Prolyl hydroxylases as regulators of cell metabolism

2009 ◽  
Vol 37 (1) ◽  
pp. 291-294 ◽  
Author(s):  
Houda Boulahbel ◽  
Raúl V. Durán ◽  
Eyal Gottlieb
Keyword(s):  
Amino Acid ◽  
Cellular Response ◽  
Oxygen Sensing ◽  
Cell Metabolism ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Oxygen Depletion ◽  
Animal Cells ◽  
Prolyl Hydroxylases ◽  
Amino Acid Availability

Cellular response to oxygen depletion is mediated by HIF (hypoxia-inducible factor). HIF is a heterodimer consisting of a constitutively expressed subunit (HIFβ) and an oxygen-regulated subunit (HIFα). HIFα stability is regulated by prolyl hydroxylation by PHD (prolyl hydroxylase domain-containing protein) family members. PHD activity depends on the availability of molecular oxygen, making PHDs the oxygen-sensing system in animal cells. However, PHDs have recently been shown to respond to stimuli other than oxygen, such as 2-oxoglutarate (α-ketoglutarate), succinate or fumarate, as illustrated by the pseudo-hypoxic response in succinate dehydrogenase- or fumarate dehydrogenase-deficient tumours. Moreover, HIFα is not the sole PHD effector, suggesting that PHDs have functions that extend beyond oxygen sensing. Currently, we are investigating the role of PHDs in the cellular response to amino acid deprivation, a process regulated by mTOR (mammalian target of rapamycin). The precise mechanism whereby amino acids are signalling to mTOR is not fully understood. Given that 2-oxoglutarate is a limiting co-substrate for PHD activity during normoxia and that 2-oxoglutarate levels depend on amino acid availability, it is possible that PHD activity depends not only on oxygen, but also on amino acid availability, suggesting a global metabolic sensor function for PHDs which could be signalling not only to HIF, but also to mTOR.

scholarly journals Amino acid transporters: roles in amino acid sensing and signalling in animal cells

2003 ◽  
Vol 373 (1) ◽  
pp. 1-18 ◽  
Author(s):  
Russell HYDE ◽  
Peter M. TAYLOR ◽  
Harinder S. HUNDAL
Keyword(s):  
Gene Expression ◽  
Amino Acids ◽  
Amino Acid ◽  
Nutrient Availability ◽  
Cellular Response ◽  
Amino Acid Transporters ◽  
Animal Cells ◽  
Amino Acid Availability ◽  
Altered Gene ◽  
Amino Acid Sensing

Amino acid availability regulates cellular physiology by modulating gene expression and signal transduction pathways. However, although the signalling intermediates between nutrient availability and altered gene expression have become increasingly well documented, how eukaryotic cells sense the presence of either a nutritionally rich or deprived medium is still uncertain. From recent studies it appears that the intracellular amino acid pool size is particularly important in regulating translational effectors, thus, regulated transport of amino acids across the plasma membrane represents a means by which the cellular response to amino acids could be controlled. Furthermore, evidence from studies with transportable amino acid analogues has demonstrated that flux through amino acid transporters may act as an initiator of nutritional signalling. This evidence, coupled with the substrate selectivity and sensitivity to nutrient availability classically associated with amino acid transporters, plus the recent discovery of transporter-associated signalling proteins, demonstrates a potential role for nutrient transporters as initiators of cellular nutrient signalling. Here, we review the evidence supporting the idea that distinct amino acid “receptors” function to detect and transmit certain nutrient stimuli in higher eukaryotes. In particular, we focus on the role that amino acid transporters may play in the sensing of amino acid levels, both directly as initiators of nutrient signalling and indirectly as regulators of external amino acid access to intracellular receptor/signalling mechanisms.

scholarly journals A Ragulator–BORC interaction controls lysosome positioning in response to amino acid availability

2017 ◽  
Vol 216 (12) ◽  
pp. 4183-4197 ◽  
Author(s):  
Jing Pu ◽  
Tal Keren-Kaplan ◽  
Juan S. Bonifacino
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Cellular Response ◽  
Mammalian Target Of Rapamycin ◽  
Small Gtpase ◽  
Regulatory Effect ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Amino Acid Availability ◽  
Amino Acid Depletion

