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  • Prolyl Hydroxylase
  • The objective of this study was to analyze the expression and regulation of prolyl hydroxylase domain (PHD) enzymes and factor-inhibiting HIF-1α (FIH-1), which regulate cellular HIF levels, and to study the roles of these enzymes in RA fibroblast-like synoviocytes (RA FLS). (ox.ac.uk)
  • normoxia
  • A fish's hypoxia tolerance can also be represented as the amount of time it can spend at a particular hypoxic PO2 before it loses dorsal-ventral equilibrium (called time-to-LOE), or the PO2 at which it loses equilibrium when PO2 is decreased from normoxia to anoxia at some set rate (called PO2-of-LOE). (wikipedia.org)
  • A PHD2 knockdown showed increased levels of HIF-1α under normoxia, and an increase in HIF-1α nuclear accumulation and HIF-dependent transcription. (wikipedia.org)
  • tumor
  • HIF-1 thus plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. (genecards.org)
  • Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma. (biomedsearch.com)
  • δ-Tocotrienol oxazine derivative antagonizes mammary tumor cell compensatory response to CoCl2-induced hypoxia. (nih.gov)
  • Treatment with 150 µM CoCl2 induced a hypoxic response in +SA mammary tumor cells as evidenced by a large increase in HIF-1α levels, and combined treatment with compound 44 attenuated this response. (nih.gov)
  • These findings demonstrate that treatment with the δ-tocotrienol oxazine derivative, compound 44, significantly attenuates +SA mammary tumor cell compensatory responses to hypoxia and suggests that this compound may provide benefit in the treatment of rapidly growing solid breast tumors. (nih.gov)
  • Therefore, SA is a leading candidate for the development of anticancer agents, and these mechanisms will be a key therapeutic target for pharmacologic and therapeutic intervention in HIF-1α-driven tumor growth and cell death. (nih.gov)
  • However, although it would seem that PHD2 downregulates HIF-1α and thus also tumorigenesis, there have been suggestions of paradoxical roles of PHD2 in tumor proliferation. (wikipedia.org)
  • For example, methylselenocysteine (MSC) inhibition of HIF-1α led to tumor growth inhibition in renal cell carcinoma in a PHD-dependent manner. (wikipedia.org)
  • pathway
  • The most significant pathway was the hypoxia-inducible factor (HIF) pathway. (nih.gov)
  • In addition, accumulation of Hif-1α protein during short-term hypoxia was found to depend on the time within the daily light and dark cycle at which hypoxia was encountered, suggesting that the hypoxia signaling pathway may be regulated by the circadian clock. (zfin.org)
  • This is supported by the fact that some of the downstream genes of the Hif signaling pathway, namely, erythropoietin and vascular endothelial growth factor , are known to be clock controlled as well. (zfin.org)
  • Here we show that Hif-1α also binds to the promoter of the period 2 gene, indicating that multiple connections between the Hif signaling pathway and the circadian clock exist. (zfin.org)
  • proline
  • The peptide binding domain spans residues 140-215 of the α subunit, and consists of a concave surface lined with multiple tyrosine residues which interact favorably with the proline-rich substrate. (wikipedia.org)
  • proteins
  • These gene products may include proteins such as glycolytic enzymes and angiogenic growth factors. (wikipedia.org)
  • Together with its auxiliary subunit Naa15, Naa10 constitutes the NatA (Nα-acetyltransferase A) complex that specifically catalyzes the transfer of an acetyl group from acetyl-CoA to the N-terminal primary amino group of certain proteins. (wikipedia.org)
  • inhibition
  • In rats, it plays a negative role in the adaptation to hypoxia, because the inhibition of HIF-3α expression leads to an increase in physical endurance. (wikipedia.org)
  • substrate
  • Substrate analog peptides have also been developed to exhibit inhibitory selectivity for PHD2 over factor inhibiting HIF (FIH), for which some other PHD-inhibitors show overlapping specificity. (wikipedia.org)
