Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chicken embryo fibroblasts (CEF) when exposed to glucose-deficient culture medium developed 4- to 10-fold enhanced hexose transport activity within a few hours. Plasma membrane fractions prepared from starved and fed CEF revealed that starved cell membranes had a threefold greater glucose transport activity and [3H]cytochalasin B binding. The close correlation between transport activities of whole CEF and plasma membrane fractions indicates that hexose transport regulation during starvation results primarily in an increase in the number of functioning hexose transporters. The effect of protein synthesis inhibition on the overall process was studied with emetine, an inhibitor of translational elongation. Glucose-fed CEF treated with low concentrations of emetine (0.1 microM) showed a loss of transport greater than 65% within 4 h, but with higher concentrations of emetine (10 microM) there was no significant effect. Emetine treatment (0.1-10 microM) of CEF undergoing starvation virtually blocked any enhancement in transport whereas treatment of starved CEF led to only a slight loss of transport. Starved CEF refed with glucose had a decline of transport that was potentiated by low concentrations of emetine (0.1 microM); however, under these conditions high concentrations of emetine (10 microM) largely prevented loss of transport. Thus hexose transport regulation of CEF seems to reflect a balance between transporter synthesis and turnover. Transporter synthesis appears more sensitive to inhibition by emetine than turnover, whereas with hexose starvation there appears to be a decline in the activity of the transporter turnover process.
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PMID:Regulation of hexose transporters of chicken embryo fibroblasts during glucose starvation. 632 51

High-fat diet (HFD) induces skeletal muscle insulin resistance. To investigate associated changes in the plasma membrane glucose transporter, male Sprague-Dawley rats were fed either chow [high-carbohydrate diet (HCD)] or HFD for 3 wk. Plasma membrane vesicles were prepared from hindlimb muscle of control, insulin-stimulated (Ins), and acutely exercised (Ex) rats. Maximal vesicle glucose transport activity (Vmax) increased threefold with Ins and Ex treatment compared with controls in HCD rats; in HFD rats, increases were less than twofold. Transporter numbers (measured by cytochalasin B binding, CB) approximately doubled with Ins and Ex in both diet groups. Intrinsic activity (carrier turnover, Vmax/CB) increased significantly with stimulation in HCD but not HFD rats. Therefore, vesicles from HFD rats showed resistance to both exercise and insulin stimulation of muscle glucose transport. Transporter number increased normally, but intrinsic activity in HFD rats did not respond. Two conclusions are discussed: 1) translocation and activation are distinct, separable steps in transporter stimulation and 2) HFD produces effects that resemble the insulin resistance of starvation.
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PMID:High-fat diet reduces glucose transporter responses to both insulin and exercise. 830 61

Cellular iron uptake and storage are coordinately controlled by binding of iron-regulatory proteins (IRP), IRP1 and IRP2, to iron-responsive elements (IREs) within the mRNAs encoding transferrin receptor (TfR) and ferritin. Under conditions of iron starvation, both IRP1 and IRP2 bind with high affinity to cognate IREs, thus stabilizing TfR and inhibiting translation of ferritin mRNAs. The IRE/IRP regulatory system receives additional input by oxidative stress in the form of H(2)O(2) that leads to rapid activation of IRP1. Here we show that treating murine B6 fibroblasts with a pulse of 100 microm H(2)O(2) for 1 h is sufficient to alter critical parameters of iron homeostasis in a time-dependent manner. First, this stimulus inhibits ferritin synthesis for at least 8 h, leading to a significant (50%) reduction of cellular ferritin content. Second, treatment with H(2)O(2) induces a approximately 4-fold increase in TfR mRNA levels within 2-6 h, and subsequent accumulation of newly synthesized protein after 4 h. This is associated with a profound increase in the cell surface expression of TfR, enhanced binding to fluorescein-tagged transferrin, and stimulation of transferrin-mediated iron uptake into cells. Under these conditions, no significant alterations are observed in the levels of mitochondrial aconitase and the Divalent Metal Transporter DMT1, although both are encoded by two as yet lesser characterized IRE-containing mRNAs. Finally, H(2)O(2)-treated cells display an increased capacity to sequester (59)Fe in ferritin, despite a reduction in the ferritin pool, which results in a rearrangement of (59)Fe intracellular distribution. Our data suggest that H(2)O(2) regulates cellular iron acquisition and intracellular iron distribution by both IRP1-dependent and -independent mechanisms.
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PMID:Modulation of cellular iron metabolism by hydrogen peroxide. Effects of H2O2 on the expression and function of iron-responsive element-containing mRNAs in B6 fibroblasts. 1126 85

