Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Local oxygen tension has a profound effect on the vasculature, which compensates vascular insufficiency through the induction of angiogenesis. An important mediator in this process is the hypoxia-inducible factor (HIF) complex, which is activated in hypoxic cells and increases transcription of a broad range of genes including angiogenic growth factors such as VEGF. HIF is primarily regulated through oxygen-dependent proteasomal destruction of the regulatory subunit, HIF-1 alpha or HIF-2 alpha. Regulation is through the modification of specific prolines in HIF- alpha chains which are hydroxylated by a recently identified family of enzymes which require molecular oxygen and 2-oxoglutarate as cosubstrates, and iron as a cofactor. Following modification HIF- alpha chains are captured by a ubiquitin ligase E3 complex containing the von Hippel-Lindau (VHL) tumour suppressor protein. The HIF prolyl hydroxylases (PHD enzymes) act as oxygen sensors regulating HIF, and hence angiogenesis. The PHD-HIF-VHL system provides a range of opportunities for therapeutic manipulation.
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PMID:Oxygen sensors and angiogenesis. 1196 69

Hypoxia-inducible factor-1 (HIF-1) is a transcriptional complex that controls cellular and systemic homeostatic responses to oxygen availability. HIF-1 alpha is the oxygen-regulated subunit of HIF-1, an alpha beta heterodimeric complex. HIF-1 alpha is stable in hypoxia, but in the presence of oxygen it is targeted for proteasomal degradation by the ubiquitination complex pVHL, the protein of the von Hippel Lindau (VHL) tumour suppressor gene and a component of an E3 ubiquitin ligase complex. Capture of HIF-1 alpha by pVHL is regulated by hydroxylation of specific prolyl residues in two functionally independent regions of HIF-1 alpha. The crystal structure of a hydroxylated HIF-1 alpha peptide bound to VCB (pVHL, elongins C and B) and solution binding assays reveal a single, conserved hydroxyproline-binding pocket in pVHL. Optimized hydrogen bonding to the buried hydroxyprolyl group confers precise discrimination between hydroxylated and unmodified prolyl residues. This mechanism provides a new focus for development of therapeutic agents to modulate cellular responses to hypoxia.
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PMID:Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL. 1205 Jun 73

Von Hippel-Lindau (VHL) disease is an autosomal, dominantly inherited, tumour syndrome. Carriers of a germline mutation in the VHL tumour suppressor genes are predisposed to develop tumours in various organs including the eye, cerebellum and kidney. These tumours are often multicentric or bilateral, and manifest at a younger age than in situations without a VHL germline mutation. VHL germline mutations are identified in virtually all families and sporadic patients with classic VHL disease. VHL associated tumours are richly vascularised. This is consistent with the involvement of the VHL protein in multiprotein complexes that degrade hypoxia-inducible factors dependent on cellular oxygen levels.
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PMID:[From gene to disease; Von Hippel-Lindau disease]. 1216 74

Many aspects of physiology and anatomy are precisely adjusted so that the right amount of oxygen reaches cell throughout the body. Hypoxia-inducible factor-1 (HIF-1) is activated by low oxygen tension in all mammalian cells and underpins many aspects of the impressive ability to match oxygen supply and demand. As examples, HIF-1 regulates: local capillary architecture via angiogenic signalling red cell production via erythropoietin cellular metabolism via increased expression of glucose transporters and glycolytic enzymes. HIF-1 is also important in disease, for example in cancer where it is involved in angiogenesis. This review describes how HIF-1 is regulated by oxygen and the central role played by the von Hippel-Lindau tumour suppressor protein. The underlying oxygen sensor is provided by a family of enzymes which oxidize specific proline residues in HIF alpha subunits. Inhibiting these newly discovered enzymes provides a way of activating HIF-1 in the presence of oxygen--an exciting prospect for therapeutic intervention in ischaemic diseases.
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PMID:Oxygen homeostasis and cancer: insights from a rare disease. 1219 66

Fanconi anaemia (FA) is a rare autosomal recessive disease characterized by increased spontaneous and DNA crosslinker-induced chromosome instability, progressive pancytopenia and cancer susceptibility. An increasing number of genes are involved in FA, including the breast cancer susceptibility gene BRCA2. Five of the FA proteins (FANCA, FANCC, FANCE, FANCF and FANCG) assemble in a complex that is required for FANCD2 activation in response to DNA crosslinks. Active FANCD2 then interacts with BRCA1 and forms discrete nuclear foci. FANCD2 is independently phosphorylated by ATM (the protein whose gene is mutated in ataxia telangiectasia) in response to ionizing radiation. In addition, the FA proteins are interconnected with other nuclear and cytoplasmic factors all related to cellular responses to carcinogenic stress and to caretaker and gatekeeper functions. In this review, the most recently published data on the molecular biology of the FA pathway and its molecular crosstalk with ATM, BRCA1 and BRCA2, proteins involved in xenobiotic and reactive oxygen species metabolism, apoptosis, cell cycle control and telomere stability, are summarized. The currently available data indicate that FA is a central node in a complex nuclear and cytoplasmic network of tumour suppressor and genome stability pathways fully committed to prevent cancer.
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PMID:The Fanconi anaemia genome stability and tumour suppressor network. 1243 50

