Reciprocal Expression of mRNA for Inhibin .BETA.C and .BETA.A Subunits in Hepatocytes.

Abstract

Abstract. Messenger RNA expression of activin fc subunit in the liver was compared with that for flA subunit before and after 70% hepatectomy.mRNA for 1k was abundantly expressed in the liver but decreased at 12 h and later after 70% hepatectomy, whereas that for f A was increased 12 h after the hepatectomy.We also compared the expression of mRNA for J3A and f3c in cultured rat hepatocytes. mRNA for /c subunit was abundantly expressed in the beginning of the culture but was reduced gradually after stimulation with epidermal growth factor. In contrast, mRNA for fA subunit was undetectable before stimulation and was increased 24 to 48 h after stimulation with the mitogen. These results indicate that expression of mRNA for f k and /3A is regulated differently. The role of activin C may be different from that of activin A in the liver. Key words:Activin, Liver regeneration, Hepatocyte (Endocrine Journal 44: 759-764, 1997) ACTIVINS belong to the transforming growth factor-fl (TGF-f3) supergene family and elicit diverse effects in various cell systems [1,2]. In particular, activin modify growth, differentiation and survival of epithelial and mesenchymal cells. In the liver, activin A is expressed predominantly in parenchymal cells and acts as an autocrine inhibitor of cell growth [3]. Activin A also induces apoptosis in parenchymal liver cells [4,5]. In cultured rat hepatocytes, the expression of activin f3A subunit is low at the beginning of the culture, but is increased 24 h after the stimulation by epidermal growth factor (EGF). The peak of the expression is observed in the middle to late Gi phase [3]. Activin A released from hepatocytes exerts tonic inhibition of DNA synthesis [3,6] so that activin A acts as a brake system for the GI progression of hepatocytes. Expression of activin A is relatively low in intact liver, reduced immediately after 70% hepatectomy, and markedly increased 24 h after the hepatectomy [3]. When the effect of endogenous activin was blocked by an administration of follistatin, liver regeneration was accelerated [7]. Therefore, activin A also acts as a brake on liver regeneration in vivo.Other subunits of activin have recently been identified [8][9][10]. Hotten et al. isolated a cDNA for the activin f3c subunit [9]. The amino acid sequence of activin 1c deduced from cDNA has 51% homology with that of activin 13A. Of particular interest is the fact that 11c mRNA is expressed predominantly in the liver [11]. This raises the possibility that activin ,Bc plays a significant role in the regulation of liver cell function including growth and differentiation.As an initial step in elucidating the role of activin f3c subunit in the liver, we studied the expression of mRNA for flc subunit in the liver of the rat and mouse before and after hepatectomy.The results indicate that the pattern of expression mRNA for flc is a mirror image of that for 13A.

Activins and follistatins: Emerging roles in liver physiology and cancer

“…In regenerating liver, activin beta A gene expression was reduced at time points when hepatocyte replication took place and was increased at time points when liver regeneration terminated [42] . Other studies, however, have described increased expression of beta A at earlier time points after partial hepatectomy [43,44] . Beside its effects on DNA synthesis and cell growth, activin A also regulates restoration of liver architecture after partial hepatectomy by stimulating collagen production in hepatic stellate cells (HSC) and tubulogenesis of sinusoidal endothelial cells [45,46] .…”

“…The activin beta C subunit was cloned from liver cDNA and demonstrated to be predominantly expressed in hepatocytes by Northern blot analysis and RNAse protection assays [11,44,75,76] . By immunohistochemistry, significant activin beta C expression has been detected in cells from additional organs, including the prostate, ovary, testes, and pituitary gland [10,77] .…”

Expression and dimerization of the rat activin subunits betaC and betaE: evidence for the ormation of novel activin dimers

“…However, so far it is unclear whether activin C or E have any similar potential. In liver regeneration activin A, C and E showed a distinct expression pattern (compare Esquela et al 1997, Zhang et al 1997, Lau et al 2000. Activin A mRNA like that of TGF-builds up to reach high levels in later phases of regeneration, possibly associated with the termination of DNA synthesis (for discussion see Rossmanith & Schulte-Hermann 2001).…”

“…Activin A mRNA like that of TGF-builds up to reach high levels in later phases of regeneration, possibly associated with the termination of DNA synthesis (for discussion see Rossmanith & Schulte-Hermann 2001). In the case of activin C mRNA, different expression patterns in regeneration have been observed by different researchers, although in neither case was there any upregulation later than 24 h after partial hepatectomy (Esquela et al 1997, Zhang et al 1997, Lau et al 2000. Expression of activin E was highly upregulated after 6 h, but declined rapidly thereafter (Lau et al 2000).…”

Cell cycle regulation and hepatocarcinogenesis

“…In contrast to C/EBPα, whose expression decreases during cell cycle progression in the regenerating liver, other proteins that inhibit or retard cell cycle progression including the cyclin dependent kinase inhibitors p21, 98 p27 99 and p18, 100 as well as p53, 101 TGF-β [102][103][104] and activin [105][106][107] are induced after partial hepatectomy, possibly as a safeguard to limit the extent of proliferation. Forced expression of some of these proteins has been shown to inhibit hepatocyte proliferation 108,109 consistent with their importance for regulating either the timing of cell cycle progression or terminating the regenerative process.…”