scholarly journals Nutrients and growth factors in mTORC1 activation

2013 ◽  
Vol 41 (4) ◽  
pp. 902-905 ◽  
Author(s):  
Alejo Efeyan ◽  
David M. Sabatini
Keyword(s):  
Human Physiology ◽  
Growth Factors ◽  
Growth Factor ◽  
Mouse Model ◽  
Mouse Models ◽  
Mechanistic Target Of Rapamycin ◽  
Rag Gtpases ◽  
Growth Factor Signalling ◽  
Mtorc1 Activation

Growth factors and nutrients regulate the mTORC1 [mammalian (or mechanistic) target of rapamycin complex 1] by different mechanisms. The players that link growth factors and mTORC1 activation have been known for several years and mouse models have validated its relevance for human physiology and disease. In contrast with the picture for growth factor signalling, the means by which nutrient availability leads to mTORC1 activation have remained elusive until recently, with the discovery of the Rag GTPases upstream of mTORC1. The Rag GTPases recruit mTORC1 to the outer lysosomal surface, where growth factor signalling and nutrient signalling converge on mTORC1 activation. A mouse model of constitutive RagA activity has revealed qualitative differences between growth-factor- and nutrient-dependent regulation of mTORC1. Regulation of mTORC1 activity by the Rag GTPases in vivo is key for enduring early neonatal starvation, showing its importance for mammalian physiology.

scholarly journals A spatially regulated GTPase cycle of Rheb controls growth factor signaling to mTORC1

2018 ◽  
Author(s):  
Marija Kovacevic ◽  
Christian H. Klein ◽  
Lisaweta Roßmannek ◽  
Antonios D. Konitsiotis ◽  
Angel Stanoev ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Small Gtpase ◽  
Target Of Rapamycin ◽  
Growth Factor Signaling ◽  
Nucleotide Exchange ◽  
Gtpase Activating Protein ◽  
Mechanistic Target Of Rapamycin ◽  
Gtpase Cycle ◽  
Mtorc1 Activation

ABSTRACTGrowth factors initiate anabolism by activating mechanistic target of rapamycin complex 1 (mTORC1) via the small GTPase Rheb. We show that the GTPase cycle of Rheb is spatially regulated by the interaction with its GDI-like solubilizing factor (GSF) – PDEδ. Arl2-GTP mediated localized release of cytosolic Rheb-GTP from PDEδ deposits it onto perinuclear membranes where it forms a complex with mTORC1. The membrane associated GTPase activating protein (GAP) TSC2 hydrolyzes Rheb-GTP, weakening the interaction with mTOR. Rheb-GDP is readily released into the cytosol where it is maintained soluble by interaction with PDEδ. This solubilized Rheb is re-activated by nucleotide exchange to be re-deposited by Arl2-mediated release onto perinuclear membranes. This spatial GTPase cycle thereby enables mTORC1 activation to be solely controlled by growth factor induced inactivation of TSC2. The coupling between mTOR activation and spatially regulated Rheb nucleotide exchange makes growth factor induced proliferation critically dependent on PDEδ expression.

scholarly journals Growth Factor Therapy for Parkinson’s Disease: Alternative Delivery Systems

2021 ◽  
pp. 1-7
Author(s):  
Sarah Jarrin ◽  
Abrar Hakami ◽  
Ben Newland ◽  
Eilís Dowd
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Growth Factors ◽  
Growth Factor ◽  
Ex Vivo ◽  
Brain Regions ◽  
Delivery Systems ◽  
Alternative Delivery

