Multiple promoters in the WNK1 gene: one controls expression of a kidney-specific kinase-defective isoform.
WNK1 is a serine-threonine kinase, the expression of which is affected in pseudohypoaldosteronism type II, a Mendelian form of arterial hypertension. We characterized human WNK1 transcripts to determine the molecular mechanisms governing WNK1 expression. We report the presence of two promoters generating two WNK1 isoforms with a complete kinase domain. Further variations are achieved by the use of two polyadenylation sites and tissue-specific splicing. We also determined the structure of a kidney-specific isoform regulated by a third promoter and starting at a novel exon. This transcript is kinase defective and has a predominant expression in the kidney compared to the other WNK1 isoforms, with, furthermore, a highly restricted expression profile in the distal convoluted tubule. We confirmed that the ubiquitous and kidney-specific promoters are functional in several cells lines and identified core promoters and regulatory elements. In particular, a strong enhancer element upstream from the kidney-specific exon seems specific to renal epithelial cells. Thus, control of human WNK1 gene expression of kinase-active or -deficient isoforms is mediated predominantly through the use of multiple transcription initiation sites and tissue-specific regulatory elements.
Delaloy
Celine
C
INSERM U36, College de France, 11 place Marcelin Berthelot, 75005 Paris, France.
Lu
Jingyu
J
Houot
Anne-Marie
AM
Disse-Nicodeme
Sandra
S
Gasc
Jean-Marie
JM
Corvol
Pierre
P
Jeunemaitre
Xavier
X
D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002460:Cell Line; D002874:Chromosome Mapping; D006224:Cricetinae; D018076:DNA, Complementary / Q000235:genetics; D004285:Dogs; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000235:genetics; D007668:Kidney / Q000201:enzymology*; D051379:Mice; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D024363:Transcription Initiation Site; D000076204:WNK Lysine-Deficient Protein Kinase 1
D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human; C498744:Wnk1 protein, mouse