Transforming growth factor beta and activin tonically inhibit DNA synthesis in the rat liver.
The present study was conducted to assess the role of transforming growth factor beta (TGF-beta) and activin(s) in the regulation of the mass of the liver. To this end, we eliminated TGF-beta or activin signaling in intact rat liver by adenovirus-mediated transfer of the gene encoding truncated type II TGF-beta receptor (AdextTR) or truncated type II activin receptor (AdextAR). In intact rat liver that received a single application of either AdextTR or AdextAR via the portal vein, DNA synthesis as assessed by bromodeoxy uridine (BrdU) labeling was induced. In AdextTR- or AdextAR-treated rats, nuclear labeling was significantly higher than that in AdexLacZ, adenovirus vector encoding Escherichia coli beta-galactosidase gene, or saline-treated rats at 3, 5, 7, and 9 days of infusion. The peak of the BrdU labeling was observed after 7 days of infusion and the labeling decreased thereafter. Apoptosis of hepatocytes, assessed by the terminal deoxynucleotidyl transferase (TdT)-mediated, dUTP-biotin nick-end labeling method was detected after 9 days of infusion. Immunoreactivity of TGF-beta and activin A increased in the liver after the blockade of the activin or TGF-beta signaling. TGF-beta and activin A may have been up-regulated when the action of these ligands was blocked. These results indicate that blockade of the action of either TGF-beta or activin leads to the initiation of DNA synthesis in intact liver. TGF-beta and activin tonically inhibit hepatocyte growth even in intact liver and may play a critical role in the maintenance of constant liver mass.
Ichikawa
T
T
First Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Japan.
Zhang
Y Q
YQ
Kogure
K
K
Hasegawa
Y
Y
Takagi
H
H
Mori
M
M
Kojima
I
I
D029404:Activin Receptors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D028341:Activins / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D001973:Bromodeoxyuridine / Q000493:pharmacokinetics; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018014:Gene Transfer Techniques; D005799:Genes, Dominant; D007150:Immunohistochemistry; D028322:Inhibin-beta Subunits / Q000378:metabolism; D008099:Liver / Q000033:anatomy & histology / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D008297:Male; D009929:Organ Size / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*
D020033:Protein Isoforms; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C422405:activin A; D028341:Activins; D004247:DNA; D028322:Inhibin-beta Subunits; D029404:Activin Receptors; D001973:Bromodeoxyuridine