Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

G-protein coupled receptor (GPCR) agonists such as neuropeptides activate the insulin-like growth factor-1 receptor (IGF-IR) or the serine-threonine protein kinase Akt, suggesting that neuropeptides-GPCR signaling can cross-communicate with IGF-IR-Akt signaling pathways. Neutral endopeptidase 24.11 (NEP) is a cell-surface peptidase that cleaves and inactivates the neuropeptides endothelin-1 (ET-1) and bombesin, which are implicated in progression to androgen-independent prostate cancer (PC). We investigated the mechanisms of NEP regulation of neuropeptide-mediated cell survival in PC cells, including whether neuropeptide substrates of NEP induce phosphorylations of IGF-IR and Akt in PC cells. Western analyses revealed ET-1 and bombesin treatment induced phosphorylation of IGF-IRbeta and Akt independent of IGF-I in TSU-Pr1, DU145, and PC-3 PC cells, which lack NEP expression, but not in NEP-expressing LNCaP cells. Recombinant NEP and induced NEP expression in TSU-Pr1 cells using a tetracycline-repressive expression system inhibited ET-1-mediated phosphorylation of IGF-IRbeta and Akt, and blocked the protective effects of ET-1 against apoptosis induced by serum starvation. Incubation of TSU-Pr1 cells with specific kinase inhibitors together with ET-1 or bombesin showed that IGF-IR activation is required for neuropeptide-induced Akt phosphorylation, and that neuropeptide-induced Akt activation is predominantly mediated by Src and phosphatidylinositol 3-kinase but not by mitogen-activated protein kinase or protein kinase C. These data show that the neuropeptides ET-1 and bombesin stimulate ligand-independent activation of the IGF-IR, which results in Akt activation, and that this cross-communication between GPCR and IGF-IR signaling is inhibited by NEP.
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PMID:Neutral endopeptidase inhibits neuropeptide-mediated transactivation of the insulin-like growth factor receptor-Akt cell survival pathway. 1130 83

Insulin inhibits the expression of the hepatic insulin-like growth factor-binding protein-1 (IGFBP-1) and glucose-6-phosphatase (G6Pase) genes. The signaling pathway that mediates these events requires the activation of phosphatidylinositol 3-kinase, whereas transfection studies have suggested an involvement of Akt (protein kinase B) and FKHR, a transcription factor regulated by Akt. We now demonstrate that insulin repression of endogenous IGFBP-1 gene transcription was blocked by rapamycin or by amino acid starvation. Rapamycin inhibited the mammalian target of rapamycin (mTOR) and the subsequent activation of p70/p85 S6 protein kinase-1 (S6K1) by insulin, whereas amino acid depletion prevented insulin induction of these signaling molecules. Importantly, we demonstrate that insulin regulation of the thymine-rich insulin response element of the IGFBP-1 promoter was also inhibited by rapamycin. However, sustained activation of S6K1 did not repress this promoter. In addition, rapamycin did not affect insulin regulation of G6Pase expression or Akt activation. We propose that these observations indicate that an mTOR-dependent, but S6K-independent mechanism regulates the suppression of IGFBP-1 (but not G6Pase) gene expression by insulin. Therefore, although the insulin-responsive sequence of the G6Pase gene promoter is related to that of the IGFBP-1 promoter, the signaling pathways that mediate suppression of these genes are distinct.
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PMID:Insulin regulation of insulin-like growth factor-binding protein-1 gene expression is dependent on the mammalian target of rapamycin, but independent of ribosomal S6 kinase activity. 1178 21

Recent studies implicate similar proteins in the regulation of longevity in organisms ranging from yeast to mice. Studies in yeast and worms suggest that inactivation of glucose or insulin/insulin-like growth factor-l (IGF-1) signaling pathways extends longevity by causing a shift from a reproductive phase to a non-reproductive maintenance phase involving the expression of many genes. These stress resistance pathways appear to have evolved to induce maintenance systems and promote longevity during periods of starvation. In yeast, mutations that decrease the activity of glucose signaling pathways extend longevity by activating stress resistance transcription factors that regulate the expression of genes involved in antioxidant and heat protection, glycogen storage, protein degradation, DNA repair, and metabolism. A remarkably similar set of proteins regulated by growth factors that control glucose metabolism is implicated in life span extension in worms, and possibly in flies and mice. Studies in worms and flies point to secondary hormones as mediators of the effect of insulin/ IGF-1 signaling on longevity, whereas studies in yeast and mammalian cells indicate that glucose or insulin/ IGF-1 may decrease longevity by directly down-regulating stress resistance genes. In yeast, longevity mutations postpone superoxide toxicity and mitochondrial damage. However, the small life span extension caused by the overexpression of superoxide dismutases and catalase in yeast and flies indicates that increased antioxidant protection alone cannot be responsible for the major life span extension caused by signal transduction mutations. Although we are only beginning to understand the molecular mechanisms that mediate life span extension, the similarities between longevity regulatory pathways in organisms ranging from yeast to mice suggest that insulin/ IGF-1 signaling pathways may also regulate cell damage and longevity in humans.
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PMID:Regulation of longevity and stress resistance: a molecular strategy conserved from yeast to humans? 1216 20

