TY  - JOUR
AB  - Chimeric antigen receptor (CAR)-T cell therapy has led to remarkable clinical outcomes in the treatment of hematological malignancies. However, challenges remain, such as limited infiltration into solid tumors, inadequate persistence, systemic toxicities, and manufacturing insufficiencies. The use of alternative cell sources for CAR-based therapies, such as natural killer cells (NK), macrophages (MΦ), invariant Natural Killer T (iNKT) cells, γδT cells, neutrophils, and induced pluripotent stem cells (iPSC), has emerged as a promising avenue. By harnessing these cells' inherent cytotoxic mechanisms and incorporating CAR technology, common CAR-T cell-related limitations can be effectively mitigated. We herein present an overview of the tumoricidal mechanisms, CAR designs, and manufacturing processes of CAR-NK cells, CAR-MΦ, CAR-iNKT cells, CAR-γδT cells, CAR-neutrophils, and iPSC-derived CAR-cells, outlining the advantages, limitations, and potential solutions of these therapeutic strategies.
AU  - Tsiverioti, C.A.*
AU  - Gottschlich, A.*
AU  - Trefny, M.P.*
AU  - Theurich, S.*
AU  - Anders, H.J.*
AU  - Kroiss, M.*
AU  - Kobold, S.
C1  - 70704
C2  - 55723
CY  - Genthiner Strasse 13, D-10785 Berlin, Germany
TI  - Beyond CAR T cells: exploring alternative cell sources for CAR-like cellular therapies.
JO  - Biol. Chem.
PB  - Walter De Gruyter Gmbh
PY  - 2024
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - The cycling import receptor PEX5 and its membrane-located binding partner PEX14 are key constituents of the peroxisomal import machinery. Upon recognition of newly synthesized cargo proteins carrying a peroxisomal targeting signal type 1 (PTS1) in the cytosol, the PEX5/cargo complex docks at the peroxisomal membrane by binding to PEX14. The PEX14 N-terminal domain (NTD) recognizes (di)aromatic peptides, mostly corresponding to Wxxx(F/Y)-motifs, with nano-to micromolar affinity. Human PEX5 possesses eight of these conserved motifs distributed within its 320-residue disordered N-terminal region. Here, we combine biophysical (ITC, NMR, CD), biochemical and computational methods to characterize the recognition of these (di)aromatic peptides motifs and identify key features that are recognized by PEX14. Notably, the eight motifs present in human PEX5 exhibit distinct affinities and energetic contributions for the interaction with the PEX14 NTD. Computational docking and analysis of the interactions of the (di)aromatic motifs identify the specific amino acids features that stabilize a helical conformation of the peptide ligands and mediate interactions with PEX14 NTD. We propose a refined consensus motif ExWΦxE(F/Y)Φ for high affinity binding to the PEX14 NTD and discuss conservation of the (di)aromatic peptide recognition by PEX14 in other species.
AU  - Gopalswamy, M.
AU  - Zheng, C.*
AU  - Gaussmann, S.
AU  - Kooshapur, H.
AU  - Hambruch, E.*
AU  - Schliebs, W.*
AU  - Erdmann, R.*
AU  - Antes, I.*
AU  - Sattler, M.
C1  - 66856
C2  - 53327
TI  - Distinct conformational and energetic features define the specific recognition of (di)aromatic peptide motifs by PEX14.
JO  - Biol. Chem.
PY  - 2022
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - The proper production, degradation, folding and activity of proteins, proteostasis, is essential for any cellular function. From single cell organisms to humans, selective pressures have led to the evolution of adaptive programs that ensure proteins are properly produced and disposed of when necessary. Environmental factors such as temperature, nutrient availability, pathogens as well as predators have greatly influenced the development of mechanisms such as the unfolded protein response, endoplasmic reticulum-associated protein degradation and autophagy, working together in concert to secure cellular proteostasis. In our modern society, the metabolic systems of the human body face the distinct challenge of changed diets, chronic overnutrition and sedentary lifestyles. Obesity and excess white adipose tissue accumulation are linked to a cluster of metabolic diseases and disturbed proteostasis is a common feature. Conversely, processes that promote energy expenditure such as exercise, shivering as well as non-shivering thermogenesis by brown adipose tissue (BAT) and beige adipocytes counter-act metabolic dysfunction. Here we review the basic concepts of proteostasis in obesity-linked metabolic diseases and focus on adipocytes, which are critical regulators of mammalian energy metabolism.
AU  - Bartelt, A.
