scholarly journals Glucose-Regulated Protein 94 (GRP94): A Novel Regulator of Insulin-Like Growth Factor Production

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1844 ◽  
Author(s):  
Yair Argon ◽  
Sophie E. Bresson ◽  
Michal T. Marzec ◽  
Adda Grimberg
Keyword(s):  
Gene Expression ◽  
Metabolic Diseases ◽  
Somatic Growth ◽  
Cellular Responses ◽  
Chaperone Protein ◽  
Igf I ◽  
Growth Factor Production ◽  
Novel Target ◽  
Glucose Regulated Protein ◽  
Insulin Like Growth Factors

Mammals have two insulin-like growth factors (IGF) that are key mediators of somatic growth, tissue differentiation, and cellular responses to stress. Thus, the mechanisms that regulate the bioavailability of IGFs are important in both normal and aberrant development. IGF-I levels are primarily controlled via the growth hormone-IGF axis, in response to nutritional status, and also reflect metabolic diseases and cancer. One mechanism that controls IGF bioavailablity is the binding of circulating IGF to a number of binding proteins that keep IGF in a stable, but receptor non-binding state. However, even before IGF is released from the cells that produce it, it undergoes an obligatory association with a ubiquitous chaperone protein, GRP94. This binding is required for secretion of a properly folded, mature IGF. This chapter reviews the known aspects of the interaction and highlights the specificity issues yet to be determined. The IGF–GRP94 interaction provides a potential novel mechanism of idiopathic short stature, involving the obligatory chaperone and not just IGF gene expression. It also provides a novel target for cancer treatment, as GRP94 activity can be either inhibited or enhanced.

scholarly journals Glucose-Regulated Protein 94 (GRP94): A Novel Regulator of Insulin-Like Growth Factor Production

2020 ◽  
Author(s):  
Yair Argon ◽  
Sophie E. Bresson ◽  
Michal T. Marzec ◽  
Adda Grimberg
Keyword(s):  
Gene Expression ◽  
Metabolic Diseases ◽  
Somatic Growth ◽  
Cellular Responses ◽  
Chaperone Protein ◽  
Igf I ◽  
Growth Factor Production ◽  
Novel Target ◽  
Glucose Regulated Protein ◽  
Insulin Like Growth Factors

Mammals have two insulin-like growth factors (IGF) that are key mediators of somatic growth, of tissue differentiation and cellular responses to stress. Thus, the mechanisms that regulate the bioavailability of IGFs are important in both normal and aberrant development. IGF-I levels are primarily controlled via the growth hormone-IGF axis, in response to nutritional status, and also reflect metabolic diseases and cancer. One mechanism that controls IGF bioavailablity is the binding of circulating IGF to a number of binding proteins that keep IGF in a stable, but receptor non-binding state. But even before IGF is released from the cells that produce it, it undergoes an obligatory association with a ubiquitous chaperone protein, GRP94. This binding is required for secretion of a properly folded, mature IGF. This chapter reviews the known aspects of the interaction and highlights the specificity issues yet to be determined. The IGF-GRP94 interaction provides a potential novel mechanism of idiopathic short stature, involving the obligatory chaperone and not just IGF gene expression. It also provides a novel target for cancer treatment, as GRP94 activity can be either inhibited or enhanced.

scholarly journals Identifying growth hormone-regulated enhancers in the Igf1 locus

2015 ◽  
Vol 47 (11) ◽  
pp. 559-568 ◽  
Author(s):  
Damir Alzhanov ◽  
Aditi Mukherjee ◽  
Peter Rotwein
Keyword(s):  
Gene Expression ◽  
Growth Hormone ◽  
Gene Transcription ◽  
Somatic Growth ◽  
Gene Promoters ◽  
Chromosomal Locus ◽  
Transcriptional Enhancers ◽  
Physiological Processes ◽  
Igf I ◽  
I Gene

