Roles of epidermal growth factor and Na+/H+ exchanger-1 in esophageal epithelial defense against acid-induced injury

2006 ◽  
Vol 290 (4) ◽  
pp. G665-G673 ◽  
Author(s):  
Yasuhiro Fujiwara ◽  
Kazuhide Higuchi ◽  
Takashi Takashima ◽  
Masaki Hamaguchi ◽  
Tsuyoshi Hayakawa ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Epithelial Cells ◽  
Acid Reflux ◽  
Dependent Manner ◽  
Egf Receptors ◽  
Epithelial Proliferation ◽  
Epidermal Growth ◽  
Esophageal Epithelial Cells ◽  
Chronic Esophagitis

Epidermal growth factor (EGF) is predominantly secreted by salivary glands and activates Na+/H+ exchanger-1 (NHE-1), which regulates intracellular pH (pHi). We investigated the roles of EGF and NHE-1 in esophageal epithelial defense against acid using human esophageal epithelial cell lines and a rat chronic esophagitis model. Esophageal epithelial cells were incubated with acidified medium in the absence or presence of EGF. Cell viability and changes in pHi were measured. Chronic acid reflux esophagitis was induced in rats with and without sialoadenectomy. Esophageal lesion index, epithelial proliferation, and expression of EGF receptors and NHE-1 were examined. EGF protected esophageal epithelial cells against acid in a dose-dependent manner, and the cytoprotective effect of EGF was completely blocked by treatment with NHE-1 inhibitors. Tyrosine kinase, calmodulin, and PKC inhibitors significantly inhibited cytoprotection by EGF, whereas MEK, phosphatidylinositol 3-kinase, and PKA inhibitors had no effect. EGF significantly increased pHi recovery after NH4Cl pulse acidification, and this increase in pHi recovery was significantly blocked by inhibitors of calmodulin and PKC. Sialoadenectomy led to an increase in the severity of chronic esophagitis but affected neither epithelial proliferation nor expression of EGF receptors. Expression of NHE-1 mRNA was increased in esophagitis and upregulated in rats with sialoadenectomy. The increasing severity of esophagitis in rats with sialoadenectomy was prevented by exogenous administration of EGF. In conclusion, EGF protects esophageal epithelial cells against acid through NHE activation via Ca2+/calmodulin and the PKC pathway. Deficiency in endogenous EGF is associated with increased severity of esophagitis. EGF and NHE-1 play crucial roles in esophageal epithelial defense against acid.

scholarly journals Expression of the v-crk oncogene product in PC12 cells results in rapid differentiation by both nerve growth factor- and epidermal growth factor-dependent pathways.

1994 ◽  
Vol 14 (3) ◽  
pp. 1964-1971 ◽  
Author(s):  
B L Hempstead ◽  
R B Birge ◽  
J E Fajardo ◽  
R Glassman ◽  
D Mahadeo ◽  
...  
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Fusion Protein ◽  
Pc12 Cells ◽  
Dependent Manner ◽  
Egf Receptors ◽  
A431 Cells ◽  
Nerve Growth ◽  
Epidermal Growth

The transforming gene of the avian sarcoma virus CT10 encodes a fusion protein (p47gag-crk or v-Crk) containing viral Gag sequences fused to cellular sequences consisting primarily of Src homology regions 2 and 3 (SH2 and SH3 sequences). Here we report a novel function of v-Crk in the mammalian pheochromocytoma cell line, PC12, whereby stable expression of v-Crk induces accelerated differentiation, as assessed by induction of neurites following nerve growth factor (NGF) or basic fibroblast growth factor (bFGF) treatment compared with the effect in native PC12 cells. Surprisingly, however, these cells also develop extensive neurite processes after epidermal growth factor (EGF) stimulation, an event which is not observed in native PC12 cells. Following EGF or NGF stimulation of the v-CrkPC12 cells, the v-Crk protein itself became tyrosine phosphorylated within 1 min. Moreover, in A431 cells or TrkA-PC12 cells, which overexpress EGF receptors and TrkA, respectively, a GST-CrkSH2 fusion protein was indeed capable of binding these receptors in a phosphotyrosine-dependent manner, suggesting that v-Crk can directly couple to receptor tyrosine kinase pathways in PC12 cells. In transformed fibroblasts, v-Crk binds to specific tyrosine-phosphorylated proteins of p130 and paxillin. Both of these proteins are also complexed to v-Crk in PC12 cells, as evidenced by their coprecipitation with v-Crk in detergent lysates, suggesting that common effector pathways may occur in both cell types. However, whereas PC12 cellular differentiation can occur solely by overexpression of the v-Src or oncogenic Ras proteins, that induced by v-Crk requires a growth factor stimulatory signal, possibility in a two-step process.