AU  - Widenmaier, S.B.*
C1  - 58211
C2  - 48219
CY  - Genthiner Strasse 13, D-10785 Berlin, Germany
SP  - 1019-1030
TI  - Proteostasis in thermogenesis and obesity.
JO  - Biol. Chem.
VL  - 401
IS  - 9
PB  - Walter De Gruyter Gmbh
PY  - 2020
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - Maintenance of cellular redox control is pivotal for normal cellular functions and cell fate decisions including cell death. Among the key cellular redox systems in mammals, the glutathione peroxidase (GPX) family of proteins is the largest conferring multifaceted functions and affecting virtually all cellular processes. The endoplasmic reticulum (ER)-resident GPXs, designated as GPX7 and GPX8, are the most recently added members of this family of enzymes. Recent studies have provided exciting insights how both enzymes support critical processes of the ER including oxidative protein folding, maintenance of ER redox control by eliminating H2O2, and preventing palmitic acid-induced lipotoxicity. Consequently, numerous pathological conditions, such as neurodegeneration, cancer and metabolic diseases have been linked with altered GPX7 and GPX8 expression. Studies in mice have demonstrated that loss of GPX7 leads to increased differentiation of preadipocytes, increased tumorigenesis and shortened lifespan. By contrast, GPX8 deficiency in mice results in enhanced caspase-4/11 activation and increased endotoxic shock in colitis model. With the increasing recognition that both types of enzymes are dysregulated in various tumor entities in man, we deem a review of the emerging roles played by GPX7 and GPX8 in health and disease development timely and appropriate.
AU  - Buday, K.
AU  - Conrad, M.
C1  - 60662
C2  - 49570
CY  - Genthiner Strasse 13, D-10785 Berlin, Germany
SP  - 271-287
TI  - Emerging roles for non-selenium containing ER-resident glutathione peroxidases in cell signaling and disease.
JO  - Biol. Chem.
VL  - 402
IS  - 3
PB  - Walter De Gruyter Gmbh
PY  - 2020
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - Helicobacter pylori infects the stomach of 50% of the population worldwide, thus causing chronic gastritis. Although this infection can be cured by antibiotic treatment, therapeutic options are increasingly limited due to the development of resistances. The γ-glutamyl-transpeptidase (gGT) of H. pylori (HpgGT) is a virulence factor important for colonization and contributes to bacterial immune evasion. Therefore, this enzyme is a potential target for developing new anti-infectives. As species specificity of such compounds is required in order to avoid off-target or adverse effects, comparative analysis of the gGTs from different organisms is a prerequisite for drug development. To allow detailed biochemical and enzymatic characterization, recombinant gGTs from five different bacteria as well as Homo sapiens were characterized and compared. Investigation of the enzymatic activity, the binding modes of known inhibitors to the catalytic center, and a high resolution X-ray structure of the HpgGT provided a starting point for the identification of new inhibitory substances targeting HpgGT. Inhibitors with Ki values in the nm to mm range were identified and their binding modes were analyzed by mass spectrometry. The results of this study provide a basis for the development of species-specific lead compounds with anti-infective potential by effectively inhibiting HpgGT.
AU  - Bolz, C.*
AU  - Bach, N.C.*
AU  - Meyer, H.*
AU  - Müller, G.*
AU  - Dawidowski, M.
AU  - Popowicz, G.M.
AU  - Sieber, S.A.*
AU  - Skerra, A.*
AU  - Gerhard, M.*
C1  - 50563
C2  - 42515
CY  - Berlin
SP  - 341-357
TI  - Comparison of enzymatic properties and small molecule inhibition of γ-glutamyltranspeptidases from pathogenic and commensal bacteria.
JO  - Biol. Chem.
VL  - 398
IS  - 3
PB  - Walter De Gruyter Gmbh
PY  - 2017
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - Bioactive lipids regulate most physiological processes, from digestion to blood flow and from hemostasis to labor. Lipid mediators are also involved in multiple pathologies including cancer, autoimmunity or asthma. The pathological roles of lipid mediators are based on their intricate involvement in the immune system, which comprises source and target cells of these mediators. Based on their biosynthetic origin, bioactive lipids can be grouped into different classes [e.g. sphingolipids, formed from sphingosine or eicosanoids, formed from arachidonic acid (AA)]. Owing to the complexity of different mediator classes and the prominent immunological roles of eicosanoids, this review will focus solely on the immune-regulation of eicosanoids. Eicosanoids do not only control key immune responses (e.g. chemotaxis, antigen presentation, phagocytosis), but they are also subject to reciprocal control by the immune system. Particularly, key immunoregulatory cytokines such as IL-4 and IFN-gamma shape the cellular eicosanoid profile, thus providing efficient feedback regulation between cytokine and eicosanoid networks. For the purpose of this review, I will first provide a short overview of the most important immunological functions of eicosanoids with a focus on prostaglandins (PGs) and leukotrienes (LTs). Second, I will summarize the current knowledge on immunological factors that regulate eicosanoid production during infection and inflammation.
