Published by De Gruyter

Volume 390 Issue 10

Issue of Biological Chemistry

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Contents
Journal Overview

Guest Editorial

September 18, 2009

Highlight: ‘Regenerative Hepatology’

Page range: 949-950

Abstract

No abstract available

Highlight: Regenerative Hepatology

May 20, 2009

The do's and don'ts of p53 isoforms

Reiner U. Jänicke, Vilma Graupner, Wilfried Budach, Frank Essmann

Page range: 951-963

Abstract

Upon DNA damage and other stresses, the transcription factor p53 elicits numerous responses including DNA repair, cell cycle arrest and apoptosis, properties that make p53 the prototype tumor suppressor. In addition, p53 also transactivates genes whose products act in an anti-apoptotic manner providing strong evidence that p53 exhibits both tumor suppressive and tumorigenic functions. Although several events were postulated to contribute to the p53-mediated decision process, the precise mechanism(s) that governs p53 activities is still elusive. Recently, it was found that the p53 gene allows expression of at least nine different isoforms that arise from multiple splicing events and the usage of alternative promoters. Several of these isoforms were shown to critically interfere with the function of the full-length p53 mainly by acting in a dominant-negative manner. However, an isoform-dependent selective activation of p53 target genes was also observed. Furthermore, certain p53 isoforms are aberrantly expressed in various tumors strongly implying their involvement in tumorigenic events. Thus, p53 isoforms may represent crucial determinants in p53-mediated decision processes whose precise functions (their do's and don'ts) are only beginning to emerge.

July 30, 2009

Mechanisms of liver disease: cross-talk between the NF-κB and JNK pathways

Salvatore Papa, Concetta Bubici, Francesca Zazzeroni, Guido Franzoso

Page range: 965-976

Abstract

The liver plays a central role in the transformation and degradation of endogenous and exogenous chemicals, and in the removal of unwanted cells such as damaged, genetically mutated and virus-infected cells. Because of this function, the liver is susceptible to toxicity caused by the products generated during these natural occurrences. Hepatocyte death is the major feature of liver injury. In response to liver injury, specific intracellular processes are initiated to maintain liver integrity. Inflammatory cytokines including tumor necrosis factor (TNF)α and interleukin-6 (IL-6) are key mediators of these processes and activate different cellular response such as proliferation, survival and death. TNFα induces specific signaling pathways in hepatocytes that lead to activation of either pro-survival mediators or effectors of cell death. Whereas activation of transcription factor NF-κB promotes survival, c-Jun N-terminal kinases (JNKs) and caspases are strategic effectors of cell death in the TNFα-mediated signaling pathway. This review summarizes recent advances in the mechanisms of TNFα-induced hepatotoxicity and suggests that NF-κB plays a protective role against JNK-induced hepatocyte death. Identification of the mechanisms regulating interplay between the NF-κB and JNK pathways is required in the search for novel targets for the treatment of liver disease, including hepatitis and hepatocellular carcinoma.

July 30, 2009

Immunologic hurdles of therapeutic stem cell transplantation

Olaf Utermöhlen, Nikola Baschuk, Zeinab Abdullah, Afra Engelmann, Udo Siebolts, Claudia Wickenhauser, Carol Stocking, Martin Krönke

Page range: 977-983

Abstract

Detailed knowledge of the immunologic properties of embryonic stem (ES) cells is a prerequisite for safe applications of ES cell-based regenerative medicine. Recently, the long-standing assumption that ES cells are ignored by immunocompetent hosts was disproved. Instead, it is becoming increasingly clear that ES cells actively protect themselves via several immunomodulatory and immunoevasive mechanisms against cytotoxic T-lymphocytes and natural killer cells. Here we review current knowledge about the immunologic properties of ES cells and discuss the implications for ES cell-based regenerative medicine, for the immunobiology of the embryo as a semi-allogeneic graft, and for the regenerative capacity of adult stem cells.

