Regulation of the rat liver sodium-dependent bile acid cotransporter gene by prolactin. Mediation of transcriptional activation by Stat5

J Clin Invest. 1997 Jun 15;99(12):2906-14. doi: 10.1172/JCI119485.


The intracellular mechanism(s) underlying the upregulation of the hepatic Na+/taurocholate cotransporting polypeptide (ntcp) by prolactin (PRL) are unknown. In this report, we demonstrate a time-dependent increase in nuclear translocation of phosphorylated liver Stat5 (a member of the ignal ransducers and ctivators of ranscription family) that correlated with suckling-induced increases in serum PRL levels. In electrophoretic mobility gel shift assays, nuclear Stat5 exhibited specific DNA-binding ability towards IFN-gamma-activated sequence (GAS)-like elements (GLEs; 5'TTC/A-PyNPu-G/TAA-3') located in the -937 to -904 bp region of the ntcp promoter. Transient cotransfections in HepG2 cells revealed that PRL inducibility (2.5-3-fold) required coexpression of the long form of the PRL receptor (PRLRL) and Stat5. Deletion analysis mapped the PRLinducible region to -1237 to -758 bp of the ntcp promoter. Linking this 0.5-kb region to a heterologous thymidine kinase (tk) promoter, or linking multimerized ntcp GLEs either upstream of the ntcp minimal promoter (-158 to +47 bp) or the heterologous promoter conferred dose-dependent PRL responsiveness. The short form of the PRL receptor failed to transactivate ntcp GLEs. These results indicate that PRL acts via the PRLRL to facilitate Stat5 binding to ntcp-GLEs and to transcriptionally regulate ntcp.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Animals, Suckling
  • Binding Sites
  • Carrier Proteins / genetics*
  • Cell Nucleus / metabolism
  • DNA / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Expression Regulation / drug effects*
  • Interferon-gamma / pharmacology
  • Kinetics
  • Liver / metabolism*
  • Milk Proteins*
  • Organic Anion Transporters, Sodium-Dependent*
  • Phosphorylation
  • Phosphotyrosine / metabolism
  • Prolactin / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Prolactin / genetics
  • STAT5 Transcription Factor
  • Sodium / pharmacology*
  • Symporters*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transfection


  • Carrier Proteins
  • DNA-Binding Proteins
  • Milk Proteins
  • Organic Anion Transporters, Sodium-Dependent
  • Receptors, Prolactin
  • STAT5 Transcription Factor
  • Symporters
  • Trans-Activators
  • sodium-bile acid cotransporter
  • Phosphotyrosine
  • Interferon-gamma
  • Prolactin
  • DNA
  • Sodium