Growth factors regulate cell survival by controlling nutrient transporter expression

2005 ◽  
Vol 33 (1) ◽  
pp. 225-227 ◽  
Author(s):  
A.L. Edinger
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Cell Survival ◽  
Mammalian Cells ◽  
Mammalian Target Of Rapamycin ◽  
Chemotherapeutic Agents ◽  
Tumour Suppressor ◽  
Nutrient Transporters ◽  
Nutrient Transporter ◽  
Transporter Expression

Growth factors provide permission signals that allow mammalian cells to grow, proliferate and survive. One mechanism by which growth factors maintain this control is through the regulation of cell surface nutrient transporter expression. Following growth factor withdrawal, nutrient transporters are endocytosed and degraded in the lysosome, effectively terminating the cell's ability to obtain nutrients. This results in a state of pseudostarvation in which cells atrophy and initiate a catabolic metabolic programme in the midst of abundant extracellular nutrients. Oncogenic forms of Akt can support growth factor-independent nutrient transporter expression through a mechanism that depends upon mTOR (mammalian target of rapamycin). The ability of activated Akt to support nutrient transporter expression is an essential component of its prosurvival function. When the destruction of nutrient transporters is inhibited, cells are capable of long-term growth-factor-independent cell survival in the absence of receptor-dependent signal transduction. These results imply that proteins involved in nutrient transporter turnover in response to growth factor withdrawal are components of a novel tumour suppressor pathway. Preliminary data suggest that Rab7, a GTPase required for transporter degradation, functions as a tumour suppressor protein, as inhibiting Rab7 activity promotes colony formation in soft agar. These studies indicate that drugs affecting this pathway might have utility as anti-cancer chemotherapeutic agents.

Apoptosis in the haemopoietic system

1994 ◽  
Vol 345 (1313) ◽  
pp. 257-263 ◽  
Keyword(s):  
Stem Cells ◽  
Growth Factors ◽  
Growth Factor ◽  
Cell Survival ◽  
Lineage Differentiation ◽  
Haemopoietic Stem Cells ◽  
Underlying Causes ◽  
Membrane Bound ◽  
Survival Signals

Our previous studies have shown that haemopoietic stem cells undergo apoptotic death as a consequence of growth factor withdrawal. In this paper we review the new data that has accumulated since this observation and compare it with older data from the ‘pre-apoptotic’ age. Models of erythropoiesis and granulopoiesis that incorporate apoptosis as a normal physiological process controlling homeostasis are examined. The converse to cell death is cell survival, and we describe experiments which suggest that haemopoietic growth factors can not only act as mitogenic or differentiation stimuli but also act as survival signals. We, and others, have proposed that these growth factor-induced survival signals act through the membrane bound polypeptide receptors and share common features of signal transduction with proliferative responses. Enforced expression of bcl-2 in haemopoietic stem cells is able to overcome apoptosis following the withdrawal of growth factor, and the cells commit into different lineage differentiation programmes. Such cells spontaneously differentiate without cell division, suggesting a stochastic model of haemopoiesis in which the major role of haemopoietic growth factors is to suppress apoptosis and act as mitogens. We review the evidence that the underlying causes of some haematological diseases may be associated with change in the balance between cell survival and death.

scholarly journals Cytokine Stimulation Promotes Glucose Uptake via Phosphatidylinositol-3 Kinase/Akt Regulation of Glut1 Activity and Trafficking

2007 ◽  
Vol 18 (4) ◽  
pp. 1437-1446 ◽  
Author(s):  
Heather L. Wieman ◽  
Jessica A. Wofford ◽  
Jeffrey C. Rathmell
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Glycogen Synthase ◽  
Mammalian Target Of Rapamycin ◽  
Phosphatidylinositol 3 Kinase ◽  
Akt Activation ◽  
Cytokine Stimulation ◽  
Phosphatidylinositol 3

