The unusual regenerative properties of the liver are a logical adaptation by organisms, as the liver is the main detoxifying organ of the body and is likely to be injured by ingested toxins. The numerous cytokine- and growth-factor-mediated pathways that are involved in regulating liver regeneration are being successfully dissected using molecular and genetic approaches. So what is known about this process at present and which questions remain?

Liver regeneration stimulated by a loss of liver mass leads to hepatocyte and nonparenchymal cell proliferation and rapid restoration of liver parenchyma. Mice with targeted disruption of the interleukin-6 (IL-6) gene had impaired liver regeneration characterized by liver necrosis and failure. There was a blunted DNA synthetic response in hepatocytes of these mice but not in nonparenchymal liver cells. Furthermore, there were discrete G1 phase (prereplicative stage in the cell cycle) abnormalities including absence of STAT3 (signal transducer and activator of transcription protein 3) activation and depressed AP-1, Myc, and cyclin D1 expression. Treatment of IL-6-deficient mice with a single preoperative dose of IL-6 returned STAT3 binding, gene expression, and hepatocyte proliferation to near normal and prevented liver damage, establishing that IL-6 is a critical component of the regenerative response.

The consistent appearance of specific chromosomal translocations in human Burkitt lymphomas and murine plasmacytomas has suggested that these translocations might play a role in malignant transformation. Here we show that transformation of these cells is frequently accompanied by the somatic rearrangement of a cellular analogue of an avian retrovirus transforming gene, c-myc. Moreover, we map c-myc to human chromosome 8 band q24, the chromosomal segment involved in the reciprocal Burkitt translocations [t(8;14), t(8;22), and t(2;8)]. In two t(8;14) human Burkitt cell lines, c-myc appears to have been translocated directly into a DNA restriction fragment that also encodes the immunoglobulin ,u chain gene. In the case of a specific cloned fragment of DNA derived from a mouse plasmacytoma, we demonstrate directly that c-myc has been translocated into the immunoglobulin a switch region. Our data provide a molecular basis for considering the role that specific translocations might play in malignant transformation.

No abstract

No abstract

Determining what factors are responsible for initiating regeneration following partial hepatectomy or toxic damage, and how the liver maintains differentiated functions while the hepatocytes are undergoing cellular proliferation are central issues in understanding the molecular bases of liver regeneration. Examination of the transcriptional milieu in the regenerating liver provides clues to the answers to these questions. Growth factor-generated intracellular signals that trigger liver regeneration result in activation via posttranslational modifications of latent, normally inactive transcription factors that preexist in the liver. Two transcription factors that are activated by this mechanism include posthepatectomy factor/nuclear factor-kappa B) and Stat3. Because cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-l (IL-1), and IL-6 can induce these factors in the liver, the finding of activated Stat3 and PHF/NF-kappa B suggests that these cytokines may play a role in some aspects of growth regulation during liver regeneration. Rapidly induced transcription factors, Stat3, PHF/NF-kappa B, and others are responsible for activation of the primary growth response or immediate-early genes, which play a role in regulating later phases of cell growth in regenerating liver and other mitogen-activated cells. Immediate-early genes encode many members of diverse transcription factor families including the Jun-Fos-LRF-1, nuclear receptor, and myc families to name a few. In this way a transcriptional cascade is established during the G1 phase of liver regeneration. Coexisting with these induced factors are liver-specific transcription factors such as the CAAT enhancer binding proteins and hepatocyte nuclear factors, which may interact with growth-induced factors to help the liver maintain metabolic homeostasis during regeneration. As a result the liver is able to accomplish the goals of reestablishing its mass while it maintains its functional capacity during regeneration.

The characteristic chromosomal translocations that occur in certain human malignancies offer opportunities to understand how two gene systems can affect one another when they are accidentally juxtaposed. In the case of Burkitt lymphoma, such a translocation joins the cellular oncogene, c-myc, to a region encoding one of the immunoglobulin genes. In at least one example, the coding sequence of the rearranged c-myc gene is identical to that of the normal gene, implying that the gene must be quantitatively, rather than qualitatively, altered in its expression if it is to play a role in transformation. One might expect to find the rearranged c-myc gene in a configuration that would allow it to take advantage of one of the known immunoglobulin promoters or enhancer elements. However, the rearranged c-myc gene is often placed so that it can utilize neither of these structures. Since the level of c-myc messenger RNA is often elevated in Burkitt cells, the translocation may lead to a deregulation of the c-myc gene. Further, since the normal allele in a Burkitt cell is often transcriptionally silent in the presence of a rearranged allele, a model for c-myc regulation is suggested that involves a trans-acting negative control element that might use as its target a highly conserved portion of the c-myc gene encoding two discrete transcriptional promoters.

STAT3 is rapidly induced during liver regeneration in an interleukin 6 (IL-6)-dependent fashion, and IL-6 is required for normal liver regeneration. We wanted to know whether STAT3 was also required for liver regeneration but disruption of the STAT3 gene during embryonic stages causes lethality. Therefore, an albumin promoter-driven Cre-loxP recombination system was used to create a STAT3 deletion in the adult mouse liver to study the role of STAT3 in liver regeneration. After partial hepatectomy, there was virtually no STAT3 RNA or protein induction in Alb Liver regeneration after a two-thirds partial hepatectomy provides an excellent in vivo model for studying cell cycle progression and cell proliferation (1). Differentiated hepatocytes rapidly reenter the cell cycle after surgical removal of the left lateral and median lobes of the liver. Following two rounds of DNA synthesis and cell division, liver mass is restored within 2 weeks (2). Interleukin-6 (IL-6) 1 is known as one of the most important initiators of the regenerative response (3, 4). IL-6Ϫ/Ϫ mice have impaired liver regeneration characterized by liver necrosis and failure, a blunted DNA synthetic response in hepatocytes, and reduced gene activation during G 1 phase. Furthermore, STAT3 activation is absent posthepatectomy in IL-6Ϫ/Ϫ livers, which supports a possible pro-proliferative role of STAT3 in hepatocytes (3). IL-6 induces a large spectrum of immediate-early genes (4), in part through direct activation via STAT3 binding sites and in part through cooperative interaction between STAT3 and other transcription factors (5). However, because IL-6 also activates other signaling pathways including the mitogen-activated protein kinase (MAPK) pathway during liver regeneration (4), it is not clear whether the absence of STAT3 is responsible for part or all of the growth defects that are seen in IL-6Ϫ/Ϫ livers.Signal transducer and activator of transcription 3 (STAT3) belongs to the family of STAT transcription factors which mediate the cellular response to a variety of cytokines and growth factors including IL-6 (6 -8). When IL-6 binds to its specific receptor subunit, it can induce dimerization of the gp130 receptor and activation of the gp130-associated Janus kinase (Jak). The Jaks in turn phosphorylate the specific tyrosines in the intracellular domain of the gp130, providing docking sites for the Src homology 2 (SH2) domain of signaling molecules including STAT3. Once recruited to the receptor chains, STAT3 itself becomes tyrosine phosphorylated by the Jaks, which leads to the dissociation, dimerization, and nuclear translocation of the activated STAT3. Nuclear STAT3 can then bind to specific promoter elements on DNA and activate target gene transcription (9 -11).Because STAT3 deletion leads to embryonic lethality (12), in vivo data could not be obtained from STAT3 knock-out mice to clarify the role of STAT3 in mediating the effect of IL-6 during liver regeneration. Recently, several laboratories independently have developed conditional STAT3 knock-o...