scholarly journals Hypoxia stimulates angiogenesis and a metabolic switch in human parathyroid adenoma cells

2021 ◽  
Author(s):  
K E Lines ◽  
M Stevenson ◽  
R Mihai ◽  
I V Grigorieva ◽  
O A Shariq ◽  
...  
Keyword(s):  
Growth Factor ◽  
Parathyroid Adenoma ◽  
Tumour Cells ◽  
Mitogen Activated Protein Kinase ◽  
Ras Signaling ◽  
Growth Factor Signaling ◽  
Metabolic Switch ◽  
Atp Production ◽  
Parathyroid Autotransplantation ◽  
Hypoxic Conditions

Hypoxia, a primary stimulus for angiogenesis, is important for tumour proliferation and survival. The effects of hypoxia on parathyroid tumour cells, which may also be important for parathyroid autotransplantation in patients, are however, unknown. We therefore assessed the effects of hypoxia on gene expression in parathyroid adenoma (PA) cells from patients with primary hyperparathyroidism. Cell suspensions from human PAs were cultured under normoxic or hypoxic conditions and then subjected to cDNA expression analysis. In total, 549 genes were significantly upregulated and 873 significantly downregulated. The most highly upregulated genes (carbonic andydrase 9 (CA9), solute carrier family 2A1 (SLC2A1) and hypoxia-inducible lipid droplet-associated protein (HIG2)) had known involvement in hypoxia responses. Dysregulation of oxidative phosphorylation and glycolysis pathway genes were also observed, consistent with data indicating that cells shift metabolic strategy of ATP production in hypoxic conditions, and that tumour cells predominantly utilise anaerobic glycolysis for energy production. Proliferation- and angiogenesis-associated genes linked with growth factor signalling such as mitogen-activated protein kinase kinase 1 (MAP2K1), Jun proto-oncogene (JUN) and ETS proto-oncogene 1 (ETS1) were increased, however Ras association domain family member 1 (RASSF1), an inhibitor of proliferation was also upregulated, indicating these pathways are unlikely to be biasing towards proliferation. Overall, there appeared to be a shift in growth factor signaling pathways from Jak-Stat and Ras signaling, to extracellular signal-regulated kinases (ERKs) and hypoxia-inducible factor (HIF)-1α signalling. Thus, our data demonstrate that PAs, under hypoxic conditions, promote expression of genes known to stimulate angiogenesis, as well as undergoing a metabolic switch.

scholarly journals AIB1 Is a Conduit for Kinase-Mediated Growth Factor Signaling to the Estrogen Receptor

2000 ◽  
Vol 20 (14) ◽  
pp. 5041-5047 ◽  
Author(s):  
Jaime Font de Mora ◽  
Myles Brown
Keyword(s):  
Estrogen Receptor ◽  
Growth Factors ◽  
Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Growth Factor Signaling ◽  
Breast Cancers ◽  
Mapk Activation ◽  
Mitogen Activated Protein

ABSTRACT Growth factor modulation of estrogen receptor (ER) activity plays an important role in both normal estrogen physiology and the pathogenesis of breast cancer. Growth factors are known to stimulate the ligand-independent activity of ER through the activation of mitogen-activated protein kinase (MAPK) and the direct phosphorylation of ER. We found that the transcriptional activity of AIB1, a ligand-dependent ER coactivator and a gene amplified preferentially in ER-positive breast cancers, is enhanced by MAPK phosphorylation. We demonstrate that AIB1 is a phosphoprotein in vivo and can be phosphorylated in vitro by MAPK. Finally, we observed that MAPK activation of AIB1 stimulates the recruitment of p300 and associated histone acetyltransferase activity. These results suggest that the ability of growth factors to modulate estrogen action may be mediated through MAPK activation of the nuclear receptor coactivator AIB1.

scholarly journals Ras links growth factor signaling to the cell cycle machinery via regulation of cyclin D1 and the Cdk inhibitor p27KIP1.