The present study characterizes the relationships between severe malnutrition, sleep, growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis, and leptin levels in anorexia nervosa (AN) patients before and after weight gain. Eleven restricting-type anorectic females (mean age = 19.7 years) with severe starvation state [mean body mass index (BMI) = 13.3] were studied using polysomnography and spectral power analysis. The hormone levels were measured in the morning after sleep recording. Eleven normal-weight, age- and gender-matched healthy volunteers without a history of any eating disorder served as controls. After nutritional treatment for about 2 months (65.7 +/- 6.4 days), sleep examinations and blood tests were repeated. At this stage, the study group consisted of 5 patients (mean BMI = 15.6). Higher IGF-1 and leptin levels were associated with longer and deeper sleep among anorectics. The sleep parameters including the percentages of stage 1 sleep and SWS as well as IGF-1 tended to normalize after only limited weight gain. Sleep disturbances in anorectics may be mediated through changes in the levels of the GH-IGF-1 axis hormones, as well as the levels of leptin.
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PMID:Growth hormone-insulin-like growth factor-1 axis, leptin and sleep in anorexia nervosa patients. 1270 89

Members of the JNK pathway are organized together by virtue of interactions with JNK interacting protein 1 (JIP1), a scaffold protein. Here we have investigated the possibility that JIP1 may also affect the catalytic activity of Akt1, a serine/threonine kinase that has been implicated in multiple cellular processes, including survival and proliferation. JIP1 expression enhanced Akt1 kinase activity in a dose-dependent manner following serum starvation in 293 cells. Cellular activation of Akt1 following stimulation with low concentrations of insulin-like growth factor (IGF-1) was elevated in the presence of JIP1. JIP1 expression also prolonged Akt1 stimulation after a short IGF-1 pulse. The mechanism of JIP1-mediated Akt1 activation involved JIP1 protein binding to the Akt1 pleckstrin homology domain, which in turn promoted the phosphorylation of the activation T-loop of Akt1 by phosphoinositide-dependent kinase-1. These results suggest that, in certain cellular contexts, JIP1 may act as an Akt1 scaffold, which regulates the enzymatic activity of Akt1. This study also indicates that JIP1 expression can exert signaling effects independent of JNK activity.
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PMID:JNK-interacting protein 1 promotes Akt1 activation. 1278 73

Malnutrition, muscle wasting and cachexia are often present in chronic heart failure (CHF). However, malnutrition in CHF patients is not always as severe as muscle wasting. Data in the literature show that 24% of CHF patients have malnutrition (albumin < 3.5 mg/dl) but 68% have muscle atrophy. This apparent discrepancy can be explained by considering the metabolic role of the striate muscle. In fact, the striate muscle maintains the body metabolic performance by continuous exchanges of fuels (amino acids) with the liver. This happens in case of malnutrition or starvation. In such situations, glucose is produced by gluconeogenesis when amino acids are metabolized in the liver. Malnutrition, muscle wasting and the frequent progression through cachexia can be reduced by specific therapy such as cytokine and/or catabolic hormone antagonists. This is because cytokines and catabolic hormones, with consequent insulin resistance, cause muscle wasting. An alternative and/or complementary therapy may be exogenous amino acid supplementation. In fact, amino acids: a) are rapidly absorbed regardless of pancreatic activity, b) reduce insulin resistance, c) induce the hepatic synthesis of anabolic molecules such as growth hormone and insulin-like growth factor, and d) modulate the catabolic hormonal-mediated effects on adipocytes. Research on the best suitable qualitative and quantitative amino acid composition for an alternative and/or complementary therapy is still being studied in different research centers.
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PMID:Malnutrition, muscle wasting and cachexia in chronic heart failure: the nutritional approach. 1278 75