Despite decades of research and billions in global investment, there remains no preventative or curative treatment for any neurodegenerative condition, including Parkinson’s disease (PD). Arguably, the most promising approach for neuroprotection and neurorestoration in PD is using growth factors which can promote the growth and survival of degenerating neurons. However, although neurotrophin therapy may seem like the ideal approach for neurodegenerative disease, the use of growth factors as drugs presents major challenges because of their protein structure which creates serious hurdles related to accessing the brain and specific targeting of affected brain regions. To address these challenges, several different delivery systems have been developed, and two major approaches—direct infusion of the growth factor protein into the target brain region and in vivo gene therapy—have progressed to clinical trials in patients with PD. In addition to these clinically evaluated approaches, a range of other delivery methods are in various degrees of development, each with their own unique potential. This review will give a short overview of some of these alternative delivery systems, with a focus on ex vivo gene therapy and biomaterial-aided protein and gene delivery, and will provide some perspectives on their potential for clinical development and translation.

scholarly journals Transactivation of the Epidermal Growth Factor Receptor Is Involved in the Lutropin Receptor-Mediated Down-Regulation of Ovarian Aromatase Expression in Vivo

2010 ◽  
Vol 24 (3) ◽  
pp. 552-560 ◽  
Author(s):  
Nebojsa Andric ◽  
Mika Thomas ◽  
Mario Ascoli
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Mouse Models ◽  
Growth Factor Receptor ◽  
Follicular Development ◽  
Down Regulation ◽  
Aromatase Expression ◽  
Epidermal Growth

Abstract Ovarian follicular development and differentiation is characterized by dramatic changes in aromatase (Cyp19a1) expression. In preovulatory follicles, activation of the FSH receptor increases aromatase expression until the surge of LH decreases it. Here we provide in vivo evidence that down-regulation of Cyp19a1 by the LH surge requires efficient signaling through the epidermal growth factor receptor (EGFR). The human chorionic gonadotropin (hCG)-induced down-regulation of Cyp19a1 expression in the two different mouse models with inactivating mutations of the EGFR (wa2 and velvet) is impaired but not abolished. The hCG-induced phosphorylation of ovarian ERK1/2, expression of C/EBPβ, and the phosphorylation of Connexin43 (two downstream targets of ERK1/2 action) are also decreased in these two mouse models. In contrast, disruption of EGFR signaling does not have any affect on the hCG-induced phosphorylation of cAMP response element-binding protein or AKT. This study provides the first in vivo evidence linking the LH receptor, the EGFR, and ERK1/2 as sequential components of a pathway that regulates ovarian Cyp19a1 expression.

scholarly journals PEG grafted chitosan scaffold for dual growth factor delivery for enhanced wound healing

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Amritha Vijayan ◽  
Sabareeswaran A. ◽  
G. S. Vinod Kumar
Keyword(s):  
Wound Healing ◽  
Growth Factors ◽  
Growth Factor ◽  
Treated Group ◽  
Growth Factor Delivery ◽  
Chitosan Scaffold ◽  
Collagen Formation ◽  
Dual Growth Factor Delivery

AbstractApplication of growth factors at wound site has improved the efficiency and quality of healing. Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) induce proliferation of various cells in wound healing. Delivery of growth factor from controlled release systems protect it from degradation and also result in sustained delivery of it at the site of injury. The goal of the study was to develop a Polyethylene glycol (PEG) cross-linked cotton-like chitosan scaffold (CS-PEG-H) by freeze-drying method and chemically conjugate heparin to the scaffold to which the growth factors can be electrostatically bound and evaluate its wound healing properties in vitro and in vivo. The growth factor containing scaffolds induced increased proliferation of HaCaT cells, increased neovascularization and collagen formation seen by H and E and Masson’s trichrome staining. Immunohistochemistry was performed using the Ki67 marker which increased proliferation of cells in growth factor containing scaffold treated group. Frequent dressing changes are a major deterrent to proper wound healing. Our system was found to release both VEGF and bFGF in a continuous manner and attained stability after 7 days. Thus our system can maintain therapeutic levels of growth factor at the wound bed thereby avoiding the need for daily applications and frequent dressing changes. Thus, it can be a promising candidate for wound healing.

scholarly journals 3D bioprinting spatiotemporally defined patterns of growth factors to tightly control tissue regeneration