1997 ◽  
Vol 17 (7) ◽  
pp. 3850-3857 ◽  
Author(s):  
H Aktas ◽  
H Cai ◽  
G M Cooper
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Constitutive Expression ◽  
Ras Signaling ◽  
Cdk Inhibitor ◽  
Growth Factor Signaling ◽  
Cycle Progression ◽  
Cell Cycle Machinery

Activation of growth factor receptors by ligand binding initiates a cascade of events leading to cell growth and division. Progression through the cell cycle is controlled by cyclin-dependent protein kinases (Cdks), but the mechanisms that link growth factor signaling to the cell cycle machinery have not been established. We report here that Ras proteins play a key role in integrating mitogenic signals with cell cycle progression through G1. Ras is required for cell cycle progression and activation of both Cdk2 and Cdk4 until approximately 2 h before the G1/S transition, corresponding to the restriction point. Analysis of Cdk-cyclin complexes indicates that Ras signaling is required both for induction of cyclin D1 and for downregulation of the Cdk inhibitor p27KIP1. Constitutive expression of cyclin D1 circumvents the requirement for Ras signaling in cell proliferation, indicating that regulation of cyclin D1 is a critical target of the Ras signaling cascade.

scholarly journals Lacrimal gland budding requires PI3K-dependent suppression of EGF signaling

2021 ◽  
Vol 7 (27) ◽  
pp. eabf1068
Author(s):  
Qian Wang ◽  
Chenqi Tao ◽  
Abdul Hannan ◽  
Sungtae Yoon ◽  
Xuanyu Min ◽  
...  
Keyword(s):  
Growth Factor ◽  
Lacrimal Gland ◽  
Cross Talk ◽  
Egf Receptor ◽  
Direct Interaction ◽  
Receptor Expression ◽  
Mitogen Activated Protein Kinase ◽  
Ras Signaling ◽  
The Cross ◽  
Egf Signaling

The patterning of epithelial buds is determined by the underlying signaling network. Here, we study the cross-talk between phosphoinositide 3-kinase (PI3K) and Ras signaling during lacrimal gland budding morphogenesis. Our results show that PI3K is activated by both the p85-mediated insulin-like growth factor (IGF) and Ras-mediated fibroblast growth factor (FGF) signaling. On the other hand, PI3K also promotes extracellular signal–regulated kinase (ERK) signaling via a direct interaction with Ras. Both PI3K and ERK are upstream regulators of mammalian target of rapamycin (mTOR), and, together, they prevent expansion of epidermal growth factor (EGF) receptor expression from the lacrimal gland stalk to the bud region. We further show that this suppression of EGF signaling is necessary for induction of lacrimal gland buds. These results reveal that the interplay between PI3K, mitogen-activated protein kinase, and mTOR mediates the cross-talk among FGF, IGF, and EGF signaling in support of lacrimal gland development.

scholarly journals Epidermal Growth Factor Signaling and Mitogenesis inPlcg1 Null Mouse Embryonic Fibroblasts

1998 ◽  
Vol 9 (4) ◽  
pp. 749-757 ◽  
Author(s):  
Qun-sheng Ji ◽  
Sandra Ermini ◽  
Josep Baulida ◽  
Feng-lei Sun ◽  
Graham Carpenter
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Receptor Activation ◽  
Mitogen Activated Protein Kinase ◽  
Null Mouse ◽  
Growth Factor Signaling ◽  
Mitogen Activated Protein ◽  
Epidermal Growth ◽  
Early Mouse

Gene targeting techniques and early mouse embryos have been used to produce immortalized fibroblasts genetically deficient in phospholipase C (PLC)-γ1, a ubiquitous tyrosine kinase substrate.Plcg1 −/− embryos die at embryonic day 9; however, cells derived from these embryos proliferate as well as cells from Plcg1 +/+ embryos. The null cells do grow to a higher saturation density in serum-containing media, as their capacity to spread out is decreased compared with that of wild-type cells. In terms of epidermal growth factor receptor activation and internalization, or growth factor induction of mitogen-activated protein kinase, c-fos, or DNA synthesis in quiescent cells, PLcg1 −/− cells respond equivalently to PLcg1 +/+ cells. Also, null cells are able to migrate effectively in a wounded monolayer. Therefore, immortalized fibroblasts do not require PLC-γ1 for many responses to growth factors.

