Mechanism and biological significance of the Ha-ras-induced activation of the Na+/H+-antiporter

Maly, Karl; Hochleitner, Boris-Wolfgang; Überall, Florian; Loferer, Hannes; Oberhuber, Hermann; Doppler, Wolfgang; Grunicke, H.

doi:10.1016/0065-2571(90)90009-q

Cited by 19 publications

(27 citation statements)

References 39 publications

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“…There is little doubt that sustained activation of ERK can increase NHE activity. Transfection of the Ha-Ras oncogene [22][23][24] stimulate sodium-dependent NHE activity in fibroblasts. This effect is most likely mediated through activation of transcription cascades that upregulate the NHE message\ protein or modulate expression of key regulators of NHE activity.…”

Section: Discussionmentioning

confidence: 99%

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Rapid activation of sodium–proton exchange and extracellular signal-regulated protein kinase in fibroblasts by G protein-coupled 5-HT1A receptor involves distinct signalling cascades

Garnovskaya

Mukhin

Raymond

1998

Biochemical Journal

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These experiments tested the hypothesis that signalling elements involved in the activation of the extracellular signal-regulated protein kinase (ERK) mediate rapid activation of sodium-proton exchange (NHE) in fibroblasts when both signals are initiated by a single G protein-coupled receptor, the 5-HT "A receptor. Similarities between the two processes were comparable concentration-response curves and time-courses, and overlapping sensitivity to some pharmacological inhibitors of tyrosine kinases (staurosporine and genistein), and phosphoinositide 3h-kinase (wortmannin and LY204002). Activation of NHE was much more sensitive to the phosphatidylcholine-specific phospholipase inhibitor (D609) than was ERK. Neither pathway was sensitive

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Section: Discussionmentioning

confidence: 99%

“…Salient to the current hypothesis are studies showing that microinjection of activated Ras [21] or transfection of the Ha-Ras oncogene [22][23][24] stimulates NHE activity in fibroblasts. The classical effect of GTP-bound Ras is the activation of the ERK1 and ERK2 [11].…”

Section: Introductionmentioning

confidence: 99%

Rapid activation of sodium–proton exchange and extracellular signal-regulated protein kinase in fibroblasts by G protein-coupled 5-HT1A receptor involves distinct signalling cascades

Garnovskaya

Mukhin

Raymond

1998

Biochemical Journal

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“…It has been well documented that malignantly transformed cells maintain abnormally high pH i . For example, microinjection of ras p21 protein (25) and stable transfection of Ha-ras oncogene (26,27) or E7 oncogene of papillomavirus type 16 (28) resulted in a marked increase in the steady-state pH i in NIH-3T3 cells through the activation of NHE1. Moreover, high pH i because of activation of NHE1 has been observed in various malignantly transformed cells, such as human leukemic (21), human malignant glioma (41), and human breast cancer cells (42).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the activation of NHE1 has often been associated with oncogenic transformation (24 -28). For example, cells transformed by ras oncogene (25)(26)(27) or E7 oncogene from papillomavirus type 16 (28) have been shown to maintain high pH i in the absence of serum with an accompanying high activity of NHE1, which may be one of key factors involved in abnormal cell growth or enhanced cell invasion. However, molecular mechanisms underlying these phenotypic alterations remain poorly understood.…”

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confidence: 99%

Expression of Calcineurin B Homologous Protein 2 Protects Serum Deprivation-induced Cell Death by Serum-independent Activation of Na+/H+ Exchanger

Pang¹,

Wakabayashi

Shigekawa

2002

Journal of Biological Chemistry

109

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The calcineurin B homologous protein (designated CHP1) has been shown to be a common essential cofactor for the plasma membrane Na ؉ /H ؉ exchangers (NHEs) (Pang, T., Su, X., Wakabayashi, S., and Shigekawa, M. (2001) J. Biol. Chem. 276, 17367-17372). In this study, we characterized the function of another isoform of CHP (designated CHP2) that has a 61% amino acid identity with CHP1. CHP2, like CHP1, conferred the ability to NHEs 1-3 to express a high exchange activity by binding to the juxtamembrane region of the cytoplasmic domain of the exchanger, but it interacts more strongly (ϳ5-fold) with NHE1 than does CHP1. Although CHP1 is expressed ubiquitously at relatively high levels, CHP2 expression was extremely low in most human tissues but was higher in tumor cells. We produced stable cell clones overexpressing either CHP1 or CHP2 in which one of them is predominantly bound to NHE1. Serum (10%) induced a significant cytoplasmic alkalinization (0.1-0.2 pH unit) in cells co-expressing CHP1 and NHE1 but not in cells co-expressing CHP2 and NHE1. In the latter, pH i was high (7.4 -7.5) even in the absence of serum, suggesting that NHE1 was already activated. Surprisingly, most (>80%) of CHP2/NHE1 cells unlike CHP1/NHE1 cells were viable even after long serum starvation (>7 days). Thus, the expression of CHP2 appears to protect cells from serum deprivationinduced death by increasing pH i . These properties of CHP2/NHE1 cells are similar to those of malignantly transformed cells. We propose that serum-independent activation of NHE1 by bound CHP2 is one of the key mechanisms for the maintenance of high pH i and the resistance to serum deprivation-induced cell death in malignantly transformed cells.