Presence of epidermal growth factor receptors on human thyroid membranes

1987 ◽  
Vol 114 (3) ◽  
pp. 396-401 ◽  
Author(s):  
Kikuo Kasai ◽  
Masaki Hiraiwa ◽  
Yoshinobu Suzuki ◽  
Tatsushi Emoto ◽  
Nobuyuki Banba ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Human Thyroid ◽  
Tissue Homogenate ◽  
Dependent Manner ◽  
Egf Receptors ◽  
Thyroid Cells ◽  
High Affinity Receptor ◽  
Epidermal Growth ◽  
Affinity Receptor

Abstract. The nature of epidermal growth factor (EGF) receptors in normal and pathological thyroid membranes was studied on a crude membrane fraction (10 000 × g pellet) of tissue homogenate. Optimal binding of 125I-EGF to human thyroid membranes was obtained at 25°C with 1-h incubation at pH 7.4. The study revealed the presence of both high and low affinity receptors in normal and pathological thyroid membranes. The association constants of high affinity receptor (3.2 × 10−9 mol/l) and of low affinity receptor (1.8 × 10−8 mol/l) observed in normal thyroid membranes were similar to those of thyroid membranes from neoplastic as well as thyrotoxic thyroid tissues. [3H]thymidine incorporation into DNA of cultured human thyroid cells was stimulated by EGF in a dose-dependent manner. A half-maximal stimulation was found around 1 × 10−10 mol/l. These results suggest that EGF may have a possible role in the regulation of thyroid growth and function in physiological and pathological situations.

scholarly journals The secretory leukocyte protease inhibitor gene is a target of epidermal growth factor receptor action in endometrial epithelial cells

2005 ◽  
Vol 184 (1) ◽  
pp. 141-151 ◽  
Author(s):  
M C Velarde ◽  
S I Parisek ◽  
R R Eason ◽  
F A Simmen ◽  
R C M Simmen
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Epithelial Cells ◽  
Protease Inhibitor ◽  
Growth Factor Receptor ◽  
Secretory Leukocyte Protease Inhibitor ◽  
Dependent Manner ◽  
Neoplastic Progression ◽  
Epidermal Growth

The over-expression of epidermal growth factor receptor (EGFR) and its ligands, epidermal growth factor (EGF) and transforming growth factor-α, is a common feature of epithelial carcinomas and correlates with neoplastic progression. Secretory leukocyte protease inhibitor (SLPI), a member of the Kazal superfamily of serine anti-proteases, induces proliferation and promotes malignancy of epithelial cells and is expressed at high levels in multiple tumor types. In the present study, we have demonstrated that EGF increases SLPI expression in the human endometrial epithelial cell line Ishikawa in a dose- and time-dependent manner. We have shown that this effect of EGF occurs, in part, at the level of the SLPI promoter and involves the MAP kinase signaling pathway. We have further shown that EGF promotion of cell proliferation, but not induction of cyclin D1 gene expression, involves SLPI. Our results suggest that the regulation of SLPI expression by EGFR ligand(s) may represent a ‘feed-forward’ mechanism by which the enhanced proliferative and migratory properties of EGFR over-expressing cancer cells are sustained. Increased SLPI expression is likely an important component of altered EGFR signaling in human tumors and may have significant therapeutic implications in cancer progression.

Demonstration of epidermal growth factor binding sites in the adult rat small intestine by autoradiography

1987 ◽  
Vol 65 (2) ◽  
pp. 109-112 ◽  
Author(s):  
J.-G. Chabot ◽  
P. Walker ◽  
G. Pelletier
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Epithelial Cells ◽  
Time Course ◽  
Specific Interaction ◽  
Duodenal Mucosa ◽  
Egf Receptors ◽  
Absorptive Cells ◽  
Epidermal Growth ◽  
Silver Grains

The distribution of epidermal growth factor (EGF) receptors was studied in the distal portion of duodenum using light microscopic autoradiography performed at different time intervals (2–60 min) after intravenous injection of 125I-labelled EGF into adult rats. The results revealed a substantial binding of EGF to both cell types of the mucosal epithelium in duodenal crypts and villi, the columnar absorptive cells and the globet cells. Labelling was also found over few cells of lamina propria. No labelling was observed over the striated border of the duodenal mucosa epithelium. The time-course study performed in epithelial cells of duodenal crypts and villi showed that most silver grains were found at the periphery of the cells 2 min after injection. At the 7 min, silver grains were found both at the periphery and over the cytoplasm, more specifically the supranuclear region of the columnar absorptive cells. The number of grains overlying the cytoplasm of these cells was markedly reduced at 60 min. By quantitative autoradiography, maximal values were reached 7 min after the injection. Control experiments indicated that the autoradiography reaction was due to specific interaction of 125I-labelled EGF with its receptor. These results clearly indicate that EGF receptors are present in epithelial cells of the duodenal mucosa and suggest that the radioactive tracer is taken up by these cells.