Recently, work on the mechanism of action of the von Hippel-Lindau tumour suppressor protein (pVHL) and studies on hypoxic gene regulation have converged, providing insights into both cellular oxygen sensing and cancer pathogenesis. pVHL is the recognition component of the E3-ubiquitin ligase complex involved in the degradation of hypoxia-inducible factor-1 (HIF) alpha-subunits, a process regulated by oxygen availability and blocked by disease causing pVHL mutations. In normoxic cells, pVHL targeting of HIF-alpha subunits follows hydroxylation of critical HIF prolyl residues by a group of oxygen, 2-oxoglutarate- and iron-dependent enzymes. In this review, we outline current understanding of HIF/pVHL/prolyl hydroxylase pathway and consider the implications for VHL-associated cancer.
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PMID:The von Hippel-Lindau tumor suppressor, hypoxia-inducible factor-1 (HIF-1) degradation, and cancer pathogenesis. 1250 60

Mammalian cell mitochondria are believed to have prokaryotic ancestry. Mitochondria are not only the powerhouse of energy generation within the eukaryotic cell but they also play a major role in inducing apoptotic cell death through release of redox proteins such as cytochrome c and the apoptosis-inducing factor (AIF), a flavoprotein with NADH oxidase activity. Recent evidence indicates that some present day prokaryotes release redox proteins that induce apoptosis in mammalian cells through stabilization of the tumour suppressor protein p53. p53 interacts with mitochondria either directly or through activation of the genes for pro-apoptotic proteins such as Bax or NOXA or genes that encode redox enzymes responsible for the production of reactive oxygen species (ROS). The analogy between the ancient ancestors of present day bacteria, the mitochondria, and the present day bacteria with regard to their ability to release redox proteins for triggering mammalian cell death is an interesting example of functional conservation during the hundreds of millions of years of evolution. It is possible that the ancestors of the present day prokaryotes released redox proteins to kill the ancestors of the eukaryotes. During evolution of the mitochondria from prokaryotes as obligate endosymbionts, the mitochondria maintained the same functions to programme their own host cell death.
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PMID:Redox proteins in mammalian cell death: an evolutionarily conserved function in mitochondria and prokaryotes. 1267 80

The tumour suppressor activity of p53 in vivo can be subject to pressure from the physiological stress of hypoxia and we report on the development of a cell system to define the p53-dependent stages in the adaptation of cells to hypoxia. p53(+/+) cells exposed to hypoxia exhibited a transient arrest in G2/M, but escaped from this checkpoint and entered a long-term G(0)/G(1) arrest. By contrast, isogenic p53-null cells exposed to hypoxic conditions exhibited a 6-10-fold higher level of apoptosis, suggesting that p53 acts as a survival factor under limiting oxygen concentrations. Surprisingly, hypoxia-dependent growth arrest in p53(+/+) cells did not result in either p21(WAF1) or HIF-1 protein stabilization, but rather promoted a significant decrease in Ser(392)-site phosphorylation at the CK2/FACT site. However, chemically induced anoxia induced Ser(392)-site phosphorylation as well as stabilization of both p53 and HIF-1 proteins. In contrast to hypoxia, 5-flourouracil (5-FU)-induced p53-dependent cell death correlated with enhanced Ser(392) phosphorylation of p53 and elevated p21(WAF1) protein levels. Hypoxia inhibited 5-FU-induced p53-dependent cell death and attenuated p53 phosphorylation at the ATM and CK2/FACT phosphorylation sites. Although anoxia activates the p53 response, hypoxia silences the p53 transactivation pathway and identifies a physiological signalling model to study mechanisms of p53 inactivation under hypoxic conditions.
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PMID:Hypoxia attenuates the p53 response to cellular damage. 1277 95

Reactive oxygen species are involved in many cellular metabolic and signalling processes and are thought to have a role in disease, particularly in carcinogenesis and ageing. We have generated mice with targeted inactivation of Prdx1, a member of the peroxiredoxin family of antioxidant enzymes. Here we show that mice lacking Prdx1 are viable and fertile but have a shortened lifespan owing to the development beginning at about 9 months of severe haemolytic anaemia and several malignant cancers, both of which are also observed at increased frequency in heterozygotes. The haemolytic anaemia is characterized by an increase in erythrocyte reactive oxygen species, leading to protein oxidation, haemoglobin instability, Heinz body formation and decreased erythrocyte lifespan. The malignancies include lymphomas, sarcomas and carcinomas, and are frequently associated with loss of Prdx1 expression in heterozygotes, which suggests that this protein functions as a tumour suppressor. Prdx1-deficient fibroblasts show decreased proliferation and increased sensitivity to oxidative DNA damage, whereas Prdx1-null mice have abnormalities in numbers, phenotype and function of natural killer cells. Our results implicate Prdx1 as an important defence against oxidants in ageing mice.
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PMID:Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression. 1289 60

Hypoxia-inducible factor (HIF), a transcriptional complex conserved from Caenorhabditis elegans to vertebrates, plays a pivotal role in cellular adaptation to low oxygen availability. In normoxia, the HIF-alpha subunits are targeted for destruction by prolyl hydroxylation, a specific modification that provides recognition for the E3 ubiquitin ligase complex containing the von Hippel-Lindau tumour suppressor protein (pVHL). Three HIF prolyl-hydroxylases (PHD1, 2 and 3) were identified recently in mammals and shown to hydroxylate HIF-alpha subunits. Here we show that specific 'silencing' of PHD2 with short interfering RNAs is sufficient to stabilize and activate HIF-1alpha in normoxia in all the human cells investigated. 'Silencing' of PHD1 and PHD3 has no effect on the stability of HIF-1alpha either in normoxia or upon re-oxygenation of cells briefly exposed to hypoxia. We therefore conclude that, in vivo, PHDs have distinct assigned functions, PHD2 being the critical oxygen sensor setting the low steady-state levels of HIF-1alpha in normoxia. Interestingly, PHD2 is upregulated by hypoxia, providing an HIF-1-dependent auto-regulatory mechanism driven by the oxygen tension.
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PMID:HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. 1291 7


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