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 chloramphenicol acetyltransferase gene cat-86 is induced through a mechanism that is a variation of classical attenuation. Induction results from the destabilization of an RNA stem-loop that normally sequesters the cat-86 ribosome-binding site. Destabilization of the stem-loop is due to the stalling of a ribosome in the leader region of cat-86 mRNA at a position that places the A site of the stalled ribosome at leader codon 6. Two events can stall ribosomes at the correct location to induce cat-86 translation: addition of chloramphenicol to cells and starvation of cells for the amino acid specified by leader codon 6. Induction by amino acid starvation is an anomaly because translation of the cat-86 coding sequence requires all 20 amino acids. To explain this apparent contradiction we postulated that amino acid starvation triggers intracellular proteolysis, thereby providing levels of the deprived amino acid sufficient for cat-86 translation. Here we show that a mutation in relA, the structural gene for stringent factor, blocks intracellular proteolysis that is normally triggered by amino acid starvation. The relA mutation also blocks induction of cat-86 by amino acid starvation, but the mutation does not interfere with chloramphenicol induction. Induction by amino acid starvation can be demonstrated in relA mutant cells if the depleted amino acid is restored at very low levels (e.g., 2 micrograms/ml). A mutation in relC, which may be the gene for ribosomal protein L11, blocks induction of cat-86 by either chloramphenicol or amino acid starvation. We believe this effect is due to a structural alteration of the ribosome resulting from the relC mutation and not to the relaxed phenotype of the cells.
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PMID:Induction of cat-86 by chloramphenicol and amino acid starvation in relaxed mutants of Bacillus subtilis. 314 54

The ribosomal protein L11 binds to and suppresses the E3 ligase function of HDM2, thus activating p53. Despite being abundant as a component of the 60S large ribosomal subunit, L11 does not induce p53 under normal growth conditions. In search of mechanisms controlling L11-HDM2 interaction, we found that the induction of p53 under growth inhibitory conditions, such as low dose of actinomycin D or serum depletion, can be significantly attenuated by knocking down L11, indicating the importance of L11 in mediating these growth inhibitory signals to p53. We show that L11 is not regulated by transcription or protein stability and its level remains relatively constant during serum starvation. However, serum starvation induces translocation of L11 from the nucleolus to the nucleoplasm, where it participates in a complex with HDM2. We propose that the nucleolus acts as a barrier to prevent L11 interacting with HDM2 during normal growth. Growth inhibition, presumably through suppression of rRNA production in the nucleolus, facilitates translocation of L11 to the nucleoplasm, thus activating p53 through inhibiting HDM2.
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PMID:Essential role of ribosomal protein L11 in mediating growth inhibition-induced p53 activation. 1515 93

Guanosine tetraphosphate (ppGpp) is a key mediator of stringent control, an adaptive response of bacteria to amino acid starvation, and has thus been termed a bacterial alarmone. Previous X-ray crystallographic analysis has provided a structural basis for the transcriptional regulation of RNA polymerase activity by ppGpp in the thermophilic bacterium Thermus thermophilus. Here we investigated the physiological basis of the stringent response by comparing the changes in intracellular ppGpp levels and the rate of RNA synthesis in stringent (rel(+); wild type) and relaxed (relA and relC; mutant) strains of T. thermophilus. We found that in wild-type T. thermophilus, as in other bacteria, serine hydroxamate, an amino acid analogue that inhibits tRNA(Ser) aminoacylation, elicited a stringent response characterized in part by intracellular accumulation of ppGpp and that this response was completely blocked in a relA-null mutant and partially blocked in a relC mutant harboring a mutation in the ribosomal protein L11. Subsequent in vitro assays using ribosomes isolated from wild-type and relA and relC mutant strains confirmed that (p)ppGpp is synthesized by ribosomes and that mutation of RelA or L11 blocks that activity. This conclusion was further confirmed in vitro by demonstrating that thiostrepton or tetracycline inhibits (p)ppGpp synthesis. In an in vitro system, (p)ppGpp acted by inhibiting RNA polymerase-catalyzed 23S/5S rRNA gene transcription but at a concentration much higher than that of the observed intracellular ppGpp pool size. On the other hand, changes in the rRNA gene promoter activity tightly correlated with changes in the GTP but not ATP concentration. Also, (p)ppGpp exerted a potent inhibitory effect on IMP dehydrogenase activity. The present data thus complement the earlier structural analysis by providing physiological evidence that T. thermophilus does produce ppGpp in response to amino acid starvation in a ribosome-dependent (i.e., RelA-dependent) manner. However, it appears that in T. thermophilus, rRNA promoter activity is controlled directly by the GTP pool size, which is modulated by ppGpp via inhibition of IMP dehydrogenase activity. Thus, unlike the case of Escherichia coli, ppGpp may not inhibit T. thermophilus RNA polymerase activity directly in vivo, as recently proposed for Bacillus subtilis rRNA transcription (L. Krasny and R. L. Gourse, EMBO J. 23:4473-4483, 2004).
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PMID:Physiological analysis of the stringent response elicited in an extreme thermophilic bacterium, Thermus thermophilus. 1701 50

