Liver hyperplasia is not necessarily associated with increased expression of c-fos and c-myc mRNA

Abstract

Experiments were designed to investigate the expression of three cell-cycle-dependent proto-oncogenes in response to two different types of proliferative stimuli: compensatory cell proliferation after partial hepatectomy (PH) or CCl4 and liver hyperplasia induced by the mitogens ethylene dibromide (EDB) and cyproterone acetate (CPA). Steady-state levels of messenger RNAs for c-fos and c-myc were found to be elevated after PH or CCl4 with a maximum increase between 0.5 and 2 h for c-fos and at 2-3 h for c-myc and a rapid decline after 3 h. However, when liver cell proliferation was induced by mitogens, no increase in the expression of c-fos mRNA was observed with both EDB or CPA during the first 24 h. In addition, elevated expression of c-myc was found only in liver hyperplasia induced by EDB, but not with CPA. While the expression of c-myc mRNA and c-fos mRNA was different in the two types of proliferative stimuli, that of c-Ha-ras and c-Ki-ras was similar in all the experimental groups. Cell proliferation monitored by means of incorporation of labelled thymidine into DNA or mitotic index at 24 h following PH, EDB and CPA occurred at a similar extent in all the experimental groups. Our data indicate that the transient and sequential expression of cell-cycle-related genes may vary in response to proliferative stimuli of different nature and suggest that increased expression of cell-cycle-related genes may not be a necessary prerequisite for the entry of the cells into the cell cycle.

Increased expression of c-fos, c-jun and LRF-1 is not required for in vivo priming of hepatocytes by the mitogen TCPOBOP

“…The results clearly show that no increase in steady state levels of c-fos occurs following treatment with both mitogens ( Figure 1A and B). This ®nding is in agreement with our previous results indicating that c-fos is not required for rat liver cell proliferation induced by cyproterone acetate and nafenopin (Coni et al, 1990). Following these studies, additional evidence has been accumulated indicating that increased c-fos expression is not necessary for hepatocyte proliferation induced by six dierent mitogens (Coni et al, 1993;Goldsworthy et al, 1994;Ohmura et al, 1996a).…”

“…In particular, it has been previously shown that direct hyperplasia induced by primary mitogens may be induced in the complete or partial absence of modi®cations in the expression of immediate early genes such as c-fos, c-jun and LRF-1 (Coni et al, 1990(Coni et al, , 1993Ohmura et al, 1996a). Therefore, we have determined the pattern of modi®cations of these genes during direct hyperplasia induced in mouse liver by two distinct mitogens, TCPOBOP and EDB.…”

“…On the other hand, c-jun and LRF-1 were induced by EDB 1 h after treatment. Interestingly, increased c-jun, but not c-fos mRNA levels, were observed also in rat liver after EDB treatment (Coni et al, 1990(Coni et al, , 1993. Expression of IGFBP-1 and PRL-1 IGFBP-1 is a kidney/liver restricted gene that is rapidly induced more than 100-fold during liver regeneration after PH with peak expression at 1 h post-hepatectomy in rats.…”

“…Enhanced expression of immediate early genes, together with activation of pre-existing latent transcription factors, such as AP-1, NF-kB and STAT3, is generally considered to be part of an obligatory set of events needed for the priming step of hepatocytes, namely the G 0 -G 1 transition (Cressman et al, 1994;FitzGerald et al, 1995). Recently, however, the notion that activation of the transcription factors AP-1 and NFkB and increased expression of immediate early genes are necessary events in the G 0 -G 1 transition has been questioned by the ®nding that rat liver cell proliferation induced by agents that do not cause previous hepatic cellular loss/death (primary mitogens) may well occur in the absence of any signi®cant change in c-fos, c-jun and c-myc expression (Coni et al, 1990(Coni et al, , 1993. Moreover, a single treatment with two peroxisome proliferators, BR931 and Nafenopin (NAF), causes hepatocyte proliferation in the absence of increased expression of other immediate early genes, such as egr-1 and LRF-1 (Ohmura et al, 1996a), and activation of the transcription factors NF-kB and AP-1 (Menegazzi et al, 1996).…”

Involvement of DNA polymerase β in proliferation of rat liver induced by lead nitrate or partial hepatectomy

“…DNA polymerase B seems to be one of the most important enzymes involved in the repair of damaged DNA because of its preference for short gaps formed during excision repair [2]. Recent studies show a different distribution of DNA polymerase B activity, as well as of the levels of its mRNA, in tissues of mouse [3] and rat 141.…”