2020 ◽  
Vol 6 (33) ◽  
pp. eabb5093 ◽  
Author(s):  
Fiona E. Freeman ◽  
Pierluca Pitacco ◽  
Lieke H. A. van Dommelen ◽  
Jessica Nulty ◽  
David C. Browe ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Tissue Regeneration ◽  
Point Of Care ◽  
Release Kinetics ◽  
Spatial Gradient ◽  
Heterotopic Bone ◽  
Heterotopic Bone Formation ◽  
Bone Defect Healing

Therapeutic growth factor delivery typically requires supraphysiological dosages, which can cause undesirable off-target effects. The aim of this study was to 3D bioprint implants containing spatiotemporally defined patterns of growth factors optimized for coupled angiogenesis and osteogenesis. Using nanoparticle functionalized bioinks, it was possible to print implants with distinct growth factor patterns and release profiles spanning from days to weeks. The extent of angiogenesis in vivo depended on the spatial presentation of vascular endothelial growth factor (VEGF). Higher levels of vessel invasion were observed in implants containing a spatial gradient of VEGF compared to those homogenously loaded with the same total amount of protein. Printed implants containing a gradient of VEGF, coupled with spatially defined BMP-2 localization and release kinetics, accelerated large bone defect healing with little heterotopic bone formation. This demonstrates the potential of growth factor printing, a putative point of care therapy, for tightly controlled tissue regeneration.

scholarly journals Growth factors are released by mechanically wounded endothelial cells.

1989 ◽  
Vol 109 (2) ◽  
pp. 811-822 ◽  
Author(s):  
P L McNeil ◽  
L Muthukrishnan ◽  
E Warder ◽  
P A D'Amore
Keyword(s):  
Endothelial Cells ◽  
Plasma Membrane ◽  
Growth Factors ◽  
Growth Factor ◽  
Mechanical Forces ◽  
Fibroblast Growth ◽  
Growth Promoting ◽  
Transient Plasma

Growth factors may be required at sites of mechanical injury and normal wear and tear in vivo, suggesting that the direct action of mechanical forces on cells could lead to growth factor release. Scraping of cells from the tissue culture substratum at 37 degrees C was used to test this possibility. We show that scraping closely mimics in vitro both the transient plasma membrane wounds observed in cells subject to mechanical forces in vivo (McNeil, P. L., and S. Ito. 1989. Gastroenterology. 96:1238-1248) and the transient plasma membrane wounds shown here to occur in endothelial cells under normal culturing conditions. Scraping of endothelial cells from the culturing substratum released into the culture medium a potent growth-promoting activity for Swiss 3T3 fibroblasts. Growth-promoting activity was released rapidly (within 5 min) after scraping but was not subsequently degraded by the endothelial cells for at least 24 h thereafter. A greater quantity of growth-promoting activity was released by cells scraped 4 h after plating than by those scraped 4 or 7 d afterwards. Thus release is not due to scraping-induced disruption of extracellular matrix. Release was only partially cold inhibitable, was poorly correlated with the level of cell death induced by scraping, and did not occur when cells were killed with metabolic poisons. These results suggest that mechanical disruption of plasma membrane, either transient or permanent, is the essential event leading to release. A basic fibroblast growth factor-like molecule and not platelet-derived growth factor appears to be partially responsible for the growth-promoting activity. We conclude that one biologically relevant route of release of basic fibroblast growth factor, a molecule which lacks the signal peptide sequence for transport into the endoplasmic reticulum, could be directly through mechanically induced membrane disruptions of endothelial cells growing in vivo and in vitro.

