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)

Cyclin-dependent kinase inhibitory proteins (CKIs) are negative regulators of the cell cycle. Of all CKIs, only p57(Kip2) plays an essential role(s) that other CKIs cannot compensate for in embryonic development. Recently, we found that p57(Kip2) is degraded through the ubiquitin-proteasome pathway in osteoblastic cells stimulated to proliferation by transforming growth factor (TGF)-beta1 (Urano, T., Yashiroda, H., Muraoka, M., Tanaka, K., Hosoi, T., Inoue, S., Ouchi, Y., and Toyoshima, H. (1999) J. Biol. Chem. 274, 12197-12200). We report here that TGF-beta1-induced p57(Kip2) proteolysis is mediated through transcription by the Smad pathway. When the constitutively active form of the TGF-beta type I receptor ALK-5(TD) was ectopically expressed in osteoblastic cells, p57(Kip2) that had been accumulated by serum starvation causing the cell-cycle arrest was rapidly degraded in a manner analogous to TGF-beta1 stimulation. Moreover, Smad2 or Smad3 with Smad4 enhanced the proteolytic pathway of p57(Kip2). The degradation of p57(Kip2) evoked by TGF-beta1 was blocked by forced expression of an inhibitory Smad called Smad7 or by the addition of actinomycin D or alpha-amanitin. These results indicate that accelerated degradation of p57(Kip2) by TGF-beta1/Smad signaling is mediated through a newly synthesized factor(s) that modifies p57(Kip2) or the ubiquitin-proteasome pathway.
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PMID:Smad-mediated transcription is required for transforming growth factor-beta 1-induced p57(Kip2) proteolysis in osteoblastic cells. 1115 74

The sensitive-to-apoptosis gene (SAG) was initially identified as a redox-inducible, apoptosis-protective protein and subsequently found to be the second family member of regulator of cullins (ROC)/RING box protein (Rbx)/Hrt, which acts as a component of E3 ubiquitin ligase. We report here that SAG promoted cell growth under serum starvation. Microinjection of SAG mRNA into quiescent NIH/3T3 cells induced S-phase entry as determined by [(3)H]-thymidine incorporation. Likewise, overexpression of SAG by either adenovirus infection of immortalized human epidermal keratinocytes (Rhek-1) or DNA transfection of SY5Y human neuroblastoma cells induced cell proliferation under serum starvation. Because cyclin-dependent kinase inhibitors (CKIs), including p21, p27, and p57, are degraded through the ubiquitin pathway, we tested whether SAG-induced cell growth is associated with CKI degradation. Although there was no significant difference in the levels of p21 and p57 between the vector controls and SAG-overexpressing cells, serum starvation induced 10- to 18-fold accumulation of p27 in control Rhek-1 cells. Accumulation of p27 was remarkably inhibited (only 2 to 5-fold) in SAG-infected cells. Inhibition of p27 accumulation was also observed in stably SAG-overexpressing SY5Y cells. Significantly, SAG-associated inhibition of p27 accumulation was largely abolished by the treatment with a proteasome inhibitor. In vivo binding of SAG and Skp2, an F-box protein that promotes p27 ubiquitination, was detected, and the binding was enhanced in SAG-overexpressing cells grown under serum starvation. Thus, SAG-induced growth with serum withdrawal appears to be associated with SAG-mediated p27 degradation. Mol. Carcinog. 30:37-46, 2001.
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PMID:Promotion of S-phase entry and cell growth under serum starvation by SAG/ROC2/Rbx2/Hrt2, an E3 ubiquitin ligase component: association with inhibition of p27 accumulation. 1125 62