The insulin-like growth factor axis is highly responsive to nutritional status and may be involved as one of the underlying mechanisms through which caloric restriction could affect cancer risk. High levels of circulating insulin-like growth factor (IGF)-I, or IGF-I relative to IGF binding protein (IGFBP)-3 have been related to various human cancer types. In a group of 87 postmenopausal women, we found that childhood exposure to the 1944-1945 Dutch famine was associated with increased plasma levels of IGF-I and IGFBP-3, whereas IGFBP-1 and -2 levels were weakly decreased. These results are opposite to immediate responses seen under starvation and we hypothesize that this could indicate a permanent overshoot upon improvement of nutritional status after the famine.
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PMID:Long term consequences of the 1944-1945 Dutch famine on the insulin-like growth factor axis. 1469 31

Estrogens such as 17-beta estradiol (E(2)) play a critical role in sporadic breast cancer progression and decrease apoptosis in breast cancer cells. Our studies using estrogen receptor-positive MCF7 cells show that E(2) abrogates apoptosis possibly through phosphorylation/inactivation of the proapoptotic protein BAD, which was rapidly phosphorylated at S112 and S136. Inhibition of BAD protein expression with specific antisense oligonucleotides reduced the effectiveness of tumor necrosis factor-alpha, H(2)O(2), and serum starvation in causing apoptosis. Furthermore, the ability of E(2) to prevent tumor necrosis factor-alpha-induced apoptosis was blocked by overexpression of the BAD S112A/S136A mutant but not the wild-type BAD. BAD S112A/S136A, which lacks phosphorylation sites for p90(RSK1) and Akt, was not phosphorylated in response to E(2) in vitro(.) E(2) treatment rapidly activated phosphatidylinositol 3-kinase (PI-3K)/Akt and p90(RSK1) to an extent similar to insulin-like growth factor-1 treatment. In agreement with p90(RSK1) activation, E(2) also rapidly activated extracellular signal-regulated kinase, and this activity was down-regulated by chemical and biological inhibition of PI-3K suggestive of cross talk between signaling pathways responding to E(2). Dominant negative Ras blocked E(2)-induced BAD phosphorylation and the Raf-activator RasV12T35S induced BAD phosphorylation as well as enhanced E(2)-induced phosphorylation at S112. Chemical inhibition of PI-3K and mitogen-activated protein kinase kinase 1 inhibited E(2)-induced BAD phosphorylation at S112 and S136 and expression of dominant negative Ras-induced apoptosis in proliferating cells. Together, these data demonstrate a new nongenomic mechanism by which E(2) prevents apoptosis.
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PMID:Estradiol abrogates apoptosis in breast cancer cells through inactivation of BAD: Ras-dependent nongenomic pathways requiring signaling through ERK and Akt. 1512 78

The insulin/insulin-like growth factor-like signaling pathway, present in all multicellular organisms, regulates diverse functions including growth, development, fecundity, metabolic homeostasis, and lifespan. In flies, ligands of the insulin/insulin-like growth factor-like signaling pathway, the Drosophila insulin-like peptides, regulate growth and hemolymph carbohydrate homeostasis during development and are expressed in a stage- and tissue-specific manner. Here, we show that ablation of Drosophila insulin-like peptide-producing median neurosecretory cells in the brain leads to increased fasting glucose levels in the hemolymph of adults similar to that found in diabetic mammals. They also exhibit increased storage of lipid and carbohydrate, reduced fecundity, and reduced tolerance of heat and cold. However, the ablated flies show an extension of median and maximal lifespan and increased resistance to oxidative stress and starvation.
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PMID:Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands. 1570 81

Leptin is an adipocyte-secreted hormone that plays a key part in energy homoeostasis. Advances in leptin physiology have established that the main role of this hormone is to signal energy availability in energy-deficient states. Studies in animals and human beings have shown that low concentrations of leptin are fully or partly responsible for starvation-induced changes in neuroendocrine axes, including low reproductive, thyroid, and insulin-like growth factor (IGF) hormones. Disease states such as exercise-induced hypothalamic amenorrhoea and anorexia nervosa are also associated with low concentrations of leptin and a similar spectrum of neuroendocrine abnormalities. We have recently shown in an interventional, proof-of-concept study that leptin can restore ovulatory menstrual cycles and improve reproductive, thyroid, and IGF hormones and bone markers in hypothalamic amenorrhoea. Further studies are warranted to establish the safety and effectiveness of leptin for the infertility and osteoporosis associated with hypothalamic amenorrhoea, and to clarify its role in anorexia nervosa.
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PMID:Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa. 1599 36


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