July 30, 2009

Ancestral vascular tube formation and its adoption by tumors

Tomáš Kučera, Eckhard Lammert

Page range: 985-994

Abstract

Similar to growing and metabolically active tissues, tumors require a dense vasculature to gain access to oxygen and nutrients. However, blood vessels in tumors differ from vessels in normal tissues in many respects. In particular, the tumor vasculature is in an active state of angiogenesis or vasculogenesis, and it is immature and leaky. Blood vessels are multicellular tubes formed by polarized endothelial cells, which face the patent vascular lumen with their apical cell surface, whereas their basal cell surface faces extracellular matrix on the outside of the vessels. The same cell polarity can be found in other tubular structures, such as in the bronchial tubes of the lung or the kidney tubules. In contrast, blood vessels in invertebrates often have a vascular lumen lined by basal cell surfaces. These vessels are often formed by a process named ‘ancestral vascular tube formation’. Here, we discuss the hypothesis that the supply of tumors with blood can be achieved by both endothelial cell-lined tubes as well as tubes formed by the tumor cells themselves using the ancestral vascular tube formation mechanism. We discuss this hypothesis with a particular focus on gastrointestinal tumors.

July 30, 2009

Cellular plasticity of the pancreas

Luc Baeyens, Luc Bouwens

Page range: 995-1001

Abstract

Cell replacement therapy holds promises for treatment of patients suffering from diabetes mellitus. When determining the appropriate strategies to amplify the amount of transplantable β-cells, sufficient knowledge of the developmental programs regulating β-cell differentiation is crucial. Here, we describe the plasticity of the different pancreatic cell types in vivo and in vitro and their potential to serve as β-cell progenitor.

July 30, 2009

Hepatic and pancreatic stellate cells in focus

Claus Kordes, Iris Sawitza, Dieter Häussinger

Page range: 1003-1012

Abstract

Stellate cells are vitamin A-storing cells of liver and pancreas and have been described in all vertebrates ranging from lampreys (primitive fish) to humans, demonstrating their major importance. This cell type is thought to contribute to fibrosis, a condition characterized by an excess deposition of extracellular matrix proteins. Recently, the expression of stem/progenitor cell markers, such as CD133 (prominin-1) and Oct4, was discovered in hepatic stellate cells (HSCs) of rats. Moreover, HSCs possess signaling pathways important for maintenance of stemness and cell differentiation, such as hedgehog, β-catenin-dependent Wnt, and Notch signaling, and are resistant to CD95-mediated apoptosis. In analogy to a stem cell niche, some characteristics of quiescent HSC are maintained by aid of a special microenvironment located in the space of Dissé. Finally, stellate cells display a differentiation potential as investigated in vitro and in vivo . Collectively all these properties are congruently found in stem/progenitor cells and support the concept that stellate cells are undifferentiated cells, which might play an important role in liver regeneration. The present review highlights findings related to this novel aspect of stellate cell biology.

July 30, 2009

Interplay between host cell and hepatitis C virus in regulating viral replication

Johannes G. Bode, Erwin D. Brenndörfer, Juliane Karthe, Dieter Häussinger

Page range: 1013-1032

Abstract

Viral life cycle as that of the hepatitis C virus (HCV) completely relies on host cell infrastructure, presupposing that the virus has evolved mechanisms to utilize and control all cellular molecules or pathways required for viral life cycle. Hence, HCV must have acquired the ability to gain access to key pathways controlling processes, such as cell growth, apoptosis and protein synthesis, which are all considered to also be crucial for liver regeneration. This occurs in a balanced way permitting persistent replication of viral genomes and production of infectious particles without endangering host cell viability and survival. In particular during the last decade, accumulating evidence indicates that HCV utilizes signaling pathways of the host with major impact on cellular growth, viability, cell cycle or cellular metabolism, such as epidermal growth factor-receptor mediated signals, the PI3K/Akt cascade or the family of Src kinases. Furthermore, HCV specifically interacts with parts of the cellular machinery involved in protein translation, processing, maturation and transport, such as components of the translation complex, the heat shock protein family, the immunophilins or the vesicle-associated membrane protein-associated proteins A and B. The present review focuses on the interplay between viral proteins and these factors of the host cell enabling the virus to utilize host cell infrastructure.