Two human di/tri-peptide transporters, hPepT1 and hPepT2 have been identified and functionally characterized. In the small intestine hPepT1 is exclusively expressed, whereas both PepT1 and PepT2 are expressed in the proximal tubule. The transport via di/tri-peptide transporters is proton-dependent, and the transporters thus belong to the Proton-dependent Oligopeptide Transporter (POT)-family. The transporters are not drug targets per se, however due to their uniquely broad substrate specificity; they have proved to be relevant drug targets at the level of drug transport. Drug molecules such as oral active beta-lactam antibiotics, bestatin, prodrugs of aciclovir and ganciclovir have oral bioavailabilities, which largely are a result of their interaction with PepT1. In the last few years an increasing number of studies concerned with regulation of di/tri-peptide transporter capacity have appeared. Studies on receptor-mediated regulation has shown that both PepT1 and PepT2 is down-regulated by long-term exposure to epidermal growth factor (EGF) due to a decreased gene transcription. PepT1-mediated transport is up-regulated by certain substrates and in response to fasting and starvation at the level of increased gene transcription. PepT1-mediated transport is up-regulated by short-term exposure to receptor agonists such as EGF, insulin, leptin, and clonidine, and down-regulated by VIP. Overall, the regulation of di/tri-peptide transport may be contributed to 1) changes in apical proton-motive force 2) recruitment of di/tri-peptide transporters from vesicular storages 3) changes in gene transcription/mRNA stability. The aim of the present review is to discuss physiological, patho-physiological and drug-induced regulation of di/tri-peptide transporter mediated transport.
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PMID:Di/tri-peptide transporters as drug delivery targets: regulation of transport under physiological and patho-physiological conditions. 1281 47

Amino acid transporter B(0)/ASC transporter 2 (ATB(0)/ASCT2) is responsible for most glutamine uptake in human hepatoma cells. Because this transporter is not expressed in normal hepatocytes, we hypothesized that its expression is necessary for growth of human liver cancer cells. To test this hypothesis, Sloan Kettering hepatoma (SK-Hep) cells were stably transfected with an inducible 1.3-kb ATB(0)/ASCT2 antisense RNA expression plasmid under the transcriptional control of mifepristone, a synthetic steroid. Induced antisense RNA expression in monolayer cultures decreased ATB(0)/ASCT2 mRNA levels by 73% and glutamine transport rates by 65% compared with controls after 24 h, leading to a 98% decrease in cell number after 48 h. Cellular death was attributable to apoptosis based on cellular blebbing, caspase-3 activation, vital dye and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, and poly-(ADP-ribose) polymerase (PARP) cleavage. Transporter knockdown also markedly increased activities of caspases-2 and -9, marginally enhanced caspase-8 activity, and dramatically increased ASCT1 mRNA levels, presumably as a futile compensatory response. Apoptosis elicited via transporter silencing was not attributable to the double-stranded RNA-dependent protein kinase R (PKR) pathway. For comparison, glutamine deprivation also caused apoptotic cell death but with slower temporal kinetics, stimulated caspases-2 and -3 but not caspases-8 or -9 activities, and led to considerable PARP cleavage. Thus ASCT2 suppression exerts proapoptotic effects transcending those of glutamine starvation alone. We conclude that ATB(0)/ASCT2 expression is necessary for SK-Hep cell growth and viability and suggest that it be further explored as a selective target for human hepatocellular carcinoma.
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PMID:Inducible antisense RNA targeting amino acid transporter ATB0/ASCT2 elicits apoptosis in human hepatoma cells. 1456 74