The c-Myc oncoprotein promotes cell growth by enhancing ribosomal biogenesis through upregulation of RNA polymerases I-, II-, and III-dependent transcription. Overexpression of c-Myc and aberrant ribosomal biogenesis leads to deregulated cell growth and tumorigenesis. Hence, c-Myc activity and ribosomal biogenesis must be regulated in cells. Here, we show that ribosomal protein L11, a component of the large subunit of the ribosome, controls c-Myc function through a negative feedback mechanism. L11 is transcriptionally induced by c-Myc, and overexpression of L11 inhibits c-Myc-induced transcription and cell proliferation. Conversely, reduction of endogenous L11 by siRNA increases these c-Myc activities. Mechanistically, L11 binds to the Myc box II (MB II), inhibits the recruitment of the coactivator TRRAP, and reduces histone H4 acetylation at c-Myc target gene promoters. In response to serum stimulation or serum starvation, L11 and TRRAP display inverse promoter-binding profiles. In addition, L11 regulates c-Myc levels. These results identify L11 as a feedback inhibitor of c-Myc and suggest a novel role for L11 in regulating c-Myc-enhanced ribosomal biogenesis.
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PMID:Inhibition of c-Myc activity by ribosomal protein L11. 1759 65

The c-Myc oncoprotein promotes cell growth by enhancing ribosomal biogenesis. Overexpression of c-Myc and aberrant ribosomal biogenesis lead to deregulated cell growth and tumorigenesis. Hence, c-Myc activity and ribosomal biogenesis must be tightly coordinated during normal homeostasis. We previously found that ribosomal protein L11 inhibits c-Myc activity by blocking the recruitment of its co-activator transformation/transcription domain-associated protein (TRRAP) to the promoter regions of c-Myc target genes that are transcribed by RNA polymerases I and II. In this study, we extended the role of L11 to the regulation of c-Myc-driven transcription of the 5 S rRNA and tRNA genes by RNA polymerase III. L11 co-resided with c-Myc at the 5 S rRNA and tRNA genes and significantly inhibited the binding of TRRAP to these genes. Knocking down endogenous L11 enhanced c-Myc-dependent transcription of these genes. Interestingly, in response to ribosomal stress induced by the treatment of cells with a low dose of actinomycin D or serum starvation, L11 binding to these genes was increased, and inversely TRRAP binding to these genes was decreased. Consistently, knockdown of L11 rescued the reduction of the expression of these genes by the two treatments. These results demonstrate that L11 suppresses c-Myc-dependent and RNA polymerase III-catalyzed transcription of 5 S rRNA and tRNA genes in response to ribosomal stress, ensuring a tight coordination between c-Myc activity and ribosomal biogenesis.
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PMID:Ribosomal protein L11 associates with c-Myc at 5 S rRNA and tRNA genes and regulates their expression. 2019 7