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)

A new strategy in anticancer gene therapy uses stress-responsive cellular promoters that offer the advantage of enhanced gene expression in a variety of tumors. Although the feasibility of their selective expression has been demonstrated, functional evidence of their ability to activate therapeutic agents within the tumor environment leading to tumor eradication has not been established. Glucose deprivation, chronic anoxia, and acidic pH known to persist in poorly vascularized solid tumors strongly induce the transcription of the glucose-regulated protein 78 (grp78) gene, which encodes an Mr 78,000 stress-inducible protein. In this report, we tested directly the efficacy of the grp78 promoter in a retroviral system to drive the expression of the herpes simplex virus-thymidine kinase (HSVtk) suicide gene, using a murine fibrosarcoma model, in the context of their syngeneic, immunocompetent hosts. Our results showed that under glucose starvation conditions, the expression of HSVTK was enhanced in tumor cells where the HSVtk gene was driven by the internal grp78 promoter, in contrast to the Moloney murine leukemia virus long terminal repeat, where suppression was observed. We further demonstrated that in vivo, HSVTK expression was elevated to much higher levels inside tumors when driven by the internal grp78 promoter, resulting in complete eradication of sizable tumor mass, with no recurrence of tumor growth. Our study suggests that the glucose starvation-inducible grp78 promoter could be useful for enhanced expression of a variety of therapeutic agents within the solid tumor environment.
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PMID:Use of the glucose starvation-inducible glucose-regulated protein 78 promoter in suicide gene therapy of murine fibrosarcoma. 1039 51

Upon deprivation of nutrients, Dictyostelium discoideum Ax-2 cells arrest proliferation and initiate a metamorphosed developmental program including induction of altered gene expressions which are necessary for differentiation. In Ax-2 cells, we found out a member of Hsp90 family usually contained in the endoplasmic reticulum (ER), Dd-GRP94 (Dictyostelium discoideum glucose-regulated protein 94). In general, GRP94 are induced either by glucose-depletion or by depletion of Ca(2+) in intracellular Ca(2+) stores. Unexpectedly, however, the expression of Dd-grp94 was greatly reduced within 60 min of starvation. Dd-grp94-overexpressing cells (GRP94(OE) cells) collected without forming distinct aggregation streams, and never formed normal fruiting bodies. Also, prespore differentiation as well as maturation into spores and stalk cells were particularly impaired in the GRP94(OE) cells. Thus Dd-GRP94 seems to be crucial in late differentiation as well as in starvation response.
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PMID:Involvement of the glucose-regulated protein 94 (Dd-GRP94) in starvation response of Dictyostelium discoideum cells. 1091 38

Induction of glucose-regulated proteins (GRPs) is a ubiquitous intracellular response to stresses such as hypoxia, glucose starvation and acidosis. The induction of GRPs offers some protection against these stresses in vitro, but the specific role of GRPs in vivo remains unclear. Hibernating bats present a good in vivo model to address this question. The bats must overcome local high oxygen demand in tissue by severe metabolic stress during arousal thermogenesis. We used brain tissue of a temperate bat Rhinolopus ferrumequinum to investigate GRP induction by high metabolic oxygen demand and to identify associated signaling molecules. We found that during 30 min of arousal, oxygen consumption increased from nearly zero to 11.9/kg/h, which was about 8.7-fold higher than its active resting metabolic rate. During this time, body temperature rose from 7 degrees C to 35 degrees C, and levels of TNF-alpha and lactate in brain tissue increased 2-2.5-fold, indicating a high risk of oxygen shortage. Concomitantly, levels of GRP75, GRP78 and GRP94 increased 1.5-1.7-fold. At the same time, c-Jun N-terminal protein kinase (JNK) activity increased 6.4-fold, and extracellular signal-regulated protein kinase (ERK) activity decreased to a similar degree (6.1-fold). p38 MAPK activity was very low and remained unchanged during arousal. In addition, survival signaling molecules protein kinase B (Akt) and protein kinase C (PKC) were activated 3- and 5-fold, respectively, during arousal. Taken together, our results showed that bat brain undergoes high oxygen demand during arousal from hibernation. Up-regulation of GRP proteins and activation of JNK, PKCgamma and Akt may be critical for neuroprotection and the survival of bats during the repeated process.
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PMID:Activation of stress signaling molecules in bat brain during arousal from hibernation. 1235 92

