Search

The physiological importance of the liver is demonstrated by its unique and essential ability to regenerate following extensive injuries affecting its function. By regenerating, the liver reacts to hepatic damage and thus enables homeostasis to be restored. The aim of this review is to add new findings that integrate the regenerative pathway to the current knowledge. An optimal regeneration is achieved through the integration of two main pathways: IL-6/JAK/STAT3, which promotes hepatocyte proliferation, and PI3K/PDK1/Akt, which in turn enhances cell growth. Proliferation and cell growth are events that must be balanced during the three phases of the regenerative process: initiation, proliferation and termination. Achieving the correct liver/body weight ratio is ensured by several pathways as extracellular matrix signalling, apoptosis through caspase-3 activation, and molecules including transforming growth factor-beta, and cyclic adenosine monophosphate. The actors involved in the regenerative process are numerous and many of them are also pivotal players in both the immune and non-immune inflammatory process, that is observed in the early stages of hepatic regeneration. Balance of Th17/Treg is important in liver inflammatory process outcomes. Knowledge of liver regeneration will allow a more detailed characterisation of the molecular mechanisms that are crucial in the interplay between proliferation and inflammation.

A tight link has been established between inflammation and cancer. Liver regeneration is a widely used model to study the correlation between inflammation and proliferation. IL-6 is essentially involved in liver regeneration and in cancer. Recently, IL-17A has been shown to regulate not only inflammation, but also cell proliferation. Here, we analyze the role played by IL-17A signaling in liver regeneration by comparing cell proliferation in Wild Type and IL-17RA -/- mice. Partial hepatectomy experiments performed in IL-17RA -/- mice showed a delay in expression of early-genes to prime the residual hepatocyte to proliferate, with subsequent delay in G 1 /S-phase transition. We demonstrated that IL-17RA regulates, by recruitment of non-parenchymal cell, the expression of IL-6, which in turn triggers the proliferation of residual hepatocytes. Our data indicate an important role played by IL-17RA in liver proliferation via IL-6.

Liver regeneration is a unique means of studying cell proliferation in vivo. Screening of a large cDNA library from regenerating liver has previously allowed us to identify and characterize a cluster of genes encoding proteins with important roles in proliferative processes. Here, by examining different rat and human tissues as well as cell lines, we characterized a highly conserved gene, guanylyl cyclase domain containing 1 (GUCD1), whose modulation occurs in liver regeneration and cell cycle progression in vitro. High-level expression of GUCD1 transcripts was observed in livers from patients with hepatocellular carcinoma. A yeast two-hybrid interaction assay, aimed at identifying any relevant interaction partners of GUCD1, revealed direct interactions with NEDD4-1 (E3 ubiquitin protein ligase neural precursor cell expressed, developmentally downregulated gene 4), resulting in control of GUCD1 stability. Thus, we have characterized expression and function of a ubiquitous protein, GUCD1, which might have a role in regulating normal and abnormal cell growth in the liver.

Background/aims: Transcription factors coupled to cyclic adenosine mono phosphate (cAMP) signalling in the cAMP-responsive elements binding (CREB)/ATF family constitute a family of activators or repressors that bind to cAMP-responsive promoter elements (CREs) in the regulatory regions of cAMP-inducible genes. A role for CREB/ATF family has been advocated in the control of hepatocellular carcinoma progression. CREB appears to be activated by the X protein of hepatitis B virus, which links to the unphosphorylated form of CREB and activates transcription, thus obviating an otherwise indispensable Ser-133 phosphorylation. Identification of factors capable of triggering transcription via cAMP-responsive elements modulator (CREM)/CREB signalling in the absence of Ser phosphorylation will improve our knowledge of the molecular mechanism of liver cell proliferation., Methods: To isolate and study proteins binding and activating CREB and/or CREM in the liver, we performed the screening of a mouse liver cDNA library using the Two-Hybrid System., Results: We report the identification and characterization of a novel peptide, VTIP-peptide (VTIP-P), which binds and enhances the activation of CREM/CREB, obviating the need for transcription factor phosphorylation. We demonstrated that VTIP-P physically interacts with the activation domain (AD) of the transcription factors CREB/CREM and activates transcription by modifying their phosphorylation pattern in hepatoma cells. The data allowed the conclusion that VTIP-P binds the AD of CREB and CREM by stabilizing their phosphorylation., Conclusion: The characterization of molecules capable of interfering in the liver with an important pathway such as CREB could be significant in designing and/or developing new therapeutic approaches to the control of liver cell proliferation.