Cells require growth factors to support glucose metabolism for survival and growth. It is unclear, however, how noninsulin growth factors may regulate glucose uptake and glucose transporters. We show that the hematopoietic growth factor interleukin (IL)3, maintained the glucose transporter Glut1 on the cell surface and promoted Rab11a-dependent recycling of intracellular Glut1. IL3 required phosphatidylinositol-3 kinase activity to regulate Glut1 trafficking, and activated Akt was sufficient to maintain glucose uptake and surface Glut1 in the absence of IL3. To determine how Akt may regulate Glut1, we analyzed the role of Akt activation of mammalian target of rapamycin (mTOR)/regulatory associated protein of mTOR (RAPTOR) and inhibition of glycogen synthase kinase (GSK)3. Although Akt did not require mTOR/RAPTOR to maintain surface Glut1 levels, inhibition of mTOR/RAPTOR by rapamycin greatly diminished glucose uptake, suggesting Akt-stimulated mTOR/RAPTOR may promote Glut1 transporter activity. In contrast, inhibition of GSK3 did not affect Glut1 internalization but nevertheless maintained surface Glut1 levels in IL3-deprived cells, possibly via enhanced recycling of internalized Glut1. In addition, Akt attenuated Glut1 internalization through a GSK3-independent mechanism. These data demonstrate that intracellular trafficking of Glut1 is a regulated component of growth factor-stimulated glucose uptake and that Akt can promote Glut1 activity and recycling as well as prevent Glut1 internalization.

scholarly journals Dual Control of Muscle Cell Survival by Distinct Growth Factor-Regulated Signaling Pathways

2000 ◽  
Vol 20 (9) ◽  
pp. 3256-3265 ◽  
Author(s):  
Margaret A. Lawlor ◽  
Xiuhong Feng ◽  
Daniel R. Everding ◽  
Kerry Sieger ◽  
Claire E. H. Stewart ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Cell Survival ◽  
Signaling Pathways ◽  
Muscle Cell ◽  
Transient Transfection ◽  
Pi3 Kinase ◽  
Signal Transduction Pathways ◽  
Apoptotic Death ◽  
Igf I

ABSTRACT In addition to their ability to stimulate cell proliferation, polypeptide growth factors are able to maintain cell survival under conditions that otherwise lead to apoptotic death. Growth factors control cell viability through regulation of critical intracellular signal transduction pathways. We previously characterized C2 muscle cell lines that lacked endogenous expression of insulin-like growth factor II (IGF-II). These cells did not differentiate but underwent apoptotic death in low-serum differentiation medium. Death could be prevented by IGF analogues that activated the IGF-I receptor or by unrelated growth factors such as platelet-derived growth factor BB (PDGF-BB). Here we analyze the signaling pathways involved in growth factor-mediated myoblast survival. PDGF treatment caused sustained activation of extracellular-regulated kinases 1 and 2 (ERK1 and -2), while IGF-I only transiently induced these enzymes. Transient transfection of a constitutively active Mek1, a specific upstream activator of ERKs, maintained myoblast viability in the absence of growth factors, while inhibition of Mek1 by the drug UO126 blocked PDGF-mediated but not IGF-stimulated survival. Although both growth factors activated phosphatidylinositol 3-kinase (PI3-kinase) to similar extents, only IGF-I treatment led to sustained stimulation of its downstream kinase, Akt. Transient transfection of a constitutively active PI3-kinase or an inducible Akt promoted myoblast viability in the absence of growth factors, while inhibition of PI3-kinase activity by the drug LY294002 selectively blocked IGF- but not PDGF-mediated muscle cell survival. In aggregate, these observations demonstrate that distinct growth factor-regulated signaling pathways independently control myoblast survival. Since IGF action also stimulates muscle differentiation, these results suggest a means to regulate myogenesis through selective manipulation of different signal transduction pathways.

Oligodendrocytes and their precursors require phosphatidylinositol 3-kinase signaling for survival

Development ◽  
1996 ◽  
Vol 122 (8) ◽  
pp. 2529-2537
Author(s):  
G.S. Vemuri ◽  
F.A. McMorris
Keyword(s):  
Cell Death ◽  
Enzyme Activity ◽  
Growth Factors ◽  
Growth Factor ◽  
Cell Survival ◽  
Nuclear Dna ◽  
Apoptotic Cell ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