  • In higher eukaryotes, 5 other N-acetyltransferase (NAT) complexes, NatB-NatF, have been described that differ both in substrate specificity and subunit composition. (wikipedia.org)
  • As a component of alpha ring, proteasome subunit alpha type-7 contributes to the formation of heptameric alpha rings and substrate entrance gate. (wikipedia.org)
  • Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. (wikipedia.org)
  • Hippel-Lindau
  • Such co-occurrences are usually seen in patients carrying hereditary syndromes like multiple endocrine neoplasia (MEN), neurofibromatosis 1 (NF1), or von Hippel-Lindau (VHL) disease. (wikipedia.org)
  • normoxic conditions
  • In this context a detailed analysis of the mRNA concentrations of hif-1 α, hif-2 α, and hif-3 α also revealed a circadian expression pattern for hif-3 α mRNA under normoxic conditions in zebrafish larvae. (zfin.org)
  • isoform-specific
  • While isoform-specific functions for Hif-1α and Hif-2α have been identified in recent years, the role of Hif-3α remains somewhat elusive. (zfin.org)
  • metabolism
  • HIF-1 also induces transcription of genes involved in cell proliferation and survival, as well as glucose and iron metabolism. (wikipedia.org)
  • Pcrit is nevertheless closely tied to a fish's hypoxia tolerance, in part because some fish prioritize their use of aerobic metabolism over anaerobic metabolism and metabolic suppression. (wikipedia.org)
  • In either case, LOE is a more holistic representation of overall hypoxia tolerance because it incorporates all contributors to hypoxia tolerance, including aerobic metabolism, anaerobic metabolism and metabolic suppression. (wikipedia.org)
  • mRNA
  • siRNA (small interfering RNA) studies for individual NF-κB members revealed differential effects on HIF-1α mRNA levels, indicating that NF-κB can regulate basal HIF-1α expression. (wikipedia.org)
  • The HIF-1α internal ribosome entry site (IRES) is an RNA element present in the 5' UTR of the mRNA of HIF-1α that allows cap-independent translation. (wikipedia.org)
  • regulation
  • The translational regulation of HIF-1α accumulation by SA was partly associated with the down-regulation of the axis of the PI3K/mTOR/STAT3 signaling pathways. (nih.gov)
  • promoters
  • Binds to core DNA sequence 5-[AG]CGTG-3 within the hypoxia response element (HRE) of target gene promoters. (genecards.org)
  • In accordance with its dynamic biological role, HIF-1 responds to systemic oxygen levels by undergoing conformational changes, and associates with HRE regions of promoters of hypoxia-responsive genes to induce transcription. (wikipedia.org)
  • HIF-1 acts by binding to HIF-responsive elements (HREs) in promoters that contain the sequence NCGTG (where N is either A or G). It has been shown that muscle A kinase-anchoring protein (mAKAP) organized E3 ubiquitin ligases, affecting stability and positioning of HIF-1 inside its action site in the nucleus. (wikipedia.org)
  • VEGF
  • CoCl2-induced hypoxia was also associated with a large increase in Akt/mTOR signaling, activation of downstream targets p70S6K and eIF-4E1, and a significant increase in VEGF production, and combined treatment with compound 44 blocked this response. (nih.gov)
  • HIF-1 is known to induce transcription of more than 60 genes, including VEGF and erythropoietin that are involved in biological processes such as angiogenesis and erythropoiesis, which assist in promoting and increasing oxygen delivery to hypoxic regions. (wikipedia.org)
  • These include glycolysis enzymes, which allow ATP synthesis in an oxygen-independent manner, and vascular endothelial growth factor (VEGF), which promotes angiogenesis. (wikipedia.org)
  • human
  • Salternamide A Suppresses Hypoxia-Induced Accumulation of HIF-1α and Induces Apoptosis in Human Colorectal Cancer Cells. (nih.gov)