A number of acute wasting conditions are associated with an upregulation of the ubiquitin-proteasome system in skeletal muscle. Eicosapentaenoic acid (EPA) is effective in attenuating the increased protein catabolism in muscle in cancer cachexia, possibly due to inhibition of 15-hydroxyeicosatetraenoic acid (15-HETE) formation. To determine if a similar pathway is involved in other catabolic conditions, the effect of EPA on muscle protein degradation and activation of the ubiquitin-proteasome pathway has been determined during acute fasting in mice. When compared with a vehicle control group (olive oil) there was a significant decrease in proteolysis of the soleus muscles of mice treated with EPA after starvation for 24 h, together with an attenuation of the proteasome "chymotryptic-like" enzyme activity and the induction of the expression of the 20S proteasome alpha-subunits, the 19S regulator and p42, an ATPase subunit of the 19S regulator in gastrocnemius muscle, and the ubiquitin-conjugating enzyme E2(14k). The effect was not shown with the related (n-3) fatty acid docosahexaenoic acid (DHA) or with linoleic acid. However, 2,3,5-trimethyl-6-(3-pyridylmethyl)1,4-benzoquinone (CV-6504), an inhibitor of 5-, 12- and 15-lipoxygenases also attenuated muscle protein catabolism, proteasome "chymotryptic-like" enzyme activity and expression of proteasome 20S alpha-subunits in soleus muscles from acute fasted mice. These results suggest that protein catabolism in starvation and cancer cachexia is mediated through a common pathway, which is inhibited by EPA and is likely to involve a lipoxygenase metabolite as a signal transducer.
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PMID:Downregulation of ubiquitin-dependent proteolysis by eicosapentaenoic acid in acute starvation. 1145 34

The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. In the yeast Saccharomyces cerevisiae, the UBR1-encoded ubiquitin ligase (E3) of the N-end rule pathway mediates the targeting of substrate proteins in part through binding to their destabilizing N-terminal residues. The functions of the yeast N-end rule pathway include fidelity of chromosome segregation and the regulation of peptide import. Our previous work described the cloning of cDNA and a gene encoding the 200-kDa mouse UBR1 (E3alpha). Here we show that mouse UBR1, in the presence of a cognate mouse ubiquitin-conjugating (E2) enzyme, can rescue the N-end rule pathway in ubr1Delta S. cerevisiae. We also constructed UBR1(-/-) mouse strains that lacked the UBR1 protein. UBR1(-/-) mice were viable and fertile but weighed significantly less than congenic +/+ mice. The decreased mass of UBR1(-/-) mice stemmed at least in part from smaller amounts of the skeletal muscle and adipose tissues. The skeletal muscle of UBR1(-/-) mice apparently lacked the N-end rule pathway and exhibited abnormal regulation of fatty acid synthase upon starvation. By contrast, and despite the absence of the UBR1 protein, UBR1(-/-) fibroblasts contained the N-end rule pathway. Thus, UBR1(-/-) mice are mosaics in regard to the activity of this pathway, owing to differential expression of proteins that can substitute for the ubiquitin ligase UBR1 (E3alpha). We consider these UBR1-like proteins and discuss the functions of the mammalian N-end rule pathway.
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PMID:Construction and analysis of mouse strains lacking the ubiquitin ligase UBR1 (E3alpha) of the N-end rule pathway. 1168 92

The fission yeast Schizosaccharomyces pombe has three putative ubiquitin-protein ligases of the Nedd4/Rsp5 family, named Pub1p, Pub2p and Pub3p. Pub1p has been reported to be involved in cell cycle regulation and proliferation under acidic pH conditions. Here we characterize Pub2p, which contains a conserved HECT domain and a WW domain but lacks a C2 domain. Transcription of the pub2(+) gene was constitutive and further enhanced by nitrogen starvation. A pub2-null mutation gave no remarkable phenotypes, but intensified temperature sensitivity in a pub1Delta background. Moderately overexpressed pub2(+) suppressed the temperature sensitivity of pub1Delta cells, which suggests that the function of Pub2p overlaps with that of Pub1p. Overexpression of pub2(+) by a strong nmt1 promoter in wild-type strains caused growth arrest and cell elongation, probably owing to defects in G2 progression or the G2/M transition. Unlike Pub1p, however, overexpression of Pub2p did not reduce the levels of Cdc25p. Pub2-GFP was found throughout the cell, especially at the cell surface in the polar regions. Pub2p contains a conserved cysteine residue (Cys639) in its putative catalytic HECT domain that can be thiol-ubiquitinated. Substitution of Cys639 by alanine (Pub2CA) caused a functional defect, because growth arrest and cell elongation were not induced by overexpression of Pub2CA. A chimeric Pub1 protein, in which the HECT domain was replaced by the Pub2 HECT domain, completely suppressed the temperature sensitivity of pub1Delta cells, suggesting that the HECT domain of Pub2p has the catalytic activity of a ubiquitin ligase. We conclude that Pub2p is a HECT-type ubiquitin-protein ligase that shares partially overlapping function with Pub1p.
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PMID:The novel HECT-type ubiquitin-protein ligase Pub2p shares partially overlapping function with Pub1p in Schizosaccharomyces pombe. 1195 16