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“…These same stimuli are also known to enhance cell survival. Many intracellular signaling components, such as protein kinase C and Ha-Ras, also lead to enhanced survival and activation of the antiport (17,18). Furthermore, the protein phosphatase inhibitor okadaic acid has been shown to activate the antiport (19).…”

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confidence: 99%

The Involvement of Protein Phosphatases in the Activation of ICE/CED-3 Protease, Intracellular Acidification, DNA Digestion, and Apoptosis

Morana

Wolf

et al. 1996

Journal of Biological Chemistry

148

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Many events in apoptosis have been identified but their temporal relationships remain obscure. Apoptosis in human ML-1 cells induced by etoposide is characterized by intracellular acidification, enhanced Hoechst 33342 fluorescence, DNA digestion, chromatin condensation, and proteolysis of poly(ADP-ribose) polymerase. This proteolysis is a marker for the action of ICE/CED-3 proteases, which are critical activators of apoptosis. We observed that three serine/threonine protein phosphatase inhibitors, okadaic acid, calyculin A, and cantharidin, prevented all of these apoptotic characteristics. To determine which protein phosphatase was involved, we investigated the dephosphorylation of the retinoblastoma susceptibility protein Rb, a substrate for protein phosphatase 1 but not protein phosphatase 2A. Rb was dephosphorylated during apoptosis, and each inhibitor prevented this dephosphorylation at the same concentrations that prevented apoptosis. No increase in protein phosphatase 1 activity was observed in apoptotic cells suggesting that dephosphorylation of Rb may result from loss of Rb kinase activity in the presence of a constant level of protein phosphatase activity. Long term inhibition of protein phosphatase 1 (>8 h) also led to the appearance of dephosphorylated Rb, cleavage of poly(ADP-ribose) polymerase and apoptosis, suggesting these events are not solely dependent upon protein phosphatase 1. Rb dephosphorylation was also observed in several other models of apoptosis. Hence, an imbalance between protein phosphatase 1 and Rb kinase may be a common means to activate ICE/CED-3 proteases resulting in the subsequent events of apoptosis.Maintaining tissue and organ homeostasis requires a delicate balance between the rate of cell division and the rate of cell death. Cells that are either metabolically compromised or no longer required are eliminated by a pathway commonly known as apoptosis. This process has been characterized by cell shrinkage, cytoplasmic blebbing, chromosome condensation, DNA digestion, and, finally, non-inflammatory removal of the cell from the tissue (1). Apoptosis occurs during development, immune regulation, and normal cell turnover, as well as being induced by many pharmacological insults. Decreased apoptosis can lead to cancer and autoimmune diseases, while increased apoptosis can result in neurodegenerative disorders and AIDS (2). Despite the importance of apoptosis, the signal transduction pathways responsible for the associated morphological and biochemical changes are poorly understood. Much recent emphasis has focused on the identification of proteases of the ICE/CED-3 family that appear essential to this pathway (3-5), but both the upstream and downstream events remain elusive.While investigating endonucleases that might be involved in apoptosis, we detected and purified deoxyribonuclease II (DNase II), an endonuclease that is active at slightly acidic pH but inactive at pH 7.0 (6). To determine whether DNase II might be responsible for the DNA digestion, we measured intracellular pH ...

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Mechanism and biological significance of the Ha-ras-induced activation of the Na+/H+-antiporter

Cited by 19 publications

References 39 publications

Rapid activation of sodium–proton exchange and extracellular signal-regulated protein kinase in fibroblasts by G protein-coupled 5-HT1A receptor involves distinct signalling cascades

Rapid activation of sodium–proton exchange and extracellular signal-regulated protein kinase in fibroblasts by G protein-coupled 5-HT1A receptor involves distinct signalling cascades

Expression of Calcineurin B Homologous Protein 2 Protects Serum Deprivation-induced Cell Death by Serum-independent Activation of Na+/H+ Exchanger

The Involvement of Protein Phosphatases in the Activation of ICE/CED-3 Protease, Intracellular Acidification, DNA Digestion, and Apoptosis

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