June 27, 2009

Epidermal growth factor receptor signaling in liver cell proliferation and apoptosis

Roland Reinehr, Dieter Häussinger

Page range: 1033-1037

Abstract

Recent evidence suggests that epidermal growth factor receptor (EGFR)-dependent signaling contributes to liver cell proliferation, as well as to apoptotic liver cell death, and represents an important regulator of hepatic regeneration. This article summarizes recent findings on the molecular mechanisms involved in EGFR-mediated cell proliferation and apoptosis. The emphasis is on the interplay between EGFR and CD95 (Fas, APO-1) death receptor-signaling, which is determined by the signaling context and liver cell type investigated.

July 30, 2009

The chemokine scavenging receptor D6 limits acute toxic liver injury in vivo

Marie-Luise Berres, Christian Trautwein, Mirko Moreno Zaldivar, Petra Schmitz, Katrin Pauels, Sergio A. Lira, Frank Tacke, Hermann E. Wasmuth

Page range: 1039-1045

Abstract

The chemokine decoy receptor D6 is a promiscuous chemokine receptor lacking classical signaling functions. It negatively regulates inflammation by targeting CC chemokines to cellular internalization and degradation. Here we analyze the function of D6 in acute CCl 4 -induced liver damage in constitutive D6 -/- and wild-type mice. The degree of liver injury was assessed by liver histology, serum transaminases, IL-6, and TNFα mRNA expression. Protein levels of D6 ligands (CCL2, CCL3, CCL5) and the non-D6-ligand CXCL9 within the livers were determined by ELISAs. The intrahepatic infiltration of immune cells was characterized by FACS. Genetic deletion of D6 led to prolonged liver damage after acute CCl 4 administration. The augmented liver damage in D6 -/- mice was associated with increased protein levels of intrahepatic inflammatory chemokines CCL2, CCL3, and CCL5 after 48 h, whereas CXCL9 was not different between knockout and wild-type mice. Functionally, increased intra-hepatic CC chemokine concentrations led to increased infiltration of CD45 + leukocytes, which were mainly identified as T and NK cells. In conclusion, the chemokine scavenger receptor D6 has a non-redundant role in acute toxic liver injury in vivo . These results support the importance of post-translational chemokine regulation and describe a new mechanism of immune modulation within the liver.

July 30, 2009

Hepatic differentiation of pluripotent stem cells

Komal Loya, Reto Eggenschwiler, Kinarm Ko, Malte Sgodda, Francoise André, Martina Bleidißel, Hans R. Schöler, Tobias Cantz

Page range: 1047-1055

Abstract

In regenerative medicine pluripotent stem cells are considered to be a valuable self-renewing source for therapeutic cell transplantations, given that a functional organ-specific phenotype can be acquired by in vitro differentiation protocols. Furthermore, derivatives of pluripotent stem cells that mimic fetal progenitor stages could serve as an important tool to analyze organ development with in vitro approaches. Because of ethical issues regarding the generation of human embryonic stem (ES) cells, other sources for pluripotent stem cells are intensively studied. Like in less developed vertebrates, pluripotent stem cells can be generated from the female germline even in mammals, via parthenogenetic activation of oocytes. Recently, testis-derived pluripotent stem cells were derived from the male germline. Therefore, we compared two different hepatic differentiation approaches and analyzed the generation of definitive endoderm progenitor cells and their further maturation into a hepatic phenotype using murine parthenogenetic ES cells, germline-derived pluripotent stem cells, and ES cells. Applying quantitative RT-PCR, both germline-derived pluripotent cell lines show similar differentiation capabilities as normal murine ES cells and can be considered an alternative source for pluripotent stem cells in regenerative medicine.

