The Expanding Family of Eucaryotic Na+/H+Exchangers

Counillon, Laurent; Pouysségur, Jacques

doi:10.1074/jbc.275.1.1

Cited by 358 publications

(341 citation statements)

References 92 publications

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“…Despite a low pHe, the intracellular pH (pHi) of tumour cells is maintained at a relatively normal pH or even slightly more alkaline pH, which is reported to result from HIF-mediated up-regulation and activation of a number of membrane located transporters, exchanges, pumps and ecto-enzymes that are implicated in pH homeostasis. Among these are the growth factor activatable and amiloride-sensitive Na + /H + Exchanger (NHE-1) [32][33][34] and the H + /lactate cotransporter (monocarboxylate transporter, MCT1 and MCT4) [35]. In addition, one of the most highly HIF-induced proteins, carbonic anhydrase IX (CA IX), an enzyme that catalyzes the reversible conversion of CO 2 to carbonic acid (Fig.…”

Section: Regulation Of Phmentioning

confidence: 99%

Hypoxia and cancer

2007

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A major feature of solid tumours is hypoxia, decreased availability of oxygen, which increases patient treatment resistance and favours tumour progression. How hypoxic conditions are generated in tumour tissues and how cells respond to hypoxia are essential questions in understanding tumour progression and metastasis. Massive tumour-cell proliferation distances cells from the vasculature, leading to a deficiency in the local environment of blood carrying oxygen and nutrients. Such hypoxic conditions induce a molecular response, in both normal and neoplastic cells, that drives the activation of a key transcription factor; the hypoxia-inducible factor. This transcription factor regulates a large panel of genes that are exploited by tumour cells for survival, resistance to treatment and escape from a nutrient-deprived environment. Although now recognized as a major contributor to cancer progression and to treatment failure, the precise role of hypoxia signalling in cancer and in prognosis still needs to be further defined. It is hoped that a better understanding of the mechanisms implicated will lead to alternative and more efficient therapeutic approaches.

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Section: Regulation Of Phmentioning

confidence: 99%

Hypoxia and cancer

2007

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“…7 Members of the Na þ /H þ exchanger (NHE) family constitute an extremely efficient system for protecting cells against internal acidification. 8 A spontaneous mouse mutant identified to be deficient for NHE1 shows a neurological syndrome including ataxia, an epilepsy phenotype consisting of 3/s absences and tonic-clonic seizures, and selective neuronal death in the cerebellum and brainstem, but otherwise is healthy. 9 Surprisingly, inhibition of the NHE has been reported to protect rats from ischemia-induced brain damage.…”

Section: Introductionmentioning

confidence: 99%

Intracellular acidification by inhibition of the Na+/H+-exchanger leads to caspase-independent death of cerebellar granule neurons resembling paraptosis

et al. 2004

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Potassium withdrawal is commonly used to induce caspasemediated apoptosis in cerebellar granule neurons in vitro. However, the underlying and cell death-initiating mechanisms are unknown. We firstly investigated potassium efflux through the outward delayed rectifier K þ current (I k ) as a potential mediator. However, tetraethylammoniumchloride, an inhibitor of I k , was ineffective to block apoptosis after potassium withdrawal. Since potassium withdrawal reduced intracellular pH (pH i ) from 7.4 to 7.2, we secondly investigated the effects of intracellular acidosis. To study intracellular acidosis in cerebellar granule neurons, we inhibited the Na þ /H þ exchanger (NHE) with 4-isopropyl-3-methylsulfonylbenzoylguanidine methanesulfonate (HOE 642) and 5-(N-ethyl-Nisopropyl)-amiloride. Both inhibitors concentration-dependently induced cell death and potentiated cell death after potassium withdrawal. Although inhibition of the NHE induced cell death with morphological criteria of apoptosis in light and electron microscopy including chromatin condensation, positive TUNEL staining and cell shrinkage, no internucleosomal DNA cleavage or activation of caspases was detected. In contrast to potassium withdrawal-induced apoptosis, cell death induced by intracellular acidification was not prevented by insulin-like growth factor-1, cyclo-adenosinemonophosphate, caspase inhibitors and transfection with an adenovirus expressing Bcl-X L . However, cycloheximide protected cerebellar granule neurons from death induced by potassium withdrawal as well as from death after treatment with HOE 642. Therefore, the molecular mechanisms leading to cell death after acidification appear to be different from the mechanisms after potassium withdrawal and resemble the biochemical but not the morphological characteristics of paraptosis.

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“…Among possible candidates is the Na + -H + exchanger (NHE), a ubiquitous membrane protein known to regulate cellular pH [72]. There are a number of NHE isoforms encoded by different genes [72]. One of the most widely distributed isoform of NHE is called NHE1 which catalyzes the extrusion of intracellular proton (H + ) ions in exchange for extracellular (Na + ) ions, thereby regulating intracellular pH (pHi) [72].…”

Section: Ha/cd44mentioning

confidence: 99%

Section: Ha/cd44mentioning

confidence: 99%

Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression

Bourguignon

2008

Seminars in Cancer Biology

271

279

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Hyaluronan (HA), a major component of the extracellular matrix (ECM), is enriched in many types of tumors. In cancer patients HA concentrations are usually higher in malignant tumors than in corresponding benign or normal tissues, and in some tumor types the level of HA is predictive of malignancy. HA is often bound to CD44 isoforms which are ubiquitous, abundant, and functionally important cell surface receptors. This article reviews the current evidence for HA/CD44-mediated activation of the ankyrin-based cytoskeleton and RhoGTPase signaling during tumor progression. A special focus is placed on the role of HA-mediated CD44 interaction with unique downstream effectors (e.g., the cytoskeletal protein, ankyrin and/or various GTPases (e.g., RhoA, Rac1 and Cdc42)) in coordinating intracellular signaling pathways (e.g., Ca 2+ mobilization, Rho signaling, PI3 kinase-AKT activation, NHE1-mediated cellular acidification, transcriptional upregulation and cytoskeletal function) and generating the concomitant onset of tumor cell activities (e.g., tumor cell adhesion, growth, survival, migration and invasion) and tumor progression. I believe this information will provide valuable new insights into poorly understood aspects of solid tumor malignancy. Furthermore, the new knowledge concerning HA/CD44-mediated oncogenic signaling events will have potentially important clinical utility, and could establish CD44 and its associated signaling molecules as important tumor markers for the early detection and evaluation of oncogenic potential. It could also serve as ground work for the future development of new drug targets to inhibit HA/ CD44-mediated tumor metastasis and cancer progression.

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The Expanding Family of Eucaryotic Na+/H+Exchangers

Cited by 358 publications

References 92 publications

Hypoxia and cancer

Hypoxia and cancer

Intracellular acidification by inhibition of the Na+/H+-exchanger leads to caspase-independent death of cerebellar granule neurons resembling paraptosis

Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression

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