  • In the present study, we demonstrate that SA efficiently inhibits the hypoxia-induced accumulation of HIF-1α in a time- and concentration-dependent manner in various human cancer cells. (nih.gov)
  • Proposed signaling pathways underlying the effects of SA on the suppression of HIF-1α and the induction of cell death in human colorectal cancer cells. (nih.gov)
  • HIF-1α steady state accumulation was dependent on the amount of PHD silencing effected by siRNA in HeLa cells and a variety of other human cell lines. (wikipedia.org)
  • The human protein Proteasome subunit alpha type-7 is 28 kDa in size and composed of 248 amino acids. (wikipedia.org)
  • auxiliary subunit
  • Together with its auxiliary subunit Naa15, Naa10 constitutes the NatA (Nα-acetyltransferase A) complex that specifically catalyzes the transfer of an acetyl group from acetyl-CoA to the N-terminal primary amino group of certain proteins. (wikipedia.org)
  • Furthermore, the recent X-ray crystal structure of the 100 kD holo-NatA (Naa10/Naa15) complex from S. pombe showed that Naa10 adopts a typical GNAT fold containing a N-terminal α1-loop-α2 segment that features one large hydrophobic interface and exhibits interactions with its auxiliary subunit Naa15, a central acetyl CoA-binding region, and C-terminal segments that are similar to the corresponding regions in Naa50, another Nα-acetyltransferase. (wikipedia.org)
  • genes
  • In addition to an immediate response, which includes inter alia an increase in the cardiac output and respiratory output and a local dilation of blood vessels by vegetative-nervous control mechanisms, hypoxia brings about a change in the transcription of numerous genes. (patentsencyclopedia.com)
  • In mammals, deletion of the HIF-1 genes results in perinatal death. (wikipedia.org)
  • Inhibition of electron transfer in the succinate dehydrogenase complex due to mutations in the SDHB or SDHD genes can cause a build-up of succinate that inhibits HIF prolyl-hydroxylase, stabilizing HIF-1α. (wikipedia.org)
  • HIF-1, when stabilized by hypoxic conditions, upregulates several genes to promote survival in low-oxygen conditions. (wikipedia.org)
  • Depletion of mAKAP or disruption of its targeting to the perinuclear (in cardiomyocytes) region altered the stability of HIF-1 and transcriptional activation of genes associated with hypoxia. (wikipedia.org)
  • humans
  • but in humans, NatB subunits are both found to be ribosome-associated and non-ribosomal form. (wikipedia.org)
  • Other significant compounds from this family, which are used in research but have not been developed for medical use in humans, include MK-8617, YC-1, IOX-2, 2-methoxyestradiol, GN-44028, AKB-4924, Bay 87-2243, FG-2216 and FG-4497. (wikipedia.org)
  • tumors
  • However, hypoxia promotes the formation of blood vessels, and is important for the formation of a vascular system in embryos and tumors. (wikipedia.org)
  • hypoxic
  • The HIF-1α internal ribosome entry site (IRES) allows translation to be maintained under hypoxic cell conditions that inhibit cap-dependent translation [1]. (wikipedia.org)
  • However, HIF-1α stabilization is also found in non-hypoxic conditions through an, until recently, unknown mechanism. (wikipedia.org)
  • aryl
  • Most, if not all, oxygen-breathing species express the highly conserved transcriptional complex HIF-1, which is a heterodimer composed of an alpha and a beta subunit, the latter being a constitutively-expressed aryl hydrocarbon receptor nuclear translocator (ARNT). (wikipedia.org)
  • composition
  • 9. A pharmaceutical composition comprising a compound as defined in claim 1 in combination with an inert, non-toxic, pharmaceutically suitable auxiliary. (patentsencyclopedia.com)
  • proteolysis
  • Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber. (wikipedia.org)
  • prevents
  • The β subunit prevents the pump from running in reverse, and it also appears to contain signals that direct the heterodimer to membrane destinations within the cell, although some of these signals are subordinate to signals found in H+/K+ ATPase α subunit. (wikipedia.org)
