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)

The acetyl-coenzyme A carboxylase (ACC) gene contains two promoters (PI and PII), both of which are active in the liver. Various physiological stimuli affect one, or both of the promoters of the ACC gene, and result in the generation of two classes of ACC mRNAs which differ in the composition of their 5' untranslated regions (5' UTR). We have analyzed the amounts of the two major mRNAs species that are generated from each of these promoters in order to examine the regulation of ACC gene activity in the liver under different physiological conditions. Our findings can be summarized as follows: (1) In liver from normal animals, fed a complete laboratory chow ad libitum, the level of class 2 ACC mRNA species generated by PII is very low. These mRNA species disappear on starvation. Refeeding starved animals with a fat-free diet stimulates both PI and PII with different time courses of induction: PII responds quickly and PII gene products accumulate to maximum levels within 18 hours, while the PI response, as measured by the accumulation of class 1 mRNAs, shows a lag period of 6 hours before reaching maximal levels at the end of a 24-hour refeeding period. The half-lives estimated from the induction kinetics were 4.4 hours for class 2 mRNAs and 11.8 hours for class 1 mRNAs. Reinstatement of starvation causes an almost instantaneous disappearance of class 1 mRNA species, as compared with class 2 mRNA species. This rapid decay of PI transcripts suggests that factors stabilizing this class of ACC mRNAs contribute to the steady-state levels reached after the dietary induction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acetyl-coenzyme A carboxylase mRNA metabolism in the rat liver. 137 Sep 75

Iron-responsive elements (IREs) are regulatory RNA elements which are characterized by a phylogenetically defined sequence-structure motif. Their biological function is to provide a specific binding site for the IRE-binding protein (IRE-BP). Iron starvation of cells induces high affinity binding of the cytoplasmic IRE-BP to an IRE which has at least two different known biological consequences, repression of ferritin mRNA translation and stabilization of the transferrin receptor transcript. We report the identification of a novel, evolutionarily conserved IRE motif in the 5' UTR of murine and human erythroid-specific delta-aminolevulinic acid synthase (eALAS) mRNA which encodes the first, and possibly rate limiting, enzyme of the heme biosynthetic pathway. We demonstrate the function of the eALAS IRE as a specific binding site for the IRE-BP by gel retardation analyses and by in vitro translation experiments. In addition, we show that the 5' UTR of eALAS mRNA is sufficient to mediate iron-dependent translational regulation in vivo. These findings strongly suggest involvement of the IRE-IRE-BP system in the control of heme biosynthesis during erythroid differentiation.
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PMID:Identification of a novel iron-responsive element in murine and human erythroid delta-aminolevulinic acid synthase mRNA. 205 Jan 26

A cDNA clone encoding full-length 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (6PF-2-K/Fru-2, 6-P2ase) was isolated and sequenced from a Sparus aurata liver cDNA library. The 2527 bp nucleotide sequence of the cDNA contains a 73 bp 5'-untranslated region (5'-UTR), an open reading frame that encodes a 469 amino acid protein and 1041 bp at the 3'-UTR. The deduced amino acid sequence is the first inferred 6PF-2-K/Fru-2, 6-P2ase in fish. The kinase and bisphosphatase domains, where the residues described as crucial for the mechanism of reaction of the bifunctional enzyme are located, present a high degree of homology with other liver isoenzymes. However, within the first 30 amino acids at the N-terminal regulatory domain of the fish enzyme a low homology is found. Nutritional regulation of the 6-phosphofructo-2-kinase activity, together with immunodetectable protein and mRNA levels of 6PF-2-K/Fru-2,6-P2ase, was observed after starvation and refeeding. In contrast to results previously described for rat liver, the decrease in immunodetectable protein and kinase activity caused by starvation was associated in the teleostean fish to a decrease in mRNA levels.
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PMID:Molecular cloning of a cDNA encoding 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase from liver of Sparus aurata: nutritional regulation of enzyme expression. 1002 46

The regulation of the high affinity cationic amino acid transporter (Cat-1) by amino acid availability has been studied. In C6 glioma and NRK kidney cells, cat-1 mRNA levels increased 3.8-18-fold following 2 h of amino acid starvation. The transcription rate of the cat-1 gene remained unchanged during amino acid starvation, suggesting a post-transcriptional mechanism of regulation. This mechanism was investigated by expressing a cat-1 mRNA from a tetracycline-regulated promoter. The cat-1 mRNA contained 1.9 kilobase pairs (kb) of coding sequence, 4.5 kb of 3'-untranslated region, and 80 base pairs of 5'-untranslated region. The full-length (7.9 kb) mRNA increased 5-fold in amino acid-depleted cells. However, a 3.4-kb species that results from the usage of an alternative polyadenylation site was not induced, suggesting that the cat-1 mRNA was stabilized by cis-acting RNA sequences within the 3'-UTR. Transcription and protein synthesis were required for the increase in full-length cat-1 mRNA level. Because omission of amino acids from the cell culture medium leads to a substantial decrease in protein synthesis, the translation of the increased cat-1 mRNA was assessed in amino acid-depleted cells. Western blot analysis demonstrated that cat-1 mRNA and protein levels changed in parallel. The increase in protein level was significantly lower than the increase in mRNA level, supporting the conclusion that cat-1 mRNA is inefficiently translated when the supply of amino acids is limited, relative to amino acid-fed cells. Finally, y(+)-mediated transport of arginine in amino acid-fed and -starved cells paralleled Cat-1 protein levels. We conclude that the cat-1 gene is subject to adaptive regulation by amino acid availability. Amino acid depletion initiates molecular events that lead to increased cat-1 mRNA stability. This causes an increase in Cat-1 protein, and y(+) transport once amino acids become available.
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PMID:Post-transcriptional regulation of the arginine transporter Cat-1 by amino acid availability. 1052 20