Amphiphysins are proteins thought to be involved in synaptic vesicle endocytosis. Amphiphysins share a common BAR domain, which can sense and/or bend membranes, and this function is believed to be essential for endocytosis. Saccharomyces cerevisiae cells lacking the amphiphysin ortholog Rvs161 are inviable when starved for glucose. Altering sphingolipid levels in rvs161 cells remediates this defect, but how lipid changes suppress remains to be elucidated. Here, we show that the sugar starvation-induced death of rvs161 cells extends to other fermentable sugar carbon sources, and the loss of sphingolipid metabolism suppresses these defects. In all cases, rvs161 cells respond to the starvation signal, elicit the appropriate transcriptional response, and properly localize the requisite sugar transporter(s). However, Rvs161 is required for transporter endocytosis. rvs161 cells accumulate transporters at the plasma membrane under conditions normally resulting in their endocytosis and degradation. Transporter endocytosis requires the endocytosis (endo) domain of Rvs161. Altering sphingolipid metabolism by deleting the very-long-chain fatty acid elongase SUR4 reinitiates transporter endocytosis in rvs161 and rvs161 endo(-) cells. The sphingolipid-dependent reinitiation of endocytosis requires the ubiquitin-regulating factors Doa1, Doa4, and Rsp5. In the case of Doa1, the phospholipase A(2) family ubiquitin binding motif is dispensable. Moreover, the conserved AAA-ATPase Cdc48 and its accessory proteins Shp1 and Ufd1 are required. Finally, rvs161 cells accumulate monoubiquitin, and this defect is remediated by the loss of SUR4. These results show that defects in sphingolipid metabolism result in the reinitiation of ubiquitin-dependent sugar transporter endocytosis and suggest that this event is necessary for suppressing the nutrient starvation-induced death of rvs161 cells.
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PMID:Altering sphingolipid metabolism in Saccharomyces cerevisiae cells lacking the amphiphysin ortholog Rvs161 reinitiates sugar transporter endocytosis. 1928 82

Sucrose (Suc) is the predominant form of carbon transported through the phloem from source to sink organs and is also a prominent sugar for short-distance transport. In all streptophytes analyzed, Suc transporter genes (SUTs or SUCs) form small families, with different subgroups evolving distinct functions. To gain insight into their capacity for moving Suc in planta, representative members of each clade were first expressed specifically in companion cells of Arabidopsis (Arabidopsis thaliana) and tested for their ability to rescue the phloem-loading defect caused by the Suc transporter mutation, Atsuc2-4. Sequence similarity was a poor indicator of ability: Several genes with high homology to AtSUC2, some of which have phloem-loading functions in other eudicot species, did not rescue the Atsuc2-4 mutation, whereas a more distantly related gene, ZmSUT1 from the monocot Zea mays, did restore phloem loading. Transporter complementary DNAs were also expressed in the companion cells of wild-type Arabidopsis, with the aim of increasing productivity by enhancing Suc transport to growing sink organs and reducing Suc-mediated feedback inhibition on photosynthesis. Although enhanced Suc loading and long-distance transport was achieved, growth was diminished. This growth inhibition was accompanied by increased expression of phosphate (P) starvation-induced genes and was reversed by providing a higher supply of external P. These experiments suggest that efforts to increase productivity by enhancing sugar transport may disrupt the carbon-to-P homeostasis. A model for how the plant perceives and responds to changes in the carbon-to-P balance is presented.
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PMID:Expression of Sucrose Transporter cDNAs Specifically in Companion Cells Enhances Phloem Loading and Long-Distance Transport of Sucrose but Leads to an Inhibition of Growth and the Perception of a Phosphate Limitation. 2477 45