AU  - Esser-von Bieren, J.
C1  - 52205
C2  - 43829
CY  - Berlin
SP  - 1177-1191
TI  - Immune-regulation and -functions of eicosanoid lipid mediators.
JO  - Biol. Chem.
VL  - 398
IS  - 11
PB  - Walter De Gruyter Gmbh
PY  - 2017
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - Triple-negative breast cancer (TNBC), lacking the steroid hormone receptors ER and PR and the oncoprotein HER2, is characterized by its aggressive pattern and insensitivity to endocrine and HER2-directed therapy. Human kallikrein-related peptidases KLK1-15 provide a rich source of serine protease-type biomarkers associated with tumor growth and cancer progression for a variety of malignant diseases. In this study, recombinant KLK4 protein was generated and affinity-purified KLK4-directed polyclonal antibody pAb587 established to allow localization of KLK4 protein expression in tumor cell lines and archived formalin-fixed, paraffin-embedded TNBC tumor tissue specimens. For this, KLK4 protein expression was assessed by immunohistochemistry in primary tumor tissue sections (tissue microarrays) of 188 TNBC patients, mainly treated with anthracycline- or CMF-based polychemotherapy. KLK4 protein is localized in the cytoplasm of tumor and stroma cells. In this patient cohort, elevated stroma cell KLK4 expression, but not tumor cell KLK4 expression, is predictive for poor disease-free survival by univariate analysis (hazard ratio: 2.26, p=0.001) and multivariable analysis (hazard ratio: 2.12, p<0.01). Likewise, univariate analysis revealed a trend for statistical significance of elevated KLK4 stroma cell expression for overall survival of TNBC patients as well.
AU  - Yang, F.*
AU  - Aubele, M.
AU  - Walch, A.K.
AU  - Gross, E.*
AU  - Napieralski, R.*
AU  - Zhao, S.*
AU  - Ahmed, N.*
AU  - Kiechle, M.*
AU  - Reuning, U.*
AU  - Dorn, J.*
AU  - Sweep, F.C.*
AU  - Magdolen, V.*
AU  - Schmitt, M.*
C1  - 51799
C2  - 43336
CY  - Berlin
SP  - 1151-1164
TI  - Tissue kallikrein-related peptidase 4 (KLK4), a novel biomarker in triple-negative breast cancer.
JO  - Biol. Chem.
VL  - 398
IS  - 10
PB  - Walter De Gruyter Gmbh
PY  - 2017
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - n serous ovarian cancer, the clinical relevance of tumor cell-expressed plasmin(ogen) (PLG) has not yet been evaluated. Due to its proteolytic activity, plasmin supports tumorigenesis, however, angiostatin(-like) fragments, derived from PLG, can also function as potent antitumorigenic factors. In the present study, we assessed PLG protein expression in 103 cases of advanced high-grade serous ovarian cancer (FIGO III/IV) by immunohistochemistry. In 70/103 cases, positive staining of tumor cells was observed. In univariate Cox regression analysis, PLG staining was positively associated with prolonged overall survival (OS) (hazard ratio [HR] = 0.59, P = 0.026) of the patients. In multivariable analysis, PLG, together with residual tumor mass, remained a statistically significant independent prognostic marker (HR = 0.49, P = 0.009). In another small patient cohort (n=29), we assessed mRNA expression levels of PLG by quantitative PCR. Here, elevated PLG mRNA levels were also significantly associated with prolonged OS of patients (Kaplan-Meier analysis; P = 0.001). This finding was validated by in silico analysis of a microarray data set (n = 398) from The Cancer Genome Atlas (Kaplan-Meier analysis; P = 0.031). In summary, these data indicate that elevated PLG expression represents a favorable prognostic biomarker in advanced (FIGO III/IV) high-grade serous ovarian cancer.
AU  - Zhao, S.*
AU  - Dorn, J.*
AU  - Napieralski, R.*
AU  - Walch, A.K.
AU  - Diersch, S.*
AU  - Kotzsch, M.*
AU  - Ahmed, N.*
AU  - Hooper, J.*
AU  - Kiechle, M.*
AU  - Schmitt, M.*
AU  - Magdolen, V.*
C1  - 50072
C2  - 41999
CY  - Berlin
SP  - 765-773
TI  - Plasmin(Ogen) serves as a favorable biomarker for prediction of survival in advanced high-grade serous ovarian cancer.