The human gene RPMS12 encodes a protein similar to bacterial ribosomal protein S12 and is proposed to represent the human mitochondrial orthologue. RPMS12 reporter gene expression in cultured human cells supports the idea that the gene product is mitochondrial and is localized to the inner membrane. Human cells contain at least four structurally distinct RPMS12 mRNAs that differ in their 5'-untranslated region (5'-UTR) as a result of alternate splicing and of 5' end heterogeneity. All of them encode the same polypeptide. The full 5'-UTR contains two types of sequence element implicated elsewhere in translational regulation as follows: a short upstream open reading frame and an oligopyrimidine tract similar to that found at the 5' end of mRNAs encoding other growth-regulated proteins, including those of cytosolic ribosomes. The fully spliced (short) mRNA is the predominant form in all cell types studied and is translationally down-regulated in cultured cells in response to serum starvation, even though it lacks both of the putative translational regulatory elements. By contrast, other splice variants containing one or both of these elements are not translationally regulated by growth status but are translated poorly in both growing and non-growing cells. Reporter analysis identified a 26-nucleotide tract of the 5'-UTR of the short mRNA that is essential for translational down-regulation in growth-inhibited cells. Such experiments also confirmed that the 5'-UTR of the longer mRNA variants contains negative regulatory elements for translation. Tissue representation of RPMS12 mRNA is highly variable, following a typical mitochondrial pattern, but the relative levels of the different splice variants are similar in different tissues. These findings indicate a complex, multilevel regulation of RPMS12 gene expression in response to signals mediating growth, tissue specialization, and probably metabolic needs.
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PMID:Expression of the gene for mitoribosomal protein S12 is controlled in human cells at the levels of transcription, RNA splicing, and translation. 1054 10

The expression of foreign proteins in Saccharomyces cerevisiae is a powerful tool for basic research and the biotechnological industry. In spite of the potential of S. cerevisiae, only a few useful expression vectors have been developed for this yeast. These vectors are based on an increasing transcription rate in combination with an increase in gene dosage. Most vectors are maintained as plasmids, which forces growth of cultures on poor selective media. Expression of the yeast Gcn4 protein is regulated at the translational level and increases strongly under amino acid starvation. Because under these conditions protein synthesis in general ceases, it is conceivable that regulatory elements that control Gcn4 expression could support selective expression of foreign genes. We cloned DNA fragments residing upstream from the GCN4 coding sequence (including the 5' UTR) and ligated them to a cDNA that encodes the human serum albumin (HSA) gene. These GCN4 regulatory elements induced efficient HSA expression at the translational level under amino acid starvation. The GCN4/HSA cassette promoted efficient, inducible expression on either a multicopy or integrative plasmid. The integrated cassette induced a high level of HSA in dense cultures grown on rich media. Thus, the GCN4-based expression system (pGES) provides high protein quantities. pGES is the first expression vector to be induced at the translational level.
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PMID:GCN4-based expression system (pGES): translationally regulated yeast expression vectors. 1072 70

Ornithine decarboxylase (ODC) of the fungus Neurospora crassa, encoded by the spe-1 gene, catalyzes an initial and rate-limiting step in polyamine biosynthesis and is highly regulated by polyamines. In N. crassa, polyamines repress the synthesis and increase the degradation of ODC protein. Changes in the rate of ODC synthesis correlate with similar changes in the abundance of spe-1 mRNA. We identify two sequence elements, one in each of the 5' and 3' regions of the spe-1 gene of N. crassa, required for this polyamine-mediated regulation. A 5' polyamine-responsive region (5' PRR) comprises DNA sequences both in the upstream untranscribed region and in the long 5' untranslated region (5'-UTR) of the gene. The 5' PRR is sufficient to confer polyamine regulation to a downstream, heterologous coding region. Use of the beta-tubulin promoter to drive the expression of various portions of the spe-1 transcribed region revealed a 3' polyamine-responsive region (3' PRR) downstream of the coding region. Neither changes in cellular polyamine status nor deletion of sequences in the 5'-UTR alters the half-life of spe-1 mRNA. Sequences in the spe-1 5'-UTR also impede the translation of a heterologous coding region, and polyamine starvation partially relieves this impediment. The results show that N. crassa uses a unique combination of polyamine-mediated transcriptional and translational control mechanisms to regulate ODC synthesis.
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PMID:Polyamine regulation of ornithine decarboxylase synthesis in Neurospora crassa. 1073 79

The X-linked Inhibitor of Apoptosis, XIAP, is a key member of the newly discovered family of intrinsic inhibitors of apoptosis (IAP) proteins. IAPs block cell death both in vitro and in vivo by virtue of inhibition of distinct caspases. Although other proteins have been identified which inhibit upstream caspases, only the IAPs have been demonstrated to be endogenous repressors of the terminal caspase cascade. In turn, the caspase inhibiting activity of XIAP is negatively regulated by at least two XIAP-interacting proteins, XAF1 and Smac/DIABLO. In addition to the inhibition of caspases, recent discoveries from several laboratories suggest that XIAP is also involved in a number of other biologically significant cellular activities including modulation of receptor-mediated signal transduction and protein ubiquitination. XIAP is also translated by a rare cap-independent mechanism mediated by a specific sequence called IRES (for Internal Ribosome Entry Site) which is found in the XIAP 5(') UTR. XIAP protein is thus synthesized under various conditions of cellular stress such as serum starvation and low dose gamma-irradiation induced apoptosis, conditions that lead to the inhibition of cellular protein synthesis. The multiple biological activities of XIAP, its unique translational and post-translational control and the centrality of the caspase cascade make the control of XIAP expression an exceptionally promising molecular target for modulating apoptosis. Therapeutic benefits can be derived from both the suppression of inappropriate cell death such as in neurodegenerative disorders and ischemic injury or in the activation of latent cell death pathways such as in autoimmune disease and cancer where apoptosis induction is the desired outcome.
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PMID:XIAP: apoptotic brake and promising therapeutic target. 1144 67

The cationic amino acid transporter, Cat-1, is a high affinity transporter of the essential amino acids, arginine and lysine. Expression of the cat-1 gene is known to be regulated by amino acid availability. It is shown here that cat-1 gene expression is also induced by Glc limitation, which causes a 7-fold increase in cat-1 mRNA, a 30-fold induction of Cat-1 protein levels, and a 4-fold stimulation of arginine uptake. Glc limitation is known to induce the unfolded protein response (UPR) by altering protein glycosylation in the endoplasmic reticulum (ER). The studies here demonstrate that synthesis of Cat-1 occurs during the UPR when global protein synthesis is inhibited. The 5'-UTR of the cat-1 mRNA contains an internal ribosomal entry site (IRES) that is activated by amino acid starvation by a mechanism that involves phosphorylation of the translation initiation factor, eukaryotic initiation factor 2alpha, by the GCN2 kinase. It is shown here that translation from the cat-1/IRES is also induced by Glc deprivation in a manner dependent upon phosphorylation of eukaryotic initiation factor 2alpha by the transmembrane ER kinase, PERK. Because PERK is a key constituent of the UPR, it is concluded that induction of cat-1 gene expression is part of the adaptive response of cells to ER stress. These results also demonstrate that regulation of IRES activity in cellular mRNAs is part of the mechanism by which the UPR protects cells from unfolded proteins in the ER.
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PMID:Translation mediated by the internal ribosome entry site of the cat-1 mRNA is regulated by glucose availability in a PERK kinase-dependent manner. 1178 18

HIF-1alpha is the regulated subunit of the HIF-1 transcription factor, which induces transcription of a number of genes involved in the cellular response to hypoxia. The HIF-1alpha protein is rapidly degraded in cells supplied with adequate oxygen but is stabilized in hypoxic cells. Using polysome profile analysis, we found that translation of HIF-1alpha mRNA in NIH3T3 cells is spared the general reduction in translation rate that occurs during hypoxia. To assess whether the 5'UTR of the HIF-1alpha mRNA contains an internal ribosome entry site (IRES), we constructed a dicistronic reporter with the HIF-1alpha 5'UTR inserted between two reporter coding regions. We found that the HIF-1alpha 5'UTR promoted translation of the downstream reporter, indicating the presence of an IRES. The IRES had activity comparable to that of the well-characterized c-myc IRES. IRES activity was not affected by hypoxic conditions that caused a reduction in cap-dependent translation, and IRES activity was less affected by serum-starvation than was cap-dependent translation. These data indicate that the presence of an IRES in the HIF-1alpha 5'UTR allows translation to be maintained under conditions that are inhibitory to cap-dependent translation.
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PMID:Hypoxia-inducible factor-1alpha mRNA contains an internal ribosome entry site that allows efficient translation during normoxia and hypoxia. 1200 70


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