Phosphorus (P) is an essential macronutrient for crop development and production. Phosphate starvation response 1 (PHR1) acts as the central regulator for Pi-signaling and Pi-homeostasis in plants by binding to the cis-element PHR1 binding sequence (P1BS; GNATATNC). However, how phosphate starvation-induced gene expression is regulated remains obscure. In this work, we investigated the DNA binding affinity of the PHR1 ortholog OsPHR2 to its downstream target genes in Oryza sativa (rice). We confirmed that a combination of P1BS and P1BS-like motifs are essential for stable binding by OsPHR2. Furthermore, we report that variations in P1BS motif bases affected the binding affinity of OsPHR2 and that the highest affinity motif was GaATATtC (designated the A-T-type P1BS). We also found that a combination of two A-T-type P1BS elements in tandem, namely HA-P1BS, was very efficient for binding of OsPHR2. Using the cis-regulator HA-P1BS, we modified the promoters of Transporter Traffic Facilitator 1 (PHF1), a key factor controlling endoplasmic reticulum-exit of phosphate transporters to the plasma membrane, for efficient uptake of phosphorous in an energetically neutral way. Transgenic plants with the modified promoters showed significantly enhanced tolerance to low phosphate stress in both solution and soil conditions, which provides a new strategy for crop improvement to enhance tolerance of nutrient deficiency.
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PMID:Genetic manipulation of a high-affinity PHR1 target cis-element to improve phosphorous uptake in Oryza sativa L. 2565 19

microRNAs (miRNAs) play an important role in plant adaptation to phosphate (Pi) starvation. Histone methylation can remodel chromatin structure and mediate gene expression. This study identified Arabidopsis miR778, a Pi-responsive miRNA, and its target gene Su(var) 3-9 homologs 6 (SUVH6) encoding a histone H3 lysine 9 (H3K9) methyltransferase. Overexpression of miR778 moderately enhanced primary and lateral root growth, free phosphate accumulation in shoots, and accumulation of anthocyanin under Pi deficient conditions. miR778 overexpression relieved the arrest of columella cell development under Pi starvation. Conversely, transgenic plants overexpressing a miR778-target mimic (35S::MIM778), that act as a sponge and sequesters miR778, showed opposite phenotypes of 35S::miR778 plants under Pi deficiency. Expression of several Pi deficiency-responsive genes such as miR399, Phosphate Transporter (PHT1;4), Low Phosphate-Resistant1 (LPR1) and Production of Anthocyanin Pigment 1 (PAP1) were elevated in the miR778 overexpressing plants, suggesting that both miR778 and SUVH6 are involved in phosphate homeostasis in plants. This study has provided a basis for further investigation on how SUVH6 regulates its downstream genes through chromatin remodeling and DNA methylation in plants stressed by Pi deficiency.
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PMID:miRNA778 and SUVH6 are involved in phosphate homeostasis in Arabidopsis. 2625 94

Plant vacuoles serve as the primary intracellular compartments for inorganic phosphate (Pi) storage. Passage of Pi across vacuolar membranes plays a critical role in buffering the cytoplasmic Pi level against fluctuations of external Pi and metabolic activities. Here we demonstrate that the SPX-MFS proteins, designated as PHOSPHATE TRANSPORTER 5 family (PHT5), also named Vacuolar Phosphate Transporter (VPT), function as vacuolar Pi transporters. Based on (31)P-magnetic resonance spectroscopy analysis, Arabidopsis pht5;1 loss-of-function mutants accumulate less Pi and exhibit a lower vacuolar-to-cytoplasmic Pi ratio than controls. Conversely, overexpression of PHT5 leads to massive Pi sequestration into vacuoles and altered regulation of Pi starvation-responsive genes. Furthermore, we show that heterologous expression of the rice homologue OsSPX-MFS1 mediates Pi influx to yeast vacuoles. Our findings show that a group of Pi transporters in vacuolar membranes regulate cytoplasmic Pi homeostasis and are required for fitness and plant growth.
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PMID:Identification of plant vacuolar transporters mediating phosphate storage. 2702 56


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