BiP is a molecular chaperone induced in the unfolded protein response (UPR). In mammalian cells, BiP is induced by glucose starvation when it is called glucose-regulated protein 78 (GRP78). In Arabidopsis thaliana, however, we demonstrated that BiP transcripts decreased with sugar depletion and increased with sugar addition. Transcripts for beta-glucuronidase (GUS) driven by BiP promoter respond to tunicamycin and sugar, being similar with endogenous BiP transcripts in transgenic A. thaliana. When GUS was regulated by P-UPRE, a cis-element responsible for the UPR identified in BiP promoter, GUS transcripts were accumulated by sugar starvation. Subsequently, transgenic A. thaliana harboring luciferase (LUC) gene regulated by P-UPRE was analyzed. Sugar depletion also increased LUC activity. It is concluded that BiP is induced by sugar independent of the cis-element responsible for the UPR.
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PMID:Induction of BiP by sugar independent of a cis-element for the unfolded protein response in Arabidopsis thaliana. 1678 68

The recent development of hormonal therapy that blocks estrogen synthesis represents a major advance in the treatment of estrogen receptor-positive breast cancer. However, cancer cells often acquire adaptations resulting in resistance. A recent report reveals that estrogen starvation-induced apoptosis of breast cancer cells requires BIK, an apoptotic BH3-only protein located primarily at the endoplasmic reticulum (ER). Searching for novel partners that interact with BIK at the ER, we discovered that BIK selectively forms complex with the glucose-regulated protein GRP78/BiP, a major ER chaperone with prosurvival properties naturally induced in the tumor microenvironment. GRP78 overexpression decreases apoptosis of 293T cells induced by ER-targeted BIK. For estrogen-dependent MCF-7/BUS breast cancer cells, overexpression of GRP78 inhibits estrogen starvation-induced BAX activation, mitochondrial permeability transition, and consequent apoptosis. Further, knockdown of endogenous GRP78 by small interfering RNA (siRNA) sensitizes MCF-7/BUS cells to estrogen starvation-induced apoptosis. This effect was substantially reduced when the expression of BIK was also reduced by siRNA. Our results provide the first evidence that GRP78 confers resistance to estrogen starvation-induced apoptosis in human breast cancer cells via a novel mechanism mediated by BIK. These results further suggest that GRP78 expression level in the tumor cells may serve as a prognostic marker for responsiveness to hormonal therapy based on estrogen starvation and that combination therapy targeting GRP78 may enhance efficacy and reduce resistance.
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PMID:GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis. 1744 86

The aim of this study was to optimize a protocol that allows identifying changes at the phosphorylation level of specific proteins in response to cell stimulation by leucine starvation. To make possible the identification of differentially phosphorylated proteins by the combination of two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), we prepared fraction enriched in phosphoproteins. For that purpose, we adapted the immobilized metal affinity chromatography (IMAC) technique to make it compatible with 2D-PAGE. On the whole, this procedure allowed identifying regulated targets of leucine deprivation: molecular chaperones glucose-regulated protein 58 kDa (GRP58) and BiP (GRP78), RNA helicase DEAD box polypeptide 3, and eukaryotic translation initiation factor 4B (eIF4B).
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PMID:Phospho-proteomic approach to identify new targets of leucine deprivation in muscle cells. 1861 11

The involvement of unfolded protein response (UPR) activation in tumor survival and resistance to chemotherapies suggests a new anticancer strategy targeting UPR pathway. Arctigenin, a natural product, has been recently identified for its antitumor activity with selective toxicity against cancer cells under glucose starvation with unknown mechanism. Here we found that arctigenin specifically blocks the transcriptional induction of two potential anticancer targets, namely glucose-regulated protein-78 (GRP78) and its analog GRP94, under glucose deprivation, but not by tunicamycin. The activation of other UPR pathways, e.g., XBP-1 and ATF4, by glucose deprivation was also suppressed by arctigenin. A further transgene experiment showed that ectopic expression of GRP78 at least partially rescued arctigenin/glucose starvation-mediated cell growth inhibition, suggesting the causal role of UPR suppression in arctigenin-mediated cytotoxicity under glucose starvation. These observations bring a new insight into the mechanism of action of arctigenin and may lead to the design of new anticancer therapeutics.
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PMID:Arctigenin suppresses unfolded protein response and sensitizes glucose deprivation-mediated cytotoxicity of cancer cells. 2071 70

