcinomas of the CIMP+ type often show a high microsatellite instability (MSI+) caused by aberrant promoter methylation of the missmatch repair gene hMLH1. Further CIMP+ are located in the proximal right-side colon and show a poor grading with mucinous or signet-cell differentiation.
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PMID:[Epigenetic alterations in colorectal carcinomas and precancerous lesions]. 1893 91

The latency-associated nuclear antigen (LANA) of Karposi's sarcoma-associated herpesvirus has been reported to interact with glycogen synthase kinase 3beta (GSK-3beta) and regulate its activity, leading to inhibition of GSK-3-dependent beta-catenin degradation. In this study, the interaction between LANA and GSK-3beta was characterized further. LANA was found to interact with GSK-3beta in vitro as well as in intact cells. However, LANA did not regulate GSK-3beta kinase activity and LANA-induced upregulation of beta-catenin was GSK-3beta independent. LANA did not regulate the stability of beta-catenin or of its reported interaction partners p53 and von Hippel-Lindau protein. Additional targets of LANA are likely to mediate its malignancy-promoting function.
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PMID:Characterization of the interaction between latency-associated nuclear antigen and glycogen synthase kinase 3beta. 1932 22

Presymptomatic genetic testing in childhood for adult onset conditions is generally discouraged as it does not directly benefit the child and removes their autonomy. In certain cancer prone conditions such as Familial Adenomatous Polyposis and Von Hippel Lindau disease there are risks of disease in childhood and benefit to children not inheriting a mutation in being able to forego unpleasant screening tests. Li-Fraumeni syndrome caused by constitutional TP53 mutations there are also implications in childhood with a risk of around 20% of a childhood malignancy. However, as yet no evidence based surveillance programme has been identified. We describe our experience of childhood testing for four children in two Li-Fraumeni families caused by TP53 mutations.
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PMID:Childhood predictive genetic testing for Li-Fraumeni syndrome. 1940 74


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