Lysosomes play key roles in the cellular response to amino acid availability. Depletion of amino acids from the medium turns off a signaling pathway involving the Ragulator complex and the Rag guanosine triphosphatases (GTPases), causing release of the inactive mammalian target of rapamycin complex 1 (mTORC1) serine/threonine kinase from the lysosomal membrane. Decreased phosphorylation of mTORC1 substrates inhibits protein synthesis while activating autophagy. Amino acid depletion also causes clustering of lysosomes in the juxtanuclear area of the cell, but the mechanisms responsible for this phenomenon are poorly understood. Herein we show that Ragulator directly interacts with BLOC-1–related complex (BORC), a multi-subunit complex previously found to promote lysosome dispersal through coupling to the small GTPase Arl8 and the kinesins KIF1B and KIF5B. Interaction with Ragulator exerts a negative regulatory effect on BORC that is independent of mTORC1 activity. Amino acid depletion strengthens this interaction, explaining the redistribution of lysosomes to the juxtanuclear area. These findings thus demonstrate that amino acid availability controls lysosome positioning through Ragulator-dependent, but mTORC1-independent, modulation of BORC.

scholarly journals Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression

2020 ◽  
Vol 21 (21) ◽  
pp. 8162
Author(s):  
Guang Yang ◽  
Rachel Shi ◽  
Qing Zhang
Keyword(s):  
Gene Regulation ◽  
Cancer Progression ◽  
Current Knowledge ◽  
Oxygen Sensing ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylases ◽  
Von Hippel Lindau ◽  
Oxygen Homeostasis ◽  
Jmjc Domain ◽  
Encoding Protein

Oxygen homeostasis regulation is the most fundamental cellular process for adjusting physiological oxygen variations, and its irregularity leads to various human diseases, including cancer. Hypoxia is closely associated with cancer development, and hypoxia/oxygen-sensing signaling plays critical roles in the modulation of cancer progression. The key molecules of the hypoxia/oxygen-sensing signaling include the transcriptional regulator hypoxia-inducible factor (HIF) which widely controls oxygen responsive genes, the central members of the 2-oxoglutarate (2-OG)-dependent dioxygenases, such as prolyl hydroxylase (PHD or EglN), and an E3 ubiquitin ligase component for HIF degeneration called von Hippel–Lindau (encoding protein pVHL). In this review, we summarize the current knowledge about the canonical hypoxia signaling, HIF transcription factors, and pVHL. In addition, the role of 2-OG-dependent enzymes, such as DNA/RNA-modifying enzymes, JmjC domain-containing enzymes, and prolyl hydroxylases, in gene regulation of cancer progression, is specifically reviewed. We also discuss the therapeutic advancement of targeting hypoxia and oxygen sensing pathways in cancer.

scholarly journals Distinct amino acid–sensing mTOR pathways regulate skeletal myogenesis

2013 ◽  
Vol 24 (23) ◽  
pp. 3754-3763 ◽  
Author(s):  
Mee-Sup Yoon ◽  
Jie Chen
Keyword(s):  
Amino Acid ◽  
Growth Regulation ◽  
Myogenic Differentiation ◽  
Mammalian Target Of Rapamycin ◽  
Acid Activation ◽  
Class Iii ◽  
Independent Manner ◽  
Inhibitory Function ◽  
Amino Acid Availability ◽  
Amino Acid Sensing

Signaling through the mammalian target of rapamycin (mTOR) in response to amino acid availability controls many cellular and developmental processes. mTOR is a master regulator of myogenic differentiation, but the pathways mediating amino acid signals in this process are not known. Here we examine the Rag GTPases and the class III phosphoinositide 3-kinase (PI3K) Vps34, two mediators of amino acid signals upstream of mTOR complex 1 (mTORC1) in cell growth regulation, for their potential involvement in myogenesis. We find that, although both Rag and Vps34 mediate amino acid activation of mTORC1 in C2C12 myoblasts, they have opposing functions in myogenic differentiation. Knockdown of RagA/B enhances, whereas overexpression of active RagB/C mutants impairs, differentiation, and this inhibitory function of Rag is mediated by mTORC1 suppression of the IRS1-PI3K-Akt pathway. On the other hand, Vps34 is required for myogenic differentiation. Amino acids activate a Vps34-phospholipase D1 (PLD1) pathway that controls the production of insulin-like growth factor II, an autocrine inducer of differentiation, through the Igf2 muscle enhancer. The product of PLD, phosphatidic acid, activates the enhancer in a rapamycin-sensitive but mTOR kinase–independent manner. Our results uncover amino acid–sensing mechanisms controlling the homeostasis of myogenesis and underline the versatility and context dependence of mTOR signaling.