A 48-h starvation period resulted in a great increase in muscle proteolysis-as measured following the release of tyrosine into the medium-in incubated isolated rat extensor digitorum longus (EDL) muscles. We have quantified the contribution of the different proteolytic systems to the increased protein degradation and observed a considerable activation in the ATP-dependent proteolytic (60%) and in the calcium-dependent (125%) systems, while no increases were observed in lysosomal proteolysis. The addition of 10 mM leucine to the incubation medium did not result in any changes in either total proteolytic rate or the activity rates of any of the different systems studied. In addition, the presence of the amino acid did not influence the levels of mRNA for the different genes studied-ubiquitin, C8 proteasome subunit, E2 conjugating enzyme, m-calpain, and cathepsin B. In a similar way, as observed during starvation, tumor growth resulted in increased protein degradation in incubated isolated EDL muscles from animals bearing the Yoshida AH-130 ascites hepatoma. The increased rate of protein degradation affected all the proteolytic systems studied: ATP- and calcium-dependent and lysosomal. Finally, leucine addition (10 mM), although not able to revert the increased proteolytic rate, resulted in a decrease in the gene expression for ubiquitin, C8 proteasome subunit and cathepsin B.
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PMID:Branched-chain amino acids: a role in skeletal muscle proteolysis in catabolic states? 1201 23

Candida albicans ubiquitin genes UBI3 and UBI4 encode a ubiquitin-hybrid protein involved in ribosome biogenesis and polyubiquitin, respectively. In this work we show that UBI3 and UBI4 promoter regions confer differential expression consistent with the function of their encoded gene products. Hybrid genes were constructed containing the SUC2 coding region under the control of UBI3 or UBI4 promoters in the yeast vector pLC7. Invertase production in Saccharomyces cerevisiae transformants was differentially regulated: the UBI4 promoter was induced by stress conditions (thermal upshift and/or starvation) whereas the UBI3 promoter conferred constitutive invertase production in growing yeast cells. These results indicate that the UBI4 promoter is regulated by stress-response signaling pathways, whereas the UBI3 promoter is controlled according to the requirement for protein synthesis to support cell growth.
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PMID:Candida albicans UBI3 and UBI4 promoter regions confer differential regulation of invertase production to saccharomyces cerevisiae cells in response to stress. 1210 35

Dictyostelium amoebae accomplish a starvation-induced developmental process by aggregating into a mound and forming a single fruiting body with terminally differentiated spores and stalk cells. culB was identified as the gene disrupted in a developmental mutant with an aberrant prestalk cell differentiation phenotype. The culB gene product appears to be a homolog of the cullin family of proteins that are known to be involved in ubiquitin-mediated protein degradation. The culB mutants form supernumerary prestalk tips atop each developing mound that result in the formation of multiple small fruiting bodies. The prestalk-specific gene ecmA is expressed precociously in culB mutants, suggesting that prestalk cell differentiation occurs earlier than normal. In addition, when culB mutant cells are mixed with wild-type cells, they display a cell-autonomous propensity to form stalk cells. Thus, CulB appears to ensure that the proper number of prestalk cells differentiate at the appropriate time in development. Activation of cyclic AMP-dependent protein kinase (PKA) by disruption of the regulatory subunit gene (pkaR) or by overexpression of the catalytic subunit gene (pkaC) enhances the prestalk/stalk cell differentiation phenotype of the culB mutant. For example, culB- pkaR- cells form stalk cells without obvious multicellular morphogenesis and are more sensitive to the prestalk O (pstO) cell inducer DIF-1. The sensitized condition of PKA activation reveals that CulB may govern prestalk cell differentiation in Dictyostelium, in part by controlling the sensitivity of cells to DIF-1, possibly by regulating the levels of one or more proteins that are rate limiting for prestalk differentiation.
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PMID:CulB, a putative ubiquitin ligase subunit, regulates prestalk cell differentiation and morphogenesis in Dictyostelium spp. 1245 79