Signal transduction in response to several growth factors that regulate oligodendrocyte development and survival involves the activation of phosphatidylinositol 3-kinase, which we detect in oligodendrocytes and their precursors. To investigate the role of this enzyme activity, we analyzed cell survival in cultures of oligodendrocytes treated with wortmannin or LY294002, two potent inhibitors of phosphatidylinositol 3-kinase. Cell survival was inhibited by 60–70% in these cultures within 24 hours, as quantitated by a tetrazolium staining assay for viable cells and by measurement of DNA content. Similar results were obtained with oligodendrocyte precursor cells. Nuclei of the dying cells contained fragmented DNA, as revealed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling assays, indicating that the cells were dying by apoptosis. Moreover, a significant increase in the number of cells with fragmented nuclear DNA was detected as early as 4 hours, well before any significant differences could be detected in glucose transport or cell viability. Exogenous addition of insulin-like growth factor-I, neurotrophin-3, platelet-derived growth factor, basic fibroblast growth factor, ciliary neurotrophic factor, N-acetyl cysteine, vitamin C, vitamin E, progesterone or serum did not prevent cell death in the presence of wortmannin or LY294002. These findings indicate that survival of oligodendrocytes and their precursors depends on a phosphatidylinositol 3-kinase mediated signaling pathway. Inhibition of this critical enzyme activity induces apoptotic cell death, even in the presence of exogenous growth factors or serum.

Muscle cell survival mediated by the transcriptional coactivators p300 and PCAF displays different requirements for acetyltransferase activity

2006 ◽  
Vol 291 (4) ◽  
pp. C699-C709 ◽  
Author(s):  
David Kuninger ◽  
Alistair Wright ◽  
Peter Rotwein
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Cell Survival ◽  
Muscle Development ◽  
Acetyltransferase Activity ◽  
Skeletal Myoblasts ◽  
Transcriptional Coactivators ◽  
Peptide Growth Factors ◽  
Promote Cell Survival ◽  
Conditioned Culture Medium

Normal skeletal muscle development requires the proper orchestration of genetic programs by myogenic regulatory factors (MRFs). The actions of the MRF protein MyoD are enhanced by the transcriptional coactivators p300 and the p300/CBP-associated factor (PCAF). We previously described C2 skeletal myoblasts lacking expression of insulin-like growth factor-II (IGF-II) that underwent progressive apoptotic death when incubated in differentiation-promoting medium. Viability of these cells was sustained by addition of IGF analogs or unrelated peptide growth factors. We now show that p300 or PCAF maintains myoblast viability as effectively as added growth factors through mechanisms requiring the acetyltransferase activity of PCAF but not of p300. The actions of p300 to promote cell survival were not secondary to increased expression of known MyoD targets, as evidenced by results of gene microarray experiments, but rather appeared to be mediated by induction of other genes, including fibroblast growth factor-1 (FGF-1). Conditioned culture medium from cells expressing p300 increased myoblast viability, and this was blocked by pharmacological inhibition of FGF receptors. Our results define a role for p300 in promoting cell survival, which is independent of its acetyltransferase activity and acts at least in part through FGF-1.

mTOR Activation Is Necessary for Primary AML Cells to Survive Genotoxic Stress.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 91-91 ◽  
Author(s):  
Qing Xu ◽  
J. Thompson ◽  
Martin Carroll
Keyword(s):  
Stem Cells ◽  
Cell Survival ◽  
Topoisomerase Ii ◽  
Mammalian Target Of Rapamycin ◽  
Genotoxic Stress ◽  
Chemotherapeutic Agents ◽  
Pi3 Kinase ◽  
Leukemic Cells ◽  
Vitro Assay