scholarly journals The chromatin remodeler ISWI regulates the cellular response to hypoxia: role of FIH

2011 ◽  
Vol 22 (21) ◽  
pp. 4171-4181 ◽  
Author(s):  
Andrew Melvin ◽  
Sharon Mudie ◽  
Sonia Rocha
Keyword(s):  
Rna Polymerase Ii ◽  
Chromatin Remodeling ◽  
Cellular Response ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylases ◽  
Additional Information ◽  
Protein Levels ◽  
Survival Factor

The hypoxia-inducible factor (HIF) is a master regulator of the cellular response to hypoxia. Its levels and activity are controlled by dioxygenases called prolyl-hydroxylases and factor inhibiting HIF (FIH). To activate genes, HIF has to access sequences in DNA that are integrated in chromatin. It is known that the chromatin-remodeling complex switch/sucrose nonfermentable (SWI/SNF) is essential for HIF activity. However, no additional information exists about the role of other chromatin-remodeling enzymes in hypoxia. Here we describe the role of imitation switch (ISWI) in the cellular response to hypoxia. We find that unlike SWI/SNF, ISWI depletion enhances HIF activity without altering its levels. Furthermore, ISWI knockdown only alters a subset of HIF target genes. Mechanistically, we find that ISWI is required for full expression of FIH mRNA and protein levels by changing RNA polymerase II loading to the FIH promoter. Of interest, exogenous FIH can rescue the ISWI-mediated upregulation of CA9 but not BNIP3, suggesting that FIH-independent mechanisms are also involved. Of importance, ISWI depletion alters the cellular response to hypoxia by reducing autophagy and increasing apoptosis. These results demonstrate a novel role for ISWI as a survival factor during the cellular response to hypoxia.

Investigation of hypoxia-inducible factor-1alpha (HIF-1α) gene polymorphisms in individuals with high levels of hemoglobin / Hemoglobin seviyesi yüksek bireylerde hipoksi ile indüklenen faktör-1 alfa (HIF-1α) gen polimorfizminin araştırılması

2016 ◽  
Vol 41 (5) ◽  
Author(s):  
Muhammet Yusuf Tepebaşı ◽  
Nilüfer Şahin Calapoğlu ◽  
Mustafa Calapoğlu
Keyword(s):  
Normal Level ◽  
Complete Blood Count ◽  
Oxygen Sensing ◽  
Cell Metabolism ◽  
Hypoxia Inducible Factor ◽  
Peripheral Blood Lymphocytes ◽  
Hypoxic Cell ◽  
Genotype Distribution ◽  
Significant Difference ◽  
High Level

AbstractObjective: A classic physiologic response to systemic hypoxia is the increase in red blood cell production. Hypoxia-inducible factors (HIFs) orchestrate oxygen-sensing machinery and hypoxic cell metabolism. Recent works suggest that mutation of the HIF oxygen-sensing pathway plays a key role in the pathogenesis of the erythrocytosis. In the present study, the probable role of the polymorphic HIF-1α variants, C1772T (P582S) (rs11549465) and G1790A (A588T) (rs115494657), which are known to enhance transcriptional activity, were evaluated in the etiology of the polycythemia.Methods: A total of 284 subjects 97 with normal levels of hemoglobin (Hgb) 157 with high levels of Hgb, and 30 with polycythemia vera (PV)) were recruited for this study. Genomic DNA was extracted from peripheral blood lymphocytes of all subjects. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was performed for HIF-1α C1772T and G1790A single nucletide polymorphisms (SNP). A complete blood count was performed for all subjects.Results: There was a significant decrease in the frequency of the HIF-1α C1772T allele T in subjects with PV compared with those in the normal level Hgb group (OR 0.51; 95% CI 0.75−0.95; p=0.03). High level Hgb subjects had a significantly higher frequency of the HIF-1α G1790A allele A (OR 10.79; 95% CI 0.62-; 187.96; p=0.027) than the subjects in the normal level Hgb group. A significant difference was observed in genotype distribution of GG and combined GA+AA genotypes of HIF-1α G1790A in PV and normal Hgb level subjects (OR 17.11; 95% CI 0.80−366,61; p>0.05).Conclusion: Our results suggest that the HIF-1α C1772T and G1790A polymorphisms may be associated with PV in the study population.

