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)

Interferon (IFN) regulatory factor-1 (IRF-1) deregulation in ras-transformed mouse fibroblasts (RS485) was studied. Treatment with the proteasome inhibitor MG132 did not alter the constitutive IRF-1 protein levels in RS485 but significantly increased them in nontransformed NIH 3T3 cells at 4 h after serum stimulation of synchronized cultures. Because IRF-1 protein levels in NIH 3T3 are minimal at 4 h after serum starvation, the cyclic expression of IRF-1 in NIH 3T3 appears to be partially due to proteasome activity; however, proteasome activity in RS485 did not appear to be defective. In NIH 3T3 and RS485 cells treated with cycloheximide, there were similar rapid drops in IRF-1 protein levels, and the addition of MG132 along with cycloheximide prevented protein loss in both cell lines. Northern blot analyses of synchronized cultures showed that the IRF-1 message closely mirrored the protein expression pattern in both NIH 3T3 and RS485 cells. In synchronized cells treated with the transcription inhibitor actinomycin D, IRF-1 mRNA half-life was only marginally longer in ras-transformed fibroblasts than in the nontransformed cells, and this difference would contribute minimally to protein overexpression. These findings indicate that IRF-1 deregulation in RS485 cells occurs primarily at the transcriptional level.
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PMID:Mechanisms of deregulation of IFN regulatory factor-1 in ras-transformed fibroblasts. 1602 87

Arabidopsis plants possess a family of nine AtAtg8 gene homologues of the yeast autophagy-associated Apg8/Aut7 gene. To gain insight into how these genes function in plants, first, the expression patterns of five AtAtg8 homologues were analysed in young Arabidopsis plants grown under favourable growth conditions or following exposure to prolonged darkness or sugar starvation. Promoters, plus the entire coding regions (exons and introns) of the AtAtg8 genes, were fused to the beta-glucuronidase reporter gene and transformed into Arabidopsis plants. In all plants, grown under favourable growth conditions, beta-glucuronidase staining was much more significant in roots than in shoots. Different genes showed distinct spatial and temporal expression patterns in roots. In some transgenic plants, beta-glucuronidase staining in leaves was induced by prolonged darkness or sugar starvation. Next, Arabidopsis plants were transformed with chimeric gene-encoding Atg8f protein fused to N-terminal green fluorescent protein and C-terminal haemagglutinin epitope tags. Analysis of these plants showed that, under favourable growth conditions, the Atg8f protein is efficiently processed and is localized to autophagosome-resembling structures, both in the cytosol and in the central vacuole, in a similar manner to its processing and localization under starvation stresses. Moreover, treatment with a cocktail of proteasome inhibitors did not prevent the turnover of this protein, implying that its turnover takes place in the vacuoles, as occurs in yeasts. The results suggest that, in plants, the cellular processes involving the Atg8 genes function efficiently in young, non-senescing tissues, both under favourable growth conditions and under starvation stresses.
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PMID:The autophagy-associated Atg8 gene family operates both under favourable growth conditions and under starvation stresses in Arabidopsis plants. 1615 55

Autophagy is a bulk degradation system within cells through which cytoplasmic components are degraded within lysosomes. Primary roles of autophagy are starvation adaptation and intracellular protein quality control. In contrast to the ubiquitin-proteasome system, autophagy can also degrade organelles. Here we examined a possible role of autophagy in organelle degradation during lens and erythroid differentiation. We observed that autophagy occurs in embryonic lens cells. However, organelle degradation in lens and erythroid cells occurred normally in autophagy-deficient Atg5(-/-) mice. Our data suggest that degradation system(s) other than autophagy play major roles in organelle degradation during these processes.
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PMID:Organelle degradation during the lens and erythroid differentiation is independent of autophagy. 1630 Jul 32