Growth hormone (GH) plays a central role in regulating somatic growth and in controlling multiple physiological processes in humans and other vertebrates. A key agent in many GH actions is the secreted peptide, IGF-I. As established previously, GH stimulates IGF-I gene expression via the Stat5b transcription factor, leading to production of IGF-I mRNAs and proteins. However, the precise mechanisms by which GH-activated Stat5b promotes IGF-I gene transcription have not been defined. Unlike other GH-regulated genes, there are no Stat5b sites near either of the two IGF-I gene promoters. Although dispersed GH-activated Stat5b binding elements have been mapped in rodent Igf1 gene chromatin, it is unknown how these distal sites might function as potential transcriptional enhancers. Here we have addressed mechanisms of regulation of IGF-I gene transcription by GH by generating cell lines in which the rat Igf1 chromosomal locus has been incorporated into the mouse genome. Using these cells we find that physiological levels of GH rapidly and potently activate Igf1 gene transcription while stimulating physical interactions in chromatin between inducible Stat5b-binding elements and the Igf1 promoters. We have thus developed a robust experimental platform for elucidating how dispersed transcriptional enhancers control Igf1 gene expression under different biological conditions.

scholarly journals Differential expression of growth and immunity related genes influenced by in ovo supplementation of amino acids in broiler chickens

2014 ◽  
Vol 59 (No. 9) ◽  
pp. 399-408 ◽  
Author(s):  
S.K. Bhanja ◽  
M. Sudhagar ◽  
A. Goel ◽  
N. Pandey ◽  
M. Mehra ◽  
...  
Keyword(s):  
Gene Expression ◽  
Amino Acids ◽  
Growth Hormone ◽  
Broiler Chickens ◽  
In Ovo ◽  
Immune Genes ◽  
Mucin Gene ◽  
Igf I ◽  
Insulin Like Growth Factors

The present study was aimed at investigating the role of in ovo administered amino acids: lysine, arginine, threonine or methionine plus cysteine (Met+Cys) in 14-day embryos on expression profile of growth (chicken growth hormone (cGH), insulin like growth factors (IGF) I and II, and mucin) and immunity related genes (IL-2, IL-4, IL-6, IL-12, TNF-α, and IFN-γ). On incubation day (ID) 18, higher (P < 0.01) cGH and mucin gene expression was observed in lysine, threonine, arginine or Met+Cys injected embryos, while IGF-II expression was higher in threonine, arginine or Met+Cys injected embryos on ID 20. Expression of growth genes was down regulated (P < 0.01) on day of hatch in most of the amino acids injected chicks. On day 7 post-hatch (PH), threonine or arginine exhibited higher expression of cGH, IGF-I, and IGF-II but higher mucin gene expression only on day 14 PH. Threonine or Met+Cys injected birds had higher expression of IL-6 and TNF-α, while arginine injected birds had higher TNF-α expression. Lysine, threonine or Met+Cys injected birds had higher IL-2, but lower of IL-12 and IFN-γ gene expression. It is concluded that arginine and threonine enhanced the expression of growth related genes, while threonine and Met+Cys modulated expression of immune genes in broiler chickens.  

scholarly journals Proliferation precedes differentiation in IGF-I-stimulated myogenesis.

1996 ◽  
Vol 135 (2) ◽  
pp. 431-440 ◽  
Author(s):  
J C Engert ◽  
E B Berglund ◽  
N Rosenthal
Keyword(s):  
Gene Expression ◽  
Time Course ◽  
Myogenic Differentiation ◽  
Transcript Accumulation ◽  
Proliferation And Differentiation ◽  
Igf I ◽  
Subsequent Activation ◽  
Myogenic Factors ◽  
Stimulation Of ◽  
Insulin Like Growth Factors

The insulin-like growth factors (IGFs) have dramatic and complex effects on the growth of many tissues and have been implicated in both the proliferation and differentiation of skeletal muscle cells. A detailed analysis of gene expression was performed in L6E9 myoblast cultures treated with IGF-I to dissect the early events leading to the stimulation of myogenic differentiation by this growth factor. A time course of transcript accumulation in confluent L6E9 myoblasts treated with defined media containing IGF-I revealed an initial transient decrease in myogenic factors, accompanied by an increase in cell cycle markers and cell proliferation. This pattern was reversed at later time points, when the subsequent activation of myogenic factors resulted in a net increase in structural gene expression and larger myotubes. The data presented here support the hypothesis that IGF-I activates proliferation first, and subsequently stimulates events leading to the expression of muscle-specific genes in myogenic cell cultures.