Background: During liver regeneration, 95% of the resting hepatocytes enter in G1/S phase of the cell cycle. A number of hormones, growth factors and cytokines were identified that activate signal transduction pathways playing a primary role in hepatocyte proliferation. A wide and representative cDNA library containing 1.5 x 106 independent clones was constructed from regenerating liver in order to identify and characterize gene the products which play a crucial role in the first hours of the proliferative process of liver regeneration., Results: A novel gene expressed in liver regeneration was cloned by subtractive hybridization. The putative protein displays in the N'-terminal a annexin-like domain and an aminopeptidase domain. We named the novel gene Liver Annexin Like-1 (lal-1). The lal-1 gene is modulated during liver regeneration, in hepatoma cells following physiological stimulation and after cAMP induction., Conclusion: The results indicate that lal-1 is involved in liver regeneration and that its expression is finely regulated during proliferative process. The isolation of lal-1 paves the way for a further characterization helping to assess lal-1 involvement in cell function and proliferation.

Liver regeneration represents an outstanding tool to study not only proliferation, but also other important processes such as inflammation, regenerative response or stem cell biology. Several novel genes have been identified as being involved in the proliferation of residual hepatocytes. One of them, HOPS/TMUB1, is proving to be a significant player in the control of proliferation, both contributing to genomic stability and as a partner of essential molecules. HOPS is an ubiquitin‐like protein, shuttling from nucleus to cytoplasm, and it is engaged in a number of biological and physiopathological functions. HOPS overexpression in tumour cell lines strongly reduces proliferation, arresting cell cycle in G0/G1. HOPS is involved in centrosome assembly and maintenance, and its knockdown causes genomic instability. Moreover, a direct interaction of HOPS with nucleophosmin (NPM) and p19Arf has been established, resulting in proper control of p19Arf stability and localization. These data indicate that HOPS acts as a functional bridge in the interaction between NPM and p19Arf, providing new mechanistic insight into how NPM and p19Arf will oppose cell proliferation. HOPS exerts a control in p53 stability, directing p53 mitochondrial apoptosis and cytoplasmic localization. HOPS plays a direct role as novel post‐translational modifier of p53, much like SUMO or NEDD. HOPS is overexpressed in a high number of human tumours in patients affected by large intestinal, CNS, liver and oesophageal tumours. This review highlights HOPS involvement in distinct cellular functions, establishing its role as a key player in cell biology and pathology in a broader context. [ABSTRACT FROM AUTHOR]

The oncosuppressor protein p53 plays a major role in transcriptionally controlling the expression of a number of genes, which in turn regulates many functions in response to DNA damage, oncogene triggering, oxidative, and additional cell stresses. A developing area of interest in p53 is the studies related to its cytoplasmic function(s). Many investigations revealed the significant role of p53 in the cytoplasm, acting in a transcriptional-independent manner in important processes related to cell homeostasis such as; apoptosis, autophagy, metabolism control, drug, and oxidative stress response. The studies on cytoplasmic p53 have shown intricate mechanisms by which posttranslational modifications allow p53 to perform its cytoplasmic functions. A number of ubiquitins, deubiquitins, and small ubiquitin-like proteins, have a pivotal role in controlling cytoplasmic stability and localization. Recently, HOPS/TMUB1 a novel small ubiquitin-like protein has been described as a vital molecule stabilizing p53 half-life, directing it to the mitochondria and favoring p53-mediated apoptosis. Furthermore, HOPS/TMUB1 competing with importin-α lessens p53 nuclear localization, thereby increasing cytoplasmic concentration. HOPS/TMUB1 as p53 modifiers could be attractive candidates to elucidate apoptosis or other important transcriptional-independent functions which are key in cancer research in order to develop new therapeutic approaches. [ABSTRACT FROM AUTHOR]

The liver has the ability to autonomously regulate growth and mass. Following partial hepatectomy, hormones, growth factors, cytokines and their coupled signal transduction pathways have been implicated in hepatocyte proliferation. To understand the mechanisms responsible for the proliferative response, we studied liver regeneration by characterization of novel genes that are activated in residual hepatocytes. A regenerating fiver cDNA library screening was performed with cDNA-subtracted probes derived from regenerating and normal liver. Here, we describe the biology of Hops (for hepatocyte odd protein shuttling). HOPS is a novel shuttling protein that contains an ubiquitin-like domain, a putative NES and a proline-rich region. HOPS is rapidly exported from the nucleus and is overexpressed during liver regeneration. Evidence shows that cAMP governs HOPS export in hepatocytes of normal and regenerating liver and is mediated via CRM-1. We demonstrate that HOPS binds to elongation factor eEF-1A and interferes in protein synthesis. HOPS overexpression in H-35-hepatoma and 3T3-NIH cells strongly reduces proliferation. [ABSTRACT FROM AUTHOR]