127 TREATMENTS WITH DIVERSE ENDOCRINE-DISRUPTING CHEMICALS RESULTED IN THE INHIBITION OF OVARIAN TUMOR PROGRESSION VIA INTERRUPTION OF TRANSFORMING GROWTH FACTOR-β IN IN VITRO AND XENOGRAFTED MOUSE MODELS

2014 ◽  
Vol 26 (1) ◽  
pp. 177
Author(s):  
H.-R. Lee ◽  
R.-E. Go ◽  
K.-C. Choi
Keyword(s):  
Ovarian Cancer ◽  
Growth Factor ◽  
Mouse Model ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Mouse Models ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Xenograft Mouse Model

Activated oestrogen receptor (ER) signaling pathway by 17β-estadiol (E2) appeared to suppress transforming growth factor β (TGF-β) signaling pathway by cross-talk with TGF-β components in ER-positive cancer cells. In this study, we further examined the inhibitory effects of alkylphenols, including 4-nonylphenol (NP), 4-otylphenol (OP), bisphenol A (BPA), and benzophenon-1 (BP-1), in TGF-β signaling pathway. The transcriptional and translational levels of TGF-β-related genes were examined by reverse-transcription PCR (RT-PCR), Western blotting analysis in xenografted mouse models of ovarian cancer BG-1 cells. The NP, OP, and BPA induced the expression of snoN, a TGF-β pathway inhibitor. Treatment with NP, BPA, and BP-1 resulted in decreased phosphorylation of Smad3, a downstream target of TGF-β. With these 2 effects, NP and BPA stimulated the proliferation of BG-1 cells via inhibition of the TGF-β signaling pathway. In a xenograft mouse model, transplanted BG-1 ovarian cancer cells showed significantly decreased phosphorylation of Smad3 and increased expression of snoN in the ovarian tumour masses following treatment with E2, NP, or BPA. In parallel with an in vitro model, the expressions of TGF-β signaling pathway were similarly regulated by NP or BPA in a xenograft mouse model, revealing consistent results. Taken together, these results support that NP and BPA may cause the disruption of the TGF-β signaling pathway and increase the risk of oestrogen-dependent cancers such as ovarian cancer. This work was supported by a grant from the Next-Generation BioGreen 21 Program (No. PJ009599), Rural Development Administration, Republic of Korea.

118. CHARACTERISATION OF HEPARAN SULPHATE PROTEOGLYCANS IN THE MATURING CUMULUS OOCYTE COMPLEX

2009 ◽  
Vol 21 (9) ◽  
pp. 37
Author(s):  
L. N. Watson ◽  
M. Sasseville ◽  
R. B. Gilchrist ◽  
D. L. Russell
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Cell Surface ◽  
Transforming Growth Factor ◽  
Heparan Sulphate ◽  
Cumulus Cells ◽  
Receptor Interaction ◽  
Heparan Sulphate Proteoglycans ◽  
Tgfβ Superfamily

Many growth factors including members of the transforming growth factor beta (TGFβ) superfamily and epidermal growth factor (Egf)-like ligands signal via interactions with heparan sulphate proteoglycans (HSPGs). Cell surface HSPGs can act by sequestering ligands at their site of action, by presenting a ligand to its signalling receptor, or by preventing ligand-receptor interaction. The oocyte secreted factors (OSF) growth differentiation factor 9 and bone morphogenetic protein 15 are members of the TGFβ superfamily that act selectively on cumulus cells. Conversely Egf-like ligands are secreted by mural granulosa cells and transmit LH-induced signals to cumulus cells. We investigated the possibility that HSPGs contribute to the spatially restricted responses these signals exert on cumulus cells. Syndecan-1 and Glypican-1 are cell surface HSPGs that are involved in numerous biological processes, including growth factor regulation, cell proliferation and differentiation. Microarray analysis showed Syndecan-1 and Glypican-1 mRNA expression induced 6-fold (P=10-9) and 3-fold (P=10-7) respectively in Egf+FSH stimulated cumulus oocyte complexes (COCs). Furthermore, Syndecan-1 and Glypican-1 mRNA were induced 27- and 16-fold respectively in COCs after hCG treatment of mice. Syndecan-1 and Glypican-1 protein was localised specifically to the COC through immunohistochemical analysis. In Vitro Maturation (IVM) of oocytes is a valuable alternative to gonadotropin mediated superovulation, but IVM COCs are less competent than those matured in vivo. Several components of the COC have been shown to be altered in IVM, including the chondroitin sulphate proteoglycan Versican. COCs from mice that underwent IVM in the presence of Egf+FSH and cilostamide for 16 hours had >16 fold reduced mRNA for Syndecan-1 when compared with In Vivo matured COCs. The lack of Syndecan-1 in IVM COCs could reduce signalling capacity of growth factors including OSFs. This may contribute to the reduced capacity of IVM oocytes to fertilise and produce a healthy embryo, and ultimately, a healthy offspring.