Abstract The signaling pathways that regulate the survival of AML cells and whether those pathways can be targeted therapeutically are still poorly defined. We have previously demonstrated that AML cells require PI3 kinase activation for survival but clinical targeting of PI3 kinase itself is not currently feasible. Therefore, we have chosen to study the role of the mammalian target of rapamycin or mTOR protein in the survival of leukemic cells. mTOR mediates the effects of PI3 kinase and can be inhibited by the immunosuppressant, rapamycin. For these studies, patient samples were collected from patients seen at the Hospital of the University of Pennsylvania and we selected samples with greater than 75% blast cells for analysis. Here we show that mTOR is activated in over 90% of patient samples examined as shown by constitutive phosphorylation of the mTOR target protein, p70 S6 kinase (p70S6K). A second substrate, 4EBP1, is phosphorylated in the majority of AML samples but less consistently than p70S6K. Inhibition of mTOR with rapamycin caused only a modest 20% decrease in cell survival based on a 48 hour in vitro assay. Strikingly, however, when AML blasts were incubated with a combination of a topoisomerase II inhibitor, etoposide, and rapamycin, the dose response to etoposide was shifted to the left with the ED50 decreased by at least one log in each of 5 tested samples. Rapamycin inhibited mTOR as shown by inhibition of p70S6K phosphorylation and this inhibition was not altered in the presence of etoposide. To determine if combinations of rapamycin and etoposide would have combined effects on leukemic stem cells, AML cells were incubated in etoposide alone or etoposide with rapamycin for 16 hours and then transplanted into NOD/SCID mice for analysis of stem cell survival. Engraftment of AML cells into NOD/SCID animals was decreased by etoposide and this inhibition was increased by the combination of etoposide and rapamycin. These studies suggest that mTOR regulates a critical cell survival pathway in AML stem cells and this pathway is necessary for survival in the presence of a distinct apoptotic signal. Furthermore, these studies suggest that combinations of rapamycin with chemotherapy may enhance the efficacy of chemotherapeutic agents in the treatment of AML and, therefore, we have recently initiated a Phase I trial of rapamycin in combination with MEC chemotherapy for the treatment of relapsed AML.

scholarly journals Evaluating Metabolic Regulation of Human Erythropoiesis By Profiling Nutrient Transporter Expression

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 342-342
Author(s):  
David Justus ◽  
Hongxia Yan ◽  
John Hale ◽  
Lionel Blanc ◽  
Floriane Bitaudeau ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Surface ◽  
Metabolic Regulation ◽  
Erythroid Differentiation ◽  
Erythroid Cell ◽  
Nutrient Transporters ◽  
Hematopoietic Stem ◽  
Nutrient Transporter ◽  
Novel Scaffold ◽  
Transporter Expression

Recent studies have documented that cell metabolism regulates hematopoietic stem cell (HSC) renewal and lineage commitment. However, the detailed metabolic changes that occur during human erythropoiesis remain to be defined. As erythroid cell differentiation is likely to be associated with changes in metabolic requirements, we hypothesized that progenitors adapt to these metabolic modulations by altering their nutrient transporter expression profile. Using an in vitro erythroid-inducing cell culture system employing CD34+ cells from human bone marrow and peripheral blood as well as primary erythroid cells isolated from fresh bone marrow samples, we assessed the cell surface nutrient transporter profiles of progenitors at different stages of erythroid development. Quantification of cell surface nutrient transporter expression was performed using a novel scaffold of retroviral envelope receptor binding domains (RBDs) that function as specific ligands of solute carrier (SLC) nutrient transporters. This bank allowed an evaluation of diverse metabolite transporters including GLUT1/SLC2A1 glucose transporter, the PiT1/SLC20A1 and PiT2/SLC20A2 phosphate importers, the XPR1/SLC53A1 phosphate exporter, the FLVCR1 heme exporter, the RFVT1/2 (SLC52A1/SLC52A2) riboflavin importers, the CAT1/SLC7A1 arginine importer, the ASCT2/SLC1A5 glutamine transporter and the SMVT/SLC5A6 sodium-dependent multivitamin transporter. Notably, the cell surface expression profiles of these nutrient transporters, as evaluated by flow cytometry, revealed marked changes as a function of the stage of erythroid differentiation, as shown in the figure below. Specifically, while FLVCR1, RFVT1/2, and SMVT are highly expressed on erythroid progenitors, the levels of these transporters decrease starting at the proerythroblast stage. In addition, PiT1, PiT2, XPR1, and CAT1 are expressed highly during the erythroid colony forming unit (CFU-E) stage while GLUT1 gradually increases and reaches a peak at late stages of erythroid differentiation, remaining elevated on mature red cells. The noted distinct changes in transporter expression are likely a reflection of the changing demands of various nutrients during human erythropoiesis. In summary, we have established a comprehensive metabolite transporter profile at distinct stages of normal human erythropoiesis using a novel experimental strategy. These original findings form a strong foundation for future studies aiming at elucidating the metabolic requirements of normal erythropoiesis, evaluating diseases affecting red blood cell maturation due to aberrant metabolic regulation, and for identifying new therapeutic targets. Figure Disclosures Bitaudeau: Metafora-biosystems: Employment. Petit:Metafora-biosystems: Equity Ownership, Other: CEO and co-founder. Sitbon:Metafora-biosystems: Membership on an entity's Board of Directors or advisory committees, Other: Co-founder.