Epidermal growth factor protecis human esophageal epithelial cells against acid-induced damage through the activation of Na+/H+ exchangers

2001 ◽  
Vol 120 (5) ◽  
pp. A145 ◽  
Author(s):  
Yasuhiro Fujiwara ◽  
Kazuhide Higuchi ◽  
Takashi Takashima ◽  
Kazunari Tominaga ◽  
Toshio Watanabe ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Epithelial Cells ◽  
Epidermal Growth ◽  
Esophageal Epithelial Cells

Expression of the v-crk oncogene product in PC12 cells results in rapid differentiation by both nerve growth factor- and epidermal growth factor-dependent pathways

1994 ◽  
Vol 14 (3) ◽  
pp. 1964-1971
Author(s):  
B L Hempstead ◽  
R B Birge ◽  
J E Fajardo ◽  
R Glassman ◽  
D Mahadeo ◽  
...  
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Fusion Protein ◽  
Pc12 Cells ◽  
Dependent Manner ◽  
Egf Receptors ◽  
A431 Cells ◽  
Nerve Growth ◽  
Epidermal Growth

The transforming gene of the avian sarcoma virus CT10 encodes a fusion protein (p47gag-crk or v-Crk) containing viral Gag sequences fused to cellular sequences consisting primarily of Src homology regions 2 and 3 (SH2 and SH3 sequences). Here we report a novel function of v-Crk in the mammalian pheochromocytoma cell line, PC12, whereby stable expression of v-Crk induces accelerated differentiation, as assessed by induction of neurites following nerve growth factor (NGF) or basic fibroblast growth factor (bFGF) treatment compared with the effect in native PC12 cells. Surprisingly, however, these cells also develop extensive neurite processes after epidermal growth factor (EGF) stimulation, an event which is not observed in native PC12 cells. Following EGF or NGF stimulation of the v-CrkPC12 cells, the v-Crk protein itself became tyrosine phosphorylated within 1 min. Moreover, in A431 cells or TrkA-PC12 cells, which overexpress EGF receptors and TrkA, respectively, a GST-CrkSH2 fusion protein was indeed capable of binding these receptors in a phosphotyrosine-dependent manner, suggesting that v-Crk can directly couple to receptor tyrosine kinase pathways in PC12 cells. In transformed fibroblasts, v-Crk binds to specific tyrosine-phosphorylated proteins of p130 and paxillin. Both of these proteins are also complexed to v-Crk in PC12 cells, as evidenced by their coprecipitation with v-Crk in detergent lysates, suggesting that common effector pathways may occur in both cell types. However, whereas PC12 cellular differentiation can occur solely by overexpression of the v-Src or oncogenic Ras proteins, that induced by v-Crk requires a growth factor stimulatory signal, possibility in a two-step process.

Retroductal Delivery of Epidermal Growth Factor Protects Salivary Progenitors after Irradiation

2021 ◽  
pp. 002203452199929
Author(s):  
J.M. Cho ◽  
Y.J. Yoon ◽  
S. Lee ◽  
D. Kim ◽  
D. Choi ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Epithelial Cells ◽  
Apoptotic Cell ◽  
Therapeutic Option ◽  
Dependent Manner ◽  
Radiation Induced ◽  
Epidermal Growth ◽  
Salivary Gland Hypofunction

Salivary gland hypofunction after irradiation is associated with a deficit of epithelial stem/progenitors in salivary glands. Although epidermal growth factor (EGF) is known to stimulate the proliferation of epithelial cells, the therapeutic effect of EGF on salivary epithelial stem/progenitors remains undetermined. In this study, we administered EGF to submandibular glands (SMGs) via a retrograde route through the SMG excretory duct before fractionated irradiation and examined whether EGF could protect salivary epithelial progenitor cells from radiation and alleviate radiation-induced salivary hypofunction. EGF-treated mice exhibited greater body and gland weights at 12 wk after irradiation than untreated mice. The retroductal delivery of EGF improved salivary secretory function and increased salivary amylase activity in a dose-dependent manner. Histological examinations highlighted the amelioration of the loss of keratine-14+ (KRT14+) basal ductal and/or MIST1+ acinar cells, as well as induction of fibrosis, following irradiation in EGF-treated mice. An additional in vitro experiment using a salivary gland organoid irradiation model indicated that the radioprotective effects of EGF promoted the growth and inhibited the apoptotic cell death of salivary epithelial cells. Our results suggest that retroductal delivery of EGF may be a promising therapeutic option for preventing radiation-induced salivary gland hypofunction.

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