scholarly journals Regulation of the SIAH2-HIF-1 Axis by Protein Kinases and Its Implication in Cancer Therapy

2021 ◽  
Vol 9 ◽  
Author(s):  
Dazhong Xu ◽  
Cen Li
Keyword(s):  
Cancer Therapy ◽  
Protein Kinases ◽  
Ubiquitin Ligase ◽  
Cancer Biology ◽  
Cellular Response ◽  
Hypoxia Inducible Factor ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Potential Implication ◽  
Prolyl Hydroxylases

The cellular response to hypoxia is a key biological process that facilitates adaptation of cells to oxygen deprivation (hypoxia). This process is critical for cancer cells to adapt to the hypoxic tumor microenvironment resulting from rapid tumor growth. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor and a master regulator of the cellular response to hypoxia. The activity of HIF-1 is dictated primarily by its alpha subunit (HIF-1α), whose level and/or activity are largely regulated by an oxygen-dependent and ubiquitin/proteasome-mediated process. Prolyl hydroxylases (PHDs) and the E3 ubiquitin ligase Von Hippel-Lindau factor (VHL) catalyze hydroxylation and subsequent ubiquitin-dependent degradation of HIF-1α by the proteasome. Seven in Absentia Homolog 2 (SIAH2), a RING finger-containing E3 ubiquitin ligase, stabilizes HIF-1α by targeting PHDs for ubiquitin-mediated degradation by the proteasome. This SIAH2-HIF-1 signaling axis is important for maintaining the level of HIF-1α under both normoxic and hypoxic conditions. A number of protein kinases have been shown to phosphorylate SIAH2, thereby regulating its stability, activity, or substrate binding. In this review, we will discuss the regulation of the SIAH2-HIF-1 axis via phosphorylation of SIAH2 by these kinases and the potential implication of this regulation in cancer biology and cancer therapy.

scholarly journals Oxygen versus Reactive Oxygen in the Regulation of HIF-1α: The Balance Tips

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Thilo Hagen
Keyword(s):  
Cellular Response ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Thioredoxin Reductase ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Prolyl Hydroxylases ◽  
Hypoxia Inducible Factor 1 ◽  
Transport Chain ◽  
Cellular Oxygen

Hypoxia inducible factor (HIF) is known as the master regulator of the cellular response to hypoxia and is of pivotal importance during development as well as in human disease, particularly in cancer. It is composed of a constitutively expressedβsubunit (HIF-1β) and an oxygen-regulatedαsubunit (HIF-1αand HIF-2α), whose stability is tightly controlled by a family of oxygen- and iron-dependent prolyl hydroxylase enzymes. Whether or not mitochondria-derived reactive oxygen species (ROS) are involved in the regulation of Hypoxia Inducible Factor-1αhas been a matter of contention for the last 10 years, with equally compelling evidence in favor and against their contribution. A number of recent papers appear to tip the balance against a role for ROS. Thus, it has been demonstrated that HIF prolyl hydroxylases are unlikely to be physiological targets of ROS and that the increase in ROS that is associated with downregulation of Thioredoxin Reductase in hypoxia does not affect HIF-1αstabilization. Finally, the protein CHCHD4, which modulates cellular HIF-1αconcentrations by promoting mitochondrial electron transport chain activity, has been proposed to exert its regulatory effect by affecting cellular oxygen availability. These reports are consistent with the hypothesis that mitochondria play a critical role in the regulation of HIF-1αby controlling intracellular oxygen concentrations.

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