  • The β subunit prevents the E2-P conformation from reverting to the E1-P conformation, making proton pumping unidirectional. (wikipedia.org)
  • endothelial
  • Tracking Neutrophil Intraluminal Crawling, Transendothelial Migration and Chemotaxis in Tissue by Intravital Video Microscopy Najia Xu 1 , Xi Lei 1 , Lixin Liu 1 1 Department of Pharmacology, University of Saskatchewan We describe a protocol of brightfield intravital microscopy for measuring dynamic neutrophil-endothelial cell interactions during neutrophil recruitment in response to the source of a neutrophil chemoattractant in vivo . (jove.com)
  • EPAS 1 is involved in the development of the embryonic heart and is expressed in the endothelial cells that line the walls of the blood vessels in the umbilical cord. (wikipedia.org)
  • siRNA
  • HIF-1α steady state accumulation was dependent on the amount of PHD silencing effected by siRNA in HeLa cells and a variety of other human cell lines. (wikipedia.org)
  • identical
  • This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. (wikipedia.org)
  • The mitochondrial form of IDH, like most isoforms, is a homodimer, in which two identical monomer subunits form one unit. (wikipedia.org)
  • response
  • Claudin multigene family in channel catfish and their expression profiles in response to bacterial infection and hypoxia as revealed by meta-analysis of RNA-Seq datasets. (auburn.edu)
  • Structure
  • The alpha and beta subunit are similar in structure and both contain the following domains: N-terminus - a bHLH domain for DNA binding central region - Per-ARNT-Sim (PAS) domain, which facilitates heterodimerization C-terminus - recruits transcriptional coregulatory proteins The following are members of the human HIF family: The HIF signaling cascade mediates the effects of hypoxia, the state of low oxygen concentration, on the cell. (wikipedia.org)
  • The structure of Mycobacterium tuberculosis IDH-1 bound with NADPH and Mn2+ has been solved by X-ray crystallography. (wikipedia.org)
  • Specifically, it is a single-subunit small GTPase, which is related in structure to the Gα subunit of heterotrimeric G proteins (large GTPases). (wikipedia.org)
  • consists
  • Ras contains six beta strands and five alpha helices: It consists of two domains, a G domain of 166 amino acids, about 20kDa, that binds guanosine nucleotides, and a C-terminal membrane targeting region (CAAX-COOH, also known as CAAX box), which is lipid-modified by farnesyl transferase, RCE1 and ICMT. (wikipedia.org)
  • cell
  • PHD2 is the primary regulator of HIF-1α steady state levels in the cell. (wikipedia.org)
  • complex
  • At the end-stage of complex assembly, the N-terminal fragment of beta1 subunit is cleaved, forming the mature beta1 subunit of 20S complex. (wikipedia.org)
  • In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. (wikipedia.org)
  • The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. (wikipedia.org)
  • beta
  • The 20S proteasome subunit beta-1 (systematic nomenclature) is originally expressed as a precursor with 239 amino acids. (wikipedia.org)
  • oxygen
  • HIF-1 has been shown to be vital to chondrocyte survival, allowing the cells to adapt to low-oxygen conditions within the growth plates of bones. (wikipedia.org)
  • It was shown that NF-κB (nuclear factor κB) is a direct modulator of HIF-1α expression in the presence of normal oxygen pressure. (wikipedia.org)
  • The gene is active under low oxygen condition called hypoxia. (wikipedia.org)
  • calcium
  • However, polypharmacy is often needed in CKD patients to achieve the target blood pressure [ 1 ], with calcium (Ca) antagonists and diuretics being recommended for combination therapy. (jocmr.org)
  • dependent
  • Finally, it was shown that, when endogenous NF-κB is induced by TNFα (tumour necrosis factor α) treatment, HIF-1α levels also change in an NF-κB-dependent manner. (wikipedia.org)