The ubiquitin-proteasome proteolytic pathway is a major route of protein degradation and of particular importance in muscle proteolysis in mammals. In this study, the beta proteasome subunit N3 and polyubiquitin genes of the rainbow trout, Oncorhynchus mykiss, were sequenced and tissue distribution of gene expression was examined. The effects of 14-day food withdrawal were assessed on the N3 subunit and polyubiquitin gene expression in terms of mRNA, 20S proteasome proteolytic activity and ubiquitin protein abundance in trout liver and muscle. Both sequences are highly conserved, and the rainbow trout ubiquitin amino acid sequence is identical to the mammalian protein. The proteasome beta subunit N3 has 92% similarity to the Xenopus sequence. Starvation halved the polyubiquitin mRNA level in liver but had no effect on muscle levels. No significant effect of food withdrawal was observed on the proteasome mRNA in liver or muscle. Food withdrawal decreased the 20S proteasome proteolytic activity and the abundance of ubiquitin protein in both muscle and liver. Co-regulation of the proteasome and ubiquitin was indicated by the high correlation ( R=0.924) between 20S activity and ubiquitin abundance. Overall, this study demonstrates that starvation down-regulates the ubiquitin-proteasome pathway, possibly highlighting differences in the regulation of protein turnover in poikilothermic and endothermic animals.
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PMID:Ubiquitin-proteasome-dependent proteolysis in rainbow trout (Oncorhynchus mykiss): effect of food deprivation. 1245 46

A DNA fragment corresponding to part of an SNF1 (sucrose non-fermenting-1)-related protein kinase (SnRK1) transcript was amplified by a polymerase chain reaction (PCR) from a wheat (Triticum aestivum) endosperm cDNA library. It was used to construct a chimaeric gene, pUasSnRKN, comprising a ubiquitin promoter, the SnRK1 PCR product in the antisense orientation and the nopaline synthase (Nos) gene terminator. This construct was used in transient gene expression experiments in cultured wheat embryos together with a series of reporter gene constructs. These included the wheat alpha amylase gene alpha-Amy2 promoter with UidA (Gus) coding region (palpha2GT), rice actin promoter with Gus (pActIDGus), ubiquitin promoter with Gus (pAHC25) and actin promoter with green fluorescent protein (GFP) gene (pAct1Is-GFP1). All of the reporter genes were found to be active when bombarded into scutellae isolated from immature grains at 25 d post-anthesis and incubated on MS medium for 24 h prior to bombardment. However, co-bombardment of palpha2GT with equimolar amounts of pUasSnRKN resulted in no detectable Gus activity, indicating that the antisense SnRK1 construct repressed the alpha-Amy2 promoter. Co-bombardment with pUasSnRKN had no effect on the activity of the other promoters used in the study. A triple bombardment with palpha2GT, pAct1Is-GFP-1 and pUasSnRKN resulted in clear green fluorescence, indicating that the bombarded cells were still viable, but no Gus activity. RT-PCR analysis showed clearly that the antisense SnRK1 gene was expressing. Northern and RT-PCR analyses confirmed that SnRK1 and both alpha-amylase genes, alpha-Amy1 and alpha-Amy2, are expressed in cultured wheat embryos harvested from grain 25 d post-anthesis. Expression of alpha-Amy1 and alpha-Amy2 was up-regulated by sugar starvation.
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PMID:Antisense SNF1-related (SnRK1) protein kinase gene represses transient activity of an alpha-amylase (alpha-Amy2) gene promoter in cultured wheat embryos. 1255 17


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