Activin A: an autocrine inhibitor of initiation of DNA synthesis in rat hepatocytes.
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.
Yasuda
H
H
Cell Biology Research Unit, Gunma University, Maebashi, Japan.
Mine
T
T
Shibata
H
H
Eto
Y
Y
Hasegawa
Y
Y
Takeuchi
T
T
Asano
S
S
Kojima
I
I
D028341:Activins; D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004261:DNA Replication / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D038681:Follistatin; D015870:Gene Expression / Q000187:drug effects; D006023:Glycoproteins / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D066298:In Vitro Techniques; D007265:Inhibins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008099:Liver / Q000166:cytology*; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D051381:Rats; D011994:Recombinant Proteins; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism
D038681:Follistatin; D006023:Glycoproteins; D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D028341:Activins; D007265:Inhibins; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D004247:DNA