Cracking the mild, difficult and fiendish codes within and downstream of the EGFR to link diagnostics and therapeutics

2007 ◽  
Vol 35 (1) ◽  
pp. 1-6 ◽  
Author(s):  
M. Waterfield
Keyword(s):  
Signal Transduction ◽  
Growth Factors ◽  
Growth Factor ◽  
Signalling Pathways ◽  
Growth Factor Signalling ◽  
Transduction Mechanisms

Over the last 45 years, I have been working on growth factors, their receptors and signal transduction mechanisms. This period has seen a tremendous growth in knowledge and technology, and all of this, together with a focus interest in oncology, has steered me along a path designed to understand growth factor signalling so that we can see how drugs that target signalling pathways might be able to control cancer. The knowledge that we already have is likely to lead to cures for many common cancers within the next 25 years.

Expression of Soluble Syndecan-1 or Heparanase by Myeloma Cells Enhances Levels of Angiogenic Growth Factors Present in Endothelial Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3448-3448
Author(s):  
Yang Yang ◽  
Ashley Elizabeth Frith ◽  
Allison Theus ◽  
Veronica Macleod ◽  
Ralph D. Sanderson
Keyword(s):  
Endothelial Cells ◽  
Growth Factors ◽  
Growth Factor ◽  
Fold Increase ◽  
Conditioned Media ◽  
High Rate ◽  
In Vivo Studies ◽  
Angiogenic Growth Factors ◽  
Myeloma Cells

Abstract Multiple myeloma is a devastating cancer with a high rate of morbidity and mortality. Our previous in vivo studies demonstrate that both shed syndecan-1 and heparanase can promote myeloma tumor growth, metastasis and angiogenesis. To examine the mechanism underlying this enhanced angiogenesis, human umbilical vein endothelial cells (HUVEC) were cocultured with cells of the CAG myeloma cell line (vector-only controls, CAGcontrol) or CAG cells engineered to express high levels of either soluble syndecan-1 ectodomain (CAGssyn1 ) or heparanase ( CAGHPSE ). After coculture for 48 hours, levels of angiogenic growth factors present in the endothelial cells were examined. The goal was to determine if expression of either soluble syndecan-1 or heparanase by CAG myeloma cells altered growth factor levels relative to those present when control CAG cells were used. Co-culture with CAGssyn1 or CAGHPSE cells did not enhance endothelial levels of FGF-2, while levels of hepatoma-derived growth factor (HDGF) and hepatocyte growth factor (HGF) were elevated in endothelia growing in the presence of CAGssyn1 cells but not CAGHPSE cells or CAGcontrol cells. However, VEGF levels present in endothelial cells were substantially enhanced by the presence of CAGssyn1 (1.9-fold increase) or CAGHPSE cells (1.6-fold increase). Surprisingly, levels of VEGF in conditioned media of cocultures containing either CAGssyn1 or CAGHPSE cells was low. In contrast, when cultured in the absence of HUVECs, VEGF levels were elevated in conditioned media of both CAGssyn1and CAGHPSE cells. Addition of this conditioned media containing high levels of VEGF to HUVECs growing in the absence of CAG cells did not result in an elevation of VEGF levels in the endothelial cells. Together, these experiments suggest that VEGF expression is upregulated in CAG cells expressing high levels of shed syndecan-1 or heparanase and that VEGF becomes associated with the endothelial cells only when they are cultured in the presence of the myeloma cells. This cross-talk between myeloma and endothelial cells may lead to the enhanced angiogenesis that occurs in vivo in tumors formed by myeloma cells producing high levels of shed syndecan-1 and/or heparanase.

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