scholarly journals Altered chicken thyroid hormone metabolism with chronic GH enhancement in vivo: consequences for skeletal muscle growth

2000 ◽  
Vol 166 (3) ◽  
pp. 609-620 ◽  
Author(s):  
R Vasilatos-Younken ◽  
Y Zhou ◽  
X Wang ◽  
JP McMurtry ◽  
RW Rosebrough ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Body Weight ◽  
Thyroid Hormone ◽  
Muscle Growth ◽  
Somatic Growth ◽  
Hormone Metabolism ◽  
Thyroid Hormone Metabolism ◽  
Igf I ◽  
Dose Dependent

In contrast to most vertebrates, GH reportedly has no effect upon somatic growth of the chicken. However, previous studies employed only one to two dosages of the hormone, and limited evidence exists of a hyperthyroid response that may confound its anabolic potential. This study evaluated the effects of 0, 10, 50, 100 and 200 microgram/kg body weight per day chicken GH (cGH) (0-200 GH) infused i.v. for 7 days in a pulsatile pattern to immature, growing broiler chickens (9-10 birds/dosage). Comprehensive profiles of thyroid hormone metabolism and measures of somatic growth were obtained. Overall (average) body weight gain was reduced 25% by GH, with a curvilinear, dose-dependent decrease in skeletal (breast) muscle mass that was maximal (12%) at 100 GH. This profile mirrored GH dose-dependent decreases in hepatic type III deiodinase (DIII) activity and increases in plasma tri-iodothyronine (T(3)), with bot! h also maximal (74 and 108% respectively) at 100 GH. No effect on type I deiodinase was observed. At the maximally effective dosage, hepatic DIII gene expression was reduced 44% versus controls. Despite dose-dependent, fold-increases in hepatic IGF-I protein content, circulating IGF-I was not altered with GH infusion, suggesting impairment of hepatic IGF-I release. Significant, GH dose-dependent increases in plasma non-esterified fatty acid and glucose, and overall decreases in triacylglycerides were also observed. At 200 GH, feed intake was significantly reduced (19%; P<0.05) versus controls; however, additional control birds pair-fed to this level did not exhibit any responses observed for GH-treated birds. The results of this study support a pathway by which GH impacts on thyroid hormone metabolism beginning at a pretranslational level, with reduced hepatic DIII gene expression, translating to reduced protein (enzyme) ex! pression, and reflected in a reduced level of peripheral T(3)-degrading activity. This contributes to decreased conversion of T(3) to its inactive form, thereby elevating circulating T(3) levels. The hyper-T(3) state leads to reduced net skeletal muscle deposition, and may impair release of GH-enhanced, hepatic IGF-I. In conclusion, GH has significant biological effects in the chicken, but profound metabolic actions predominate that may confound positive, IGF-I-mediated skeletal muscle growth.

Gene therapy vector-mediated expression of insulin-like growth factors protects cardiomyocytes from apoptosis and enhances neovascularization

2003 ◽  
Vol 284 (4) ◽  
pp. H1429-H1440 ◽  
Author(s):  
E. J. Su ◽  
C. L. Cioffi ◽  
S. Stefansson ◽  
N. Mittereder ◽  
M. Garay ◽  
...  
Keyword(s):  
Growth Factors ◽  
Cellular Responses ◽  
Adenoviral Vectors ◽  
Single Chain ◽  
Gene Therapy Vector ◽  
Polypeptide Growth Factors ◽  
Igf I ◽  
Robust Response ◽  
Insulin Like Growth Factors