The angiogenic regulator CD13/APN is a transcriptional target of Ras signaling pathways in endothelial morphogenesis

Blood ◽  
2003 ◽  
Vol 101 (5) ◽  
pp. 1818-1826 ◽  
Author(s):  
Shripad V. Bhagwat ◽  
Nenad Petrovic ◽  
Yasuhiro Okamoto ◽  
Linda H. Shapiro
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Blood Vessels ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Endothelial Cell Migration ◽  
Proximal Promoter ◽  
Limiting Factor ◽  
Ras Signaling

Angiogenesis, the formation of new blood vessels, is a critical step for tumor growth and metastasis and an integral component of the pathologic inflammatory response in arthritis and the proliferative retinopathies. The CD13/aminopeptidase N (CD13/APN) metalloprotease is an important regulator of angiogenesis where its expression on activated blood vessels is induced by angiogenic signals. Here, we show that cytokine induction of CD13/APN in endothelial cells is regulated by distinct Ras effector pathways involving Ras/mitogen-activated protein kinase (MAPK) or PI-3K. Signals transduced by activated Ras, Raf, and mitogen-induced extracellular kinase (MEK) stimulate transcription from theCD13/APN proximal promoter. Inhibition of these pathways and extracellular signal–regulated serine/threonine kinase (ERK-2) and PI-3K by expression of dominant-negative proteins or chemical inhibitors prevented induction of CD13/APNtranscription in response to basic fibroblast growth factor (bFGF). We show that Ras-induced signal transduction is required for growth factor–induced angiogenesis, because inhibition of downstream mediators of Ras signaling (MEK or PI-3K) abrogated endothelial cell migration, invasion, and morphogenesis in vitro. Reintroduction of CD13/APN, a shared downstream target of these pathways, overrode the suppressive effect of these inhibitors and restored the function of endothelial cells in migration/invasion and capillary morphogenesis assays. Similarly, inhibition of MEK abrogated cell invasion and the formation of endothelial-lined capillaries in vivo, which was effectively rescued by addition of exogenous CD13/APN protein. These studies provide strong evidence that CD13/APN is an important target of Ras signaling in angiogenesis and is a limiting factor in angiogenic progression.

Extracellular cysteine/cystine redox regulates the p44/p42 MAPK pathway by metalloproteinase-dependent epidermal growth factor receptor signaling

2005 ◽  
Vol 289 (1) ◽  
pp. G70-G78 ◽  
Author(s):  
Yvonne S. Nkabyo ◽  
Young-Mi Go ◽  
Thomas R. Ziegler ◽  
Dean P. Jones
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Redox State ◽  
Mapk Pathway ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Growth Factor Signaling ◽  
Epidermal Growth ◽  
Mapk Inhibitors

Previous research shows that stimulation of proliferation of colon carcinoma (Caco-2) cells by a more reduced extracellular cysteine/cystine (Cys/CySS) redox state occurs with no apparent effect on intracellular glutathione and that this stimulation is lost on addition of epidermal growth factor. The purpose of the present study was to determine whether a more reduced extracellular Cys/CySS redox state activates the mitogenic p44/p42 mitogen-activated protein kinase (MAPK) pathway and whether this is signaled through the epidermal growth factor receptor (EGFR). Caco-2 cells were exposed to a range of physiological extracellular redox conditions from −150 to 0 mV. In the absence of added growth factors, the most reduced (−150 mV) redox state induced an 80% increase in EGFR phosphorylation, and this was followed by a marked increase in phosphorylation of p44/p42 MAPK. Inhibitors of EGFR (AG1478) and p44/p42 MAPK (U0126) phosphorylation blocked redox-dependent p44/p42 phosphorylation, indicating that signaling occurred by EGFR. These effects were inhibited by pretreatment with a nonpermeant alkylating agent, showing that signaling involved thiols accessible to the extracellular space. The EGFR ligand TGF-α was increased in culture medium at more reduced redox states. Redox-dependent phosphorylation of EGFR was completely prevented by a metalloproteinase inhibitor (GM6001), and an antibody to TGF-α partially inhibited the phosphorylation of p44/p42 MAPK by redox. Thus the data show that a redox-dependent activation of metalloproteinase can stimulate the mitogenic p44/p42 MAPK pathway by a TGF-α-dependent mechanism. Because Cys availability and Cys/CySS redox are dependent on nutrition, disease, and environmental exposures, the results suggest that cell proliferation could be influenced physiologically by Cys-dependent redox effects on growth factor signaling pathways.

Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma

Blood ◽  
2002 ◽  
Vol 99 (4) ◽  
pp. 1405-1410 ◽  
Author(s):  
Patrick W. B. Derksen ◽  
Robert M. J. Keehnen ◽  
Ludo M. Evers ◽  
Marinus H. J. van Oers ◽  
Marcel Spaargaren ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Protein Kinase ◽  
Hepatocyte Growth Factor ◽  
Heparan Sulfate ◽  
Growth Regulation ◽  
Plasma Cells ◽  
Mitogen Activated Protein Kinase ◽  
Growth Factor Signaling ◽  
Hepatocyte Growth

Heparan sulfate proteoglycans (HSPGs) play a crucial role in growth regulation by assembling signaling complexes and presenting growth factors to their cognate receptors. Within the immune system, expression of the HSPG syndecan-1 (CD138) is characteristic of terminally differentiated B cells, ie, plasma cells, and their malignant counterpart, multiple myeloma (MM). This study explored the hypothesis that syndecan-1 might promote growth factor signaling and tumor growth in MM. For this purpose, the interaction was studied between syndecan-1 and hepatocyte growth factor (HGF), a putative paracrine and autocrine regulator of MM growth. The study demonstrates that syndecan-1 is capable of binding HGF and that this growth factor is indeed a potent stimulator of MM survival and proliferation. Importantly, the interaction of HGF with heparan sulfate moieties on syndecan-1 strongly promotes HGF-mediated signaling, resulting in enhanced activation of Met, the receptor tyrosine kinase for HGF. Moreover, HGF binding to syndecan-1 promotes activation of the phosphatidylinositol 3-kinase/protein kinase B and RAS/mitogen-activated protein kinase pathways, signaling routes that have been implicated in the regulation of cell survival and proliferation, respectively. These results identify syndecan-1 as a functional coreceptor for HGF that promotes HGF/Met signaling in MM cells, thus suggesting a novel function for syndecan-1 in MM tumorigenesis.

scholarly journals Integrins direct Src family kinases to regulate distinct phases of oligodendrocyte development

2004 ◽  
Vol 167 (2) ◽  
pp. 365-375 ◽  
Author(s):  
Holly Colognato ◽  
Shwetha Ramachandrappa ◽  
Inger M. Olsen ◽  
Charles ffrench-Constant
Keyword(s):  
Growth Factor ◽  
Cell Lineage ◽  
Src Family Kinases ◽  
Mitogen Activated Protein Kinase ◽  
Specific Cell ◽  
Growth Factor Signaling ◽  
Similar Region ◽  
Mitogen Activated Protein ◽  
The Central Nervous System ◽  
Oligodendrocyte Development

Specific integrins expressed on oligodendrocytes, the myelin-forming cells of the central nervous system, promote either differentiation and survival or proliferation by amplification of growth factor signaling. Here, we report that the Src family kinases (SFKs) Fyn and Lyn regulate each of these distinct integrin-driven behaviors. Fyn associates with α6β1 and is required to amplify platelet-derived growth factor survival signaling, to promote myelin membrane formation, and to switch neuregulin signaling from a phosphatidylinositol 3-kinase to a mitogen-activated protein kinase pathway (thereby changing the response from proliferation to differentiation). However, earlier in the lineage Lyn, not Fyn, is required to drive αVβ3-dependent progenitor proliferation. The two SFKs respond to integrin ligation by different mechanisms: Lyn, by increased autophosphorylation of a catalytic tyrosine; and Fyn, by reduced Csk phosphorylation of the inhibitory COOH-terminal tyrosine. These findings illustrate how different SFKs can act as effectors for specific cell responses during development within a single cell lineage, and, furthermore, provide a molecular mechanism to explain similar region-specific hypomyelination in laminin- and Fyn-deficient mice.

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