Pro-survival signalling mediated by the androgen receptor (AR) is implicated as a key contributor to prostate carcinogenesis. As prostate tumours are characterized by nutrient-poor, hypoxic and acidified microenvironments, one mechanism whereby AR signalling may contribute to survival is by promoting adaptation to cellular stress. Here we have identified a novel role for AR in the inhibition of autophagy induced by serum withdrawal. This blockade is attributed to AR-mediated upregulation of the endoplasmic reticulum (ER) chaperone glucose-regulated protein 78/BiP (Grp78/BiP), and occurs independently of ER stress response pathway activation. Interestingly, AR activation did not affect serum starvation-induced mammalian target of rapamycin inhibition, illustrating that the adaptive role for androgens lies not in the ability to modulate nutrient sensing, but in the promotion of ER stability. Finally, we show that the adaptive advantage conferred by AR-mediated Grp78/BiP upregulation is temporary, as upon chronic serum starvation, AR activation delayed but did not suppress the onset of autophagy and cell death. This study reveals a novel mechanism whereby maintained AR signalling promotes temporary adaptation to cellular stress and in turn may contribute to the evasion of prostate tumour cell death.
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PMID:Androgens modulate autophagy and cell death via regulation of the endoplasmic reticulum chaperone glucose-regulated protein 78/BiP in prostate cancer cells. 2136 76

Despite the established role of insulin-like growth factor binding protein-3 (IGFBP-3) as a growth inhibitor in vitro, a high level of IGFBP-3 in breast tumor tissue is associated with the stimulation of xenograft growth in mice and poor prognosis in patients. To understand the contribution of IGFBP-3 to breast cancer progression, tandem affinity purification was used to identify novel interacting proteins. The endoplasmic reticulum protein, glucose-regulated protein 78 (GRP78), was shown to bind to IGFBP-3, confirmed by colocalization, coimmunoprecipitations, glutathione S-transferase (GST) pulldowns and a nanomolar binding affinity. GST pulldowns also indicated that the GRP78 ATPase domain mediated the interaction with IGFBP-3. The critical roles of GRP78 in the unfolded protein response and macroautophagy led to an investigation of possible links between IGFBP-3, GRP78 and cellular stress responses. IGFBP-3 was found to stimulate the survival of breast cancer cells subjected to glucose starvation and hypoxia. Pharmacological inhibitors and small interfering RNA knockdown established that the increased survival of IGFBP-3-expressing cells was dependent on an intact autophagy response, as well as GRP78. The contribution of autophagy was confirmed by the demonstration that IGFBP-3 expression increases both the formation of autophagic puncta and flux through the system. In conclusion, we have shown that IGFBP-3 stimulates autophagy and thereby promotes the survival of breast cancer cells exposed to conditions that represent the adverse microenvironments encountered by solid tumor cells in vivo.
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PMID:IGFBP-3 binds GRP78, stimulates autophagy and promotes the survival of breast cancer cells exposed to adverse microenvironments. 2275 Nov 33

Gp96 (also known as glucose-regulated protein 94, endoplasmin) is the endoplasmic reticulum (ER)-resident protein, which belongs to the heat shock protein HSP90 family. It is upregulated in response to glucose starvation and other stressful stimuli that disrupt protein synthesis in the ER. There, it is acting as a molecular chaperon involved in the correction of unfolded proteins, in the activation of proteasome-dependent ER-associated degradation of the misfolded proteins, and in activation of protein translations that modulate the polypeptide traffic into the ER. In addition, it has been implicated in antigen presentation and MHC class I and II upregulation, in the activation and maturation of dendritic cells and proinflammatory cytokine secretion, as well as in chaperoning of integrins and Toll-like receptors, acting as a "danger signal" to the innate and adaptive immunity. Moreover, owing to its specific function in Ca2+ homeostasis and in the insulin- IGF/signaling pathways, it has been proposed that gp96 might participate in mechanisms that are critical for cell growth, differentiation, and responses to ER stress. Emphasizing that gp96, as a natural adjuvant for chaperoning antigenic self peptides into the immune surveillance pathways, may also be involved in the maintenance of morphostasis and self tolerance, in this survey we show that high levels of upregulation of gp96 in regenerating liver and thymus are followed by signs of transient autoimmunity, augmented apoptosis in thymus, and the presence of autoreactive NKT and regulatory T cells that might be involved in the control of rapid liver growth induced by partial hepatectomy.
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PMID:Heat shock protein Gp96 as potential regulator of morphostasis after partial hepatectomy in mice. 2338 88


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