Protein quality-control, especially the removal of proteins with aberrant structures, has an important role in maintaining the homeostasis of non-dividing neural cells. In addition to the ubiquitin-proteasome system, emerging evidence points to the importance of autophagy--the bulk protein degradation pathway involved in starvation-induced and constitutive protein turnover--in the protein quality-control process. However, little is known about the precise roles of autophagy in neurons. Here we report that loss of Atg7 (autophagy-related 7), a gene essential for autophagy, leads to neurodegeneration. We found that mice lacking Atg7 specifically in the central nervous system showed behavioural defects, including abnormal limb-clasping reflexes and a reduction in coordinated movement, and died within 28 weeks of birth. Atg7 deficiency caused massive neuronal loss in the cerebral and cerebellar cortices. Notably, polyubiquitinated proteins accumulated in autophagy-deficient neurons as inclusion bodies, which increased in size and number with ageing. There was, however, no obvious alteration in proteasome function. Our results indicate that autophagy is essential for the survival of neural cells, and that impairment of autophagy is implicated in the pathogenesis of neurodegenerative disorders involving ubiquitin-containing inclusion bodies.
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PMID:Loss of autophagy in the central nervous system causes neurodegeneration in mice. 2086 78

There is increased evidence for the importance of autophagy as a membrane trafficking mechanism that delivers cytoplasmic constituents into the lysosome/vacuole for bulk protein degradation. In this review, we introduce the in vivo role of autophagy in mammals. Recently, we generated conditional-knockout mice of Atg7, an essential gene for autophagy in yeast. Atg7 disruption resulted in impairment of starvation-induced protein degradation in the adult liver, and Atg7-null mice died within 1 day after birth, associated with low concentrations of plasma amino acids as well as the other autophagy-essential gene, Atg5. Furthermore, loss of Atg7 led to pleiotropic defects, in particular, accumulation of abnormal organelles and ubiquitin-positive inclusions without obvious failure of proteasome function. These results indicate the important role of autophagy in starvation response and the quality control of proteins and organelles in quiescent cells.
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PMID:[Autophagic-lysosomal system: physiology and pathology]. 1672 64

Mammals survive starvation by activating proteolysis and lipolysis in many different tissues. These responses are triggered, at least in part, by changing hormonal and neural statuses during starvation. Pathways of proteolysis that are activated during starvation are surprisingly diverse, depending on tissue type and duration of starvation. The ubiquitin-proteasome system is primarily responsible for increased skeletal muscle protein breakdown during starvation. However, in most other tissues, lysosomal pathways of proteolysis are stimulated during fasting. Short-term starvation activates macroautophagy, whereas long-term starvation activates chaperone-mediated autophagy. Lipolysis also increases in response to starvation, and the breakdown of triacylglycerols provides free fatty acids to be used as an energy source by skeletal muscle and other tissues. In addition, glycerol released from triacylglycerols can be converted to glucose by hepatic gluconeogenesis. During long-term starvation, oxidation of free fatty acids by the liver leads to the production of ketone bodies that can be used for energy by skeletal muscle and brain. Tissues that cannot use ketone bodies for energy respond to these small molecules by activating chaperone-mediated autophagy. This is one form of interaction between proteolytic and lipolytic responses to starvation.
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PMID:Proteolytic and lipolytic responses to starvation. 1681 97

Misfolded proteins can be directed into cytoplasmic aggregates such as aggresomes and dendritic cell aggresome-like induced structures (DALIS). DALIS were originally identified in lipopolysaccharide-stimulated dendritic cells and act as storage compartments for polyubiquitinated Defective Ribosomal Products (DRiPs) prior to their clearance by the proteasome. Here we demonstrate that ubiquitinated protein aggregates that are similar to DALIS, and not related to aggresomes, can be observed in several cell types in response to stress, including oxidative stress, transfection, and starvation. Significantly, both immune and nonimmune cells could form these aggresome-like induced structures (ALIS). Protein synthesis was essential for ALIS formation in response to oxidative stress, indicating that DRiP formation was required. Furthermore, puromycin, which increases DRiP formation, was sufficient to induce ALIS formation. Inhibition of either proteasomes or of autophagy interfered with ALIS clearance in puromycin treated cells. Autophagy inhibition enhanced ALIS formation under a variety of stress conditions. During starvation, ALIS formation in autophagy-deficient cells was only partially inhibited by protein synthesis inhibitors, indicating that both long-lived proteins and DRiPs can be targeted to ALIS. Together, these findings demonstrate that ALIS act as generalized stress-induced protein storage compartments for substrates of the proteasome and autophagy.
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PMID:ALIS are stress-induced protein storage compartments for substrates of the proteasome and autophagy. 1687 9

