VHL tumor suppressor regulates Cl-/HCO3- exchange and Na+/H+ exchange activities in renal carcinoma cells.
Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene are thought to play a critical role in the pathogenesis of both sporadic and VHL disease-associated clear-cell renal carcinomas (RCC). Differential display-PCR identified the AE2 anion exchanger as a candidate VHL target gene. AE2 mRNA and polypeptide levels were approximately threefold higher in 786-O VHL cells than in 786-O Neo cells. In contrast, Cl(-)/HCO(3)(-) exchange activity in 786-O VHL cells was 50% lower than in 786-O Neo cells. Since resting intracellular pH (pH(i)) values were indistinguishable, we postulated that Na(+)/H(+) exchange activity (NHE) might be similarly reduced in 786-O VHL cells. NHE-mediated pH(i) recovery from acid load was less than 50% that in 786-O Neo cells, whereas hypertonicity-stimulated, amiloride-sensitive NHE was indistinguishable in the two cell lines. The NHE3 mRNA level was higher in 786-O VHL than 786-O Neo cells, but NHE1 mRNA levels did not differ. AE2 and NHE3 are the first transcripts reported to be upregulated by pVHL. Elucidation of mechanisms responsible for downregulation of both ion exchange activities will require further investigation.
Karumanchi
S A
SA
Renal Division, Beth Israel Deaconess Medical Center, Departments of Medicine and Cell Biology, Harvard Medical School, Boston, Massachusetts 02215, USA.
Jiang
L
L
Knebelmann
B
B
Stuart-Tilley
A K
AK
Alper
S L
SL
Sukhatme
V P
VP
D000643:Ammonium Chloride / Q000494:pharmacology; D027321:Anion Transport Proteins; D017920:Antiporters / Q000235:genetics / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism*; D027963:Chloride-Bicarbonate Antiporters; D015536:Down-Regulation; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006982:Hypertonic Solutions; D008025:Ligases; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012334:RNA, Neoplasm / Q000096:biosynthesis; D064606:SLC4A Proteins; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D027321:Anion Transport Proteins; D017920:Antiporters; D027963:Chloride-Bicarbonate Antiporters; D006982:Hypertonic Solutions; D008565:Membrane Proteins; D011506:Proteins; D012334:RNA, Neoplasm; D064606:SLC4A Proteins; C000613385:SLC9A3 protein, human; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D025521:Tumor Suppressor Proteins; C069139:growth factor-activatable Na-H exchanger NHE-1; D000643:Ammonium Chloride; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D002256:Carbonic Anhydrases; D008025:Ligases; C497446:VHL protein, human