Cyclic AMP signalling pathway and cellular proliferation: induction of CREM during liver regeneration

Abstract

The CREM gene encodes both activators and repressors of cAMP-induced gene expression. An isoform of CREM encodes the powerful transcriptional repressor ICER (Inducible cAMP Early Repressor), which has been shown to be inducible by virtue of an alternative, intronic promoter. The CREM gene belongs to the early response class and displays a characteristic neuroendocrine cell-and tissue-speci®c expression. To date ICER inducibility has been described in non-replicating, terminally di erentiated tissues. In this paper we document a robust induction of CREM expression in the regenerating rat liver after partial hepatectomy. This represents the ®rst link of inducible CREM expression to the phenomenon of cellular proliferation. Furthermore, it represents the ®rst example of transcriptional activation of a cAMP-responsive factor in the regenerating liver. This has signi®cant physiological relevance since the adenylate cyclase signalling pathway is strongly implicated in liver regeneration. Finally, we show that the repressor ICER is inducible in the hepatoma cell line H35 upon activation of the adenylate cyclase and phosphorylation of the activator CREB.

Cyclic AMP signalling and cellular proliferation: regulation of CREB and CREM

“…1). The markedly transient induction of ICER protein following PH [14], which differs from that observed in other systems [19,20], may suggest a distinct function. The involvement of CREM gene products in the regulation of cyclin A gene and possibly of the cell cycle has been also forwarded [21].…”

“…Various studies have documented associated changes in the expression of PKA subunits [5] and have strongly implicated cAMP in the regulation of hepatocyte proliferation [13]. Importantly, recent results indicate that treatment of hepatoma cells in vitro with cAMP results in a powerful CREB phosphorylation and in an increase of ICER levels [14]. These findings implicate the CREM gene as a major player in the cAMP-regulated response of hepatocytes [14].…”

“…As mentioned, recent results document dynamic expression of CRE-binding factors in liver and cultured hepatoma cells [14]. Indeed, both CREB phosphorylation and ICER [15,16] expression are powerfully induced following partial hepatectomy.…”

“…Importantly, recent results indicate that treatment of hepatoma cells in vitro with cAMP results in a powerful CREB phosphorylation and in an increase of ICER levels [14]. These findings implicate the CREM gene as a major player in the cAMP-regulated response of hepatocytes [14]. Thus, in addition to modulating gene expression in response to hormonal stimuli in differentiated cells, these transcription factors have a role in the proliferative events linked to liver regeneration after partial hepatectomy (Fig.…”

“…The first peak occurs 2-6 h after partial hepatectomy, while the second peak, which precedes DNA synthesis, occurs 10-16 h after partial hepatectomy [4,12]. ICER inducibility coincides with the first peak [14].…”