Protein Structure and Function

June 27, 2009

Effect of curcumin on amyloidogenic property of molten globule-like intermediate state of 2,5-diketo-d-gluconate reductase A

Nandini Sarkar, Abhay Narain Singh, Vikash Kumar Dubey

Page range: 1057-1061

Abstract

We identified a molten globule-like intermediate of 2,5-diketo- d -gluconate reductase A (DKGR) at pH 2.5, which has a prominent β-sheet structure. The molten globule state of the protein shows amyloidogenic property >50 μ m protein concentration. Interestingly, a 1:1 molar ratio of curcumin prevents amyloid formation as shown by the Thioflavin-T assay and atomic force microscopy. To the best of our knowledge, this is the first report on amyloid formation by an (α/β) 8 -barrel protein. The results presented here indicate that the molten globule state has an important role in amyloid formation and potential application of curcumin in protein biotechnology as well as therapeutics against amyloid diseases.

Cell Biology and Signaling

July 30, 2009

Specific induction of migration and invasion of pancreatic carcinoma cells by RhoC, which differs from RhoA in its localisation and activity

Karin-Almut Dietrich, Rene Schwarz, Martina Liska, Stefanie Graß, Andre Menke, Michael Meister, Gesa Kierschke, Claudia Längle, Felicitas Genze, Klaudia Giehl

Page range: 1063-1077

Abstract

RhoA and RhoC are highly related Rho GTPases, but differentially control cellular behaviour. We combined molecular, cellular, and biochemical experiments to characterise differences between these highly similar GTPases. Our findings demonstrate that enhanced expression of RhoC results in a striking increase in the migration and invasion of pancreatic carcinoma cells, whereas forced expression of RhoA decreases these actions. These isoform-specific functions correlate with differences in the cellular activity of RhoA and RhoC in human cells, with RhoC being more active than RhoA in activity assays and serum-response factor-dependent gene transcription. Subcellular localisation studies revealed that RhoC is predominantly localised in the membrane-containing fraction, whereas RhoA is mainly localised in the cytoplasmic fraction. These differences are not mediated by a different interaction with RhoGDIs. In vitro GTP/GDP binding analyses demonstrate different affinity of RhoC for GTP[S] and faster intrinsic and guanine nucleotide exchange factor (GEF)-stimulated GDP/GTP exchange rates compared to RhoA. Moreover, the catalytic domains of SopE and Dbs are efficacious GEFs for RhoC. mRNA expression of RhoC is markedly enhanced in advanced pancreatic cancer stages, and thus the differences discovered between RhoA and RhoC might provide explanations for their different influences on cell migration and tumour invasion.

July 30, 2009

Autoregulatory control of the p53 response by Siah-1L-mediated HIPK2 degradation

Marco A. Calzado, Laureano de la Vega, Eduardo Muñoz, M. Lienhard Schmitz

Page range: 1079-1083

Abstract

The different activities of the tumor suppressor p53 are tightly regulated by various negative and positive feedback loops, which allow accurate control of its function. Here we show that the p53-inducible ubiquitin E3 ligase Siah-1L can bind to the p53 phosphorylating kinase HIPK2 and thus allows its ubiquitination and proteasomal elimination. Siah-1L also eliminates the HIPK family member HIPK3, indicating that its activity is not restricted to one member of the HIPK family. The stimulating effect of HIPK2 on p53-triggered transcription is counteracted by Siah-1L, thus showing the occurrence of another negative feedback loop controlling the p53 response.

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Biological Chemistry keeps you up-to-date with all new developments in the molecular life sciences. In addition to original research reports, authoritative reviews written by leading researchers in the field keep you informed about the latest advances in the molecular life sciences. Rapid, yet rigorous reviewing ensures fast access to recent research results of exceptional significance in the biological sciences.

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general biochemistry
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