IGF-I and IGF-II are single-chain polypeptide growth factors that regulate pleiotropic cellular responses. We have characterized the effect of recombinant IGF proteins, as well as third-generation adenoviral vectors encoding either IGF-I or IGF-II genes, on cardiomyocyte apoptosis and on angiogenesis. We found that endothelial cells cultured in the presence of the extracellular protein laminin exhibit a robust response to IGF-I and -II proteins via enhanced cell migration and angiogenic outgrowth. Furthermore, IGF vectors greatly enhanced neovascularization in an in vivo Matrigel model. Transduction of cardiomyocytes with the IGF adenoviral vectors resulted in a dose- and time-dependent increase in the expression of IGF-I or IGF-II protein. This correlated with abrogation of apoptosis induced by ischemia-reoxygenation, ceramide, or heat shock with optimal inhibition of ∼80%. We conclude that gene transfer of IGF-I and IGF-II is a plausible strategy for the local delivery of IGFs to treat ischemic heart disease and heart failure by stimulating angiogenesis and protecting cardiomyocytes from cell death.

Induction of renal kallikrein and renin gene expression by insulin and IGF-I in the diabetic rat

Diabetes ◽  
1997 ◽  
Vol 46 (12) ◽  
pp. 2049-2056 ◽  
Author(s):  
A. A. Jaffa ◽  
C. Vio ◽  
V. Velarde ◽  
D. LeRoith ◽  
R. K. Mayfield
Keyword(s):  
Gene Expression ◽  
Diabetic Rat ◽  
Renin Gene ◽  
Igf I ◽  
Renal Kallikrein

tiRNAs & tRFs Biogenesis and Regulation of Diseases: A Review

2019 ◽  
Vol 26 (31) ◽  
pp. 5849-5861 ◽  
Author(s):  
Pan Jiang ◽  
Feng Yan
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Metabolic Diseases ◽  
Viral Infections ◽  
Regulatory Mechanisms ◽  
Biological Functions ◽  
Reverse Transcriptases ◽  
Dna Damage Responses ◽  
Potential Applications ◽  
Viral Reverse Transcriptases

tiRNAs & tRFs are a class of small molecular noncoding tRNA derived from precise processing of mature or precursor tRNAs. Most tiRNAs & tRFs described originate from nucleus-encoded tRNAs, and only a few tiRNAs and tRFs have been reported. They have been suggested to play important roles in inhibiting protein synthesis, regulating gene expression, priming viral reverse transcriptases, and the modulation of DNA damage responses. However, the regulatory mechanisms and potential function of tiRNAs & tRFs remain poorly understood. This review aims to describe tiRNAs & tRFs, including their structure, biological functions and subcellular localization. The regulatory roles of tiRNAs & tRFs in translation, neurodegeneration, metabolic diseases, viral infections, and carcinogenesis are also discussed in detail. Finally, the potential applications of these noncoding tRNAs as biomarkers and gene regulators in different diseases is also highlighted.

scholarly journals CircFAM13B promotes the proliferation of hepatocellular carcinoma by sponging miR-212, upregulating E2F5 expression and activating the P53 pathway

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ying Xie ◽  
Xiaofeng Hang ◽  
Wensheng Xu ◽  
Jing Gu ◽  
Yuanjing Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Gene Expression Omnibus ◽  
Differentially Expressed ◽  
In Vivo Studies ◽  
Circular Rnas ◽  
Novel Target ◽  
Underlying Mechanisms

Abstract Background Most of the biological functions of circular RNAs (circRNAs) and the potential underlying mechanisms in hepatocellular carcinoma (HCC) have not yet been discovered. Methods In this study, using circRNA expression data from HCC tumor tissues and adjacent tissues from the Gene Expression Omnibus database, we identified out differentially expressed circRNAs and verified them by qRT-PCT. Functional experiments were performed to evaluate the effects of circFAM13B in HCC in vitro and in vivo. Results We found that circFAM13B was the most significantly differentially expressed circRNA in HCC tissue. Subsequently, in vitro and in vivo studies also demonstrated that circFAM13B promoted the proliferation of HCC. Further studies revealed that circFAM13B, a sponge of miR-212, is involved in the regulation of E2F5 gene expression by competitively binding to miR-212, inhibits the activation of the P53 signalling pathway, and promotes the proliferation of HCC cells. Conclusions Our findings revealed the mechanism underlying the regulatory role played by circFAM13B, miR-212 and E2F5 in HCC. This study provides a new theoretical basis and novel target for the clinical prevention and treatment of HCC.

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