Starvation in the midst of plenty: making sense of ceramide-induced autophagy by analysing nutrient transporter expression

2009 ◽  
Vol 37 (1) ◽  
pp. 253-258 ◽  
Author(s):  
Aimee L. Edinger
Keyword(s):  
Heat Stress ◽  
Mammalian Cells ◽  
Cellular Response ◽  
Lethal Dose ◽  
Culture Conditions ◽  
Making Sense ◽  
Nutrient Transporter ◽  
Increased Sensitivity ◽  
Methyl Pyruvate ◽  
Transporter Expression

Ceramide induces differentiation, proliferative arrest, senescence and death in mammalian cells. The mechanism by which ceramide produces these outcomes has proved difficult to define. Building on observations that ceramide stimulates autophagy, we have identified a novel mechanism of action for this sphingolipid: ceramide starves cells to death subsequent to profound nutrient transporter down-regulation. In yeast, ceramide generated in response to heat stress adaptively slows cell growth by down-regulating nutrient permeases. In mammalian cells, a lethal dose of ceramide triggers a bioenergetic crisis by so severely limiting cellular access to extracellular nutrients that autophagy is insufficient to meet the metabolic demands of the cell. In keeping with this bioenergetic explanation for ceramide toxicity, methyl pyruvate, a membrane-permeable nutrient, protects cells from ceramide-induced starvation. Also consistent with this model, we have found that the metabolic state of the cell determines its sensitivity to ceramide. Thus the increased sensitivity of cancer cells to ceramide may relate to their inflexible biosynthetic metabolic programme. These studies highlight the value of assessing nutrient transporter expression in autophagic cells and the important role that culture conditions play in determining the cellular response to ceramide.

scholarly journals Insulin-Like Growth Factor-Mediated Muscle Cell Survival: Central Roles for Akt and Cyclin-Dependent Kinase Inhibitor p21

2000 ◽  
Vol 20 (23) ◽  
pp. 8983-8995 ◽  
Author(s):  
Margaret A. Lawlor ◽  
Peter Rotwein
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Cell Viability ◽  
Cell Survival ◽  
Muscle Cell ◽  
Kinase Inhibitor ◽  
Insulin Like Growth Factor ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Igf I

ABSTRACT Polypeptide growth factors activate specific transmembrane receptors, leading to the induction of multiple intracellular signal transduction pathways which control cell function and fate. Recent studies have shown that growth factors promote cell survival by stimulating the serine-threonine protein kinase Akt, which appears to function primarily as an antiapoptotic agent by inactivating death-promoting molecules. We previously established C2 muscle cell lines lacking endogenous expression of insulin-like growth factor II (IGF-II). These cells underwent apoptotic death in low-serum differentiation medium but could be maintained as viable myoblasts by IGF analogues that activated the IGF-I receptor or by unrelated growth factors such as platelet-derived growth factor BB (PDGF-BB). Here we show that IGF-I promotes muscle cell survival through Akt-mediated induction of the cyclin-dependent kinase inhibitor p21. Treatment of myoblasts with IGF-I or transfection with an inducible Akt maintained muscle cell survival and enhanced production of p21, and ectopic expression of p21 was able to sustain viability in the absence of growth factors. Blocking of p21 protein accumulation through a specific p21 antisense cDNA prevented survival regulated by IGF-I or Akt but did not block muscle cell viability mediated by PDGF-BB. Our results define Akt as an intermediate and p21 as a critical effector of an IGF-controlled myoblast survival pathway that is active during early myogenic differentiation and show that growth factors are able to maintain cell viability by inducing expression of pro-survival molecules.

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