Valosin-containing protein (VCP; p97; cdc48 in yeast) is a hexameric ATPase of the AAA family (ATPases with multiple cellular activities) involved in multiple cellular functions, including degradation of proteins by the ubiquitin (Ub)-proteasome system (UPS). We examined the consequences of the reduction of VCP levels after RNA interference (RNAi) of VCP. A new stringent method of microarray analysis demonstrated that only four transcripts were nonspecifically affected by RNAi, whereas approximately 30 transcripts were affected in response to reduced VCP levels in a sequence-independent manner. These transcripts encoded proteins involved in endoplasmic reticulum (ER) stress, apoptosis, and amino acid starvation. RNAi of VCP promoted the unfolded protein response, without eliciting a cytosolic stress response. RNAi of VCP inhibited the degradation of R-GFP (green fluorescent protein) and Ub-(G76V)-GFP, two cytoplasmic reporter proteins degraded by the UPS, and of alpha chain of the T-cell receptor, an established substrate of the ER-associated degradation (ERAD) pathway. Surprisingly, RNAi of VCP had no detectable effect on the degradation of two other ERAD substrates, alpha1-antitrypsin and deltaCD3. These results indicate that VCP is required for maintenance of normal ER structure and function and mediates the degradation of some proteins via the UPS, but is dispensable for the UPS-dependent degradation of some ERAD substrates.
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PMID:Valosin-containing protein (p97) is a regulator of endoplasmic reticulum stress and of the degradation of N-end rule and ubiquitin-fusion degradation pathway substrates in mammalian cells. 1691 19

SHP-2 phosphatase forms a stable protein complex with and is heavily tyrosine-phosphorylated by the oncogenic tyrosine kinase Bcr-Abl. However, the role of SHP-2 in Bcr-Abl-mediated leukemogenesis is unclear. In the present report, we provide evidence that SHP-2 is required for hematopoietic cell transformation by Bcr-Abl. In vitro biological effects of Bcr-Abl transduction were diminished in SHP-2Delta/Delta hematopoietic cells, and the leukemic potential of Bcr-Abl-transduced SHP-2Delta/Delta cells in recipient animals was compromised. Further analyses showed that Bcr-Abl protein (p210) was degraded, and its oncogenic signaling was greatly decreased in SHP-2Delta/Delta cells. Treatment with proteasome inhibitors or reintroduction of SHP-2 restored p210 level in Bcr-Abl-transduced SHP-2Delta/Delta cells. Subsequent investigation revealed that SHP-2 interacted with heat shock protein 90, an important chaperone protein protecting p210 from proteasome-mediated degradation. The role of SHP-2 in the stability of p210 is independent of its catalytic activity. Blockade of SHP-2 expression in p210-expressing cells by antisense or small-interfering RNA approaches decreased p210 level, causing cell death. Inhibition of SHP-2 enzymatic activity by overexpression of catalytically inactive SHP-2 mutant did not destabilize p210 but enhanced serum starvation-induced apoptosis, suggesting that SHP-2 also plays an important role in downstream signaling of p210 kinase. These studies identified a novel function of SHP-2 and suggest that SHP-2 might be a useful target for controlling Bcr-Abl-positive leukemias.
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PMID:SHP-2 phosphatase is required for hematopoietic cell transformation by Bcr-Abl. 1700 74

Severe or chronic disease can lead to cachexia which involves weight loss and muscle wasting. Cancer cachexia contributes significantly to disease morbidity and mortality. Multiple studies have shown that the metabolic changes that occur with cancer cachexia are unique compared to that of starvation. Specifically, cancer patients seem to lose a larger proportion of skeletal muscle mass. There are three pathways that contribute to muscle protein degradation: the lysosomal system, cytosolic proteases and the ubiquitin (Ub)-proteasome pathway. The Ub-proteasome pathway seems to account for the majority of skeletal muscle degradation in cancer cachexia and is stimulated by several cytokines including tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, interferon-gamma and proteolysis-inducing factor. Cachexia is particularly severe in pancreatic cancer and contributes significantly to the quality of life and mortality of these patients. Several factors contribute to weight loss in these patients, including alimentary obstruction, pain, depression, side effects of therapy and a high catabolic state. Although no single agent has proven to halt cachexia in these patients there has been some progress in the areas of nutrition with supplementation and pharmacological agents such as megesterol acetate, steroids and experimental trials targeting cytokines that stimulate the Ub-proteasome pathway.
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PMID:Mechanisms of skeletal muscle degradation and its therapy in cancer cachexia. 1745 54


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