Multiple promoters in the WNK1 gene: one controls expression of a kidney-specific kinase-defective isoform

Mol Cell Biol. 2003 Dec;23(24):9208-21. doi: 10.1128/MCB.23.24.9208-9221.2003.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Base Sequence
  • CHO Cells
  • Cell Line
  • Chromosome Mapping
  • Cricetinae
  • DNA, Complementary / genetics
  • Dogs
  • Gene Expression Regulation, Enzymologic
  • Humans
  • In Vitro Techniques
  • Intracellular Signaling Peptides and Proteins
  • Isoenzymes / genetics
  • Kidney / enzymology*
  • Mice
  • Minor Histocompatibility Antigens
  • Molecular Sequence Data
  • Promoter Regions, Genetic*
  • Protein Serine-Threonine Kinases / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sequence Homology, Nucleic Acid
  • Transcription Initiation Site
  • WNK Lysine-Deficient Protein Kinase 1

Substances

  • DNA, Complementary
  • Intracellular Signaling Peptides and Proteins
  • Isoenzymes
  • Minor Histocompatibility Antigens
  • RNA, Messenger
  • Protein Serine-Threonine Kinases
  • WNK Lysine-Deficient Protein Kinase 1
  • WNK1 protein, human
  • Wnk1 protein, mouse

Associated data

  • GENBANK/AY231477