Extracellular ATP activates c-jun N-terminal kinase signaling and cell cycle progression in hepatocytes

Hepatology. 2004 Feb;39(2):393-402. doi: 10.1002/hep.20075.


Partial hepatectomy leads to an orchestrated regenerative response, activating a cascade of cell signaling events necessary for cell cycle progression and proliferation of hepatocytes. However, the identity of the humoral factors that trigger the activation of these pathways in the concerted regenerative response in hepatocytes remains elusive. In recent years, extracellular ATP has emerged as a rapidly acting signaling molecule that influences a variety of liver functions, but its role in hepatocyte growth and regeneration is unknown. In this study, we sought to determine if purinergic signaling can lead to the activation of c-jun N-terminal kinase (JNK), a known central player in hepatocyte proliferation and liver regeneration. Hepatocyte treatment with ATPgammaS, a nonhydrolyzable ATP analog, recapitulated early signaling events associated with liver regeneration-that is, rapid and transient activation of JNK signaling, induction of immediate early genes c-fos and c-jun, and activator protein-1 (AP-1) DNA-binding activity. The rank order of agonist preference, UTP>ATP>ATPgammaS, suggests that the effects of extracellular ATP is mediated through the activation of P2Y2 receptors in hepatocytes. ATPgammaS treatment alone and in combination with epidermal growth factor (EGF) substantially increased cyclin D1 and proliferating cell nuclear antigen (PCNA) protein expression and hepatocyte proliferation in vitro. Extracellular ATP as low as 10 nM was sufficient to potentiate EGF-induced cyclin D1 expression. Infusion of ATP by way of the portal vein directly activated hepatic JNK signaling, while infusion of a P2 purinergic receptor antagonist prior to partial hepatectomy inhibited JNK activation. In conclusion, extracellular ATP is a hepatic mitogen that can activate JNK signaling and hepatocyte proliferation in vitro and initiate JNK signaling in regenerating liver in vivo. These findings have implications for enhancing our understanding of novel factors involved in the initiation of regeneration, liver growth, and development.

Publication types

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

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Adenosine Triphosphate / pharmacology
  • Animals
  • Cell Division / physiology
  • Cells, Cultured
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Extracellular Space / metabolism
  • Gene Expression Regulation, Enzymologic
  • Hepatocytes / cytology
  • Hepatocytes / enzymology*
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Mitogens / metabolism*
  • Mitogens / pharmacology
  • Phosphorylation
  • Proliferating Cell Nuclear Antigen / genetics
  • Proliferating Cell Nuclear Antigen / metabolism
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Purinergic P2 Receptor Antagonists
  • Rats
  • Receptors, Purinergic P2 / metabolism
  • Receptors, Purinergic P2Y2
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Transcription Factor AP-1 / metabolism


  • Mitogens
  • Proliferating Cell Nuclear Antigen
  • Proto-Oncogene Proteins c-fos
  • Purinergic P2 Receptor Antagonists
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2Y2
  • Transcription Factor AP-1
  • Cyclin D1
  • Adenosine Triphosphate
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases