Activin A: an autocrine inhibitor of initiation of DNA synthesis in rat hepatocytes

J Clin Invest. 1993 Sep;92(3):1491-6. doi: 10.1172/JCI116727.


The present study was conducted to examine the effect of activin A on growth of rat hepatocytes. EGF induced a 10-fold increase in DNA synthesis as assessed by [3H]thymidine incorporation in cultured hepatocytes. When activin A was added together with EGF, DNA synthesis induced by EGF was markedly inhibited. Inhibition was detected at a concentration of 10(-10) M, and 5 x 10(-9) M activin A almost completely blocked EGF-mediated DNA synthesis. Similarly, activin A completely blocked DNA synthesis induced by hepatocyte growth factor/scatter factor. Activin A was capable of inhibiting EGF-mediated DNA synthesis, even when added 36 h after the addition of EGF. With the same time interval, TGF-beta also blocked EGF-induced DNA synthesis. Although both activin A and TGF-beta inhibited growth of hepatocytes in a similar manner, either activin A or TGF-beta did not compete with each other in their binding when assessed by competitive binding using an iodinated ligand. When hepatocytes were incubated with EGF, release of bioactivity of activin A into culture medium was detected after 48 h or later. Activity of activin A was released from parenchymal cells but not from nonparenchymal cells. mRNA for beta A subunit of activin was detected only slightly in unstimulated hepatocytes, but markedly increased at 48 h after the addition of EGF. To determine whether endogenously produced activin A affects DNA synthesis, we examined the effect of follistatin, an activin-binding protein that blocks the action of activin A. An addition of follistatin significantly enhanced EGF-induced DNA synthesis. Finally, in partial hepatectomized rat, expression of mRNA for beta A subunit in liver was markedly increased 24 h after the partial hepatectomy. These results indicate that activin A inhibits initiation of DNA synthesis in hepatocytes by acting on its own receptor and that activin A acts as an autocrine inhibitor of DNA synthesis in rat hepatocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins
  • Animals
  • Base Sequence
  • Cell Division / drug effects
  • Cells, Cultured
  • DNA / biosynthesis*
  • DNA Replication / drug effects
  • Epidermal Growth Factor / pharmacology
  • Follistatin
  • Gene Expression / drug effects
  • Glycoproteins / pharmacology
  • Hepatocyte Growth Factor / pharmacology
  • In Vitro Techniques
  • Inhibins / genetics
  • Inhibins / metabolism
  • Inhibins / pharmacology*
  • Liver / cytology*
  • Molecular Sequence Data
  • Oligodeoxyribonucleotides / chemistry
  • Rats
  • Recombinant Proteins
  • Time Factors
  • Transforming Growth Factor beta / metabolism


  • Follistatin
  • Glycoproteins
  • Oligodeoxyribonucleotides
  • Recombinant Proteins
  • Transforming Growth Factor beta
  • Activins
  • Inhibins
  • Epidermal Growth Factor
  • Hepatocyte Growth Factor
  • DNA