Transcription factor CREM coordinates the timing of hepatocyte proliferation in the regenerating liver

Abstract

The liver regenerates upon partial hepatectomy (PH) as terminally differentiated hepatocytes undergo a tremendous proliferative process. CREM gene expression is powerfully induced during liver regeneration. We show that cell proliferation is significantly reduced upon PH in CREM −/− mice. There is a reduction in DNA synthesis, in the number of mitosis and of phosphorylated histone H3-positive cells. The post-PH proliferation peak is delayed by 10 hr, indicating an altered hepatocyte cell cycle. Expression of cyclins A, B, D1, E, and cdc2, of c-fos and tyrosine aminotransferase is deregulated. CREM mutation results in delayed S-phase entry, impairing the synchronization of proliferation. Received September 10, 1998; revised version accepted October 15, 1998. The liver is one of the most important organs for homeostasis in mammals. Among its properties is the remarkable ability to regenerate following partial hepatectomy (Michalopoulos 1990;Fausto 1994). As much as 70% of the liver can be surgically removed and hepatocytes will proliferate to fully regenerate the original cell mass. The initial rounds of cell division are synchronous, and the first DNA replication occurs within 24 hr of surgery in the rat. The regeneration process is completed within 10-15 days (Bucher 1963).A number of hormones, growth factors, and cytokines and their coupled signal transduction pathways have been implicated in governing hepatocyte proliferation, but the precise orchestration of these factors is poorly understood (Diehl and Rai 1996;Michalopoulos and De Frances 1997). In particular, cytokines IL-6 and TNF have been implicated in initiating hepatocyte DNA synthesis during regeneration (Fausto et al. 1995;Cressman et al. 1996;Yamada et al. 1997), whereas the DNA-binding activity of the downstream transcription factors Stat3 and NF-B increases during the first hours following hepatectomy (Taub 1996).A characteristic feature of liver regeneration is the dramatic increase in intracellular cAMP levels during the hepatocyte proliferation process, although its significance has remained elusive (Diehl et al. 1992). cAMP peaks during the first hours following partial hepatectomy, whereas elevated levels of cAMP also correlate with the proliferation of liver cell at birth (Diehl and Rai 1996). These notions underscore the critical role that must be played by cAMP-responsive transcription factors in liver regeneration.Transcription factors coupled to cAMP signaling constitute a family of closely related bZIP proteins, either activators or repressors, binding to cAMP-responsive promoter elements (CREs) located within the regulatory regions of cAMP-inducible genes (Sassone-Corsi 1995; Montminy 1997). The factors CREB (CRE-binding protein), CREM (CRE modulator), and ATF-1 (activator transcription factor 1) are turned into activators by phosphorylation at a serine residue (Ser-133 in CREB; Ser-117 in CREM) (Gonzalez and Montminy 1989;De Groot et al. 1993) elicited by PKA and other kinases (SassoneCorsi 1995;Montminy 1997). Interestingly, a C...

Mitogen-activated Protein Kinase Phosphorylates and Targets Inducible cAMP Early Repressor to Ubiquitin-mediated Destruction

“…1D). These results demonstrate that the cAMP pathway not only induced ICER RNA and protein levels as demonstrated before (12)(13)(14)(15)(16)(17)(18)23) but also regulated ICER protein stability. In this study, we examined the molecular mechanism of these phenomena and its implications on the regulation of ICER protein.…”

“…ICER has been linked to regulation of cell growth (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). ICER blocks cells at the S and G 2 /M phases of the cell cycle (15).…”

Antagonistic control of cell fates by JNK and p38-MAPK signaling

“…Partial hepatectomy was performed as described previously. 16 Mouse experiments were performed according to institutional guidelines.…”

Expression and distribution of immunoglobulin G in the normal liver, hepatocarcinoma and postpartial hepatectomy liver

“…After an overnight fast, rats were anesthetized with sodium pentobarbital (30 mg/kg, intraperitoneally), and the large left lateral lobe and median lobes were ligated and removed according to the method of Higgins and Anderson. 25 At the indicated time points (0, 1, 3, 5, 7 or 10 days after surgery), the animals were euthanized, and the livers were collected and examined.…”