JO  - Biol. Chem.
VL  - 398
IS  - 7
PB  - Walter De Gruyter Gmbh
PY  - 2017
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - The CARMA1-BCL10-MALT1 (CBM) signalosome triggers canonical NF-κB signaling and lymphocyte activation upon antigen receptor stimulation. Genetic studies in mice and the analysis of human immune pathologies unveiled a critical role of the CBM complex in adaptive immune responses. Great progress has been made in elucidating the fundamental mechanisms that dictate CBM assembly and disassembly. By bridging proximal antigen receptor signaling to downstream signaling pathways, the CBM complex exerts a crucial scaffolding function. Moreover, the MALT1 subunit confers a unique proteolytic activity that is key for lymphocyte activation. Deregulated 'chronic' CBM signaling drives constitutive NF-κB signaling and MALT1 activation, which contribute to the development of autoimmune and inflammatory diseases as well as lymphomagenesis. Thus, the processes that govern CBM activation and function are promising targets for the treatment of immune disorders. Here, we summarize the current knowledge on the functions and mechanisms of CBM signaling in lymphocytes and how CBM deregulations contribute to aberrant signaling in malignant lymphomas.
AU  - Meininger, I.
AU  - Krappmann, D.
C1  - 49152
C2  - 41683
CY  - Berlin
SP  - 1315-1333
TI  - Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome.
JO  - Biol. Chem.
VL  - 397
IS  - 12
PB  - Walter De Gruyter Gmbh
PY  - 2016
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - Mitochondria are a major source of reactive oxygen species (ROS) in the cell, particularly of superoxide and hydrogen peroxide. A number of dedicated enzymes regulate the conversion and consumption of superoxide and hydrogen peroxide in the intermembrane space and the matrix of mitochondria. Nevertheless, hydrogen peroxide can also interact with many other mitochondrial enzymes, particularly those with reactive cysteine residues, modulating their reactivity in accordance with changes in redox conditions. In this review we will describe the general redox systems in mitochondria of animals, fungi and plants and discuss potential target proteins that were proposed to contain regulatory thiol switches.
AU  - Riemer, J.*
AU  - Schwarzländer, M.*
AU  - Conrad, M.
AU  - Herrmann, J.M.*
C1  - 44005
C2  - 36683
CY  - Berlin
SP  - 465-482
TI  - Thiol switches in mitochondria: Operation and physiological relevance.
JO  - Biol. Chem.
VL  - 396
IS  - 5
PB  - Walter De Gruyter Gmbh
PY  - 2015
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - The production and processing of ribosomal RNA is a complex and well-coordinated nucleolar process for ribosome biogenesis. Progress in understanding nucleolar structure and function has lead to the unexpected discovery of the nucleolus as a highly sensitive sensor of cellular stress and an important regulator of the tumor suppressor p53. Inhibition of ribosomal RNA metabolism has been shown to activate a signaling pathway for p53 induction. This review elucidates the potential of classical and recently developed chemotherapeutic drugs to stabilize p53 by inhibiting nucleolar functions.
AU  - Burger, K.
AU  - Eick, D.
C1  - 27185
C2  - 32578
SP  - 1133-1143
TI  - Functional ribosome biogenesis is a prerequisite for p53 destabilization: Impact of chemotherapy on nucleolar functions and RNA metabolism.
JO  - Biol. Chem.
VL  - 394
IS  - 9
PB  - De Gruyter
PY  - 2013
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - Wnt/beta-catenin signaling is of fundamental importance in the regulation of self-renewal, migration/invasion, and differentiation of human mesenchymal stem cells (hMSCs). Because little information is available about the function of Frizzled receptors (Fzds) as the main receptors of Wnt proteins in hMSCs, we first performed comparative Fzd mRNA expression profiling. Fzd9 and Fzd10 were not expressed in hMSCs. While Fzd3 was expressed at low levels in hMSCs, the other Fzds exhibited high expression rates. Activation and repression of Wnt signaling in hMSCs revealed that the expression levels of Fzd1, Fzd6, and Fzd7 are positively correlated with the Wnt/beta-catenin activation status, whereas Fzd8 exhibited an inverse relation. For studying the functional relevance of Fzds in Wnt/beta-catenin signaling, RNA interference, ectopic expression studies, and rescue approaches were performed in hMSCs carrying a highly sensitive TCF/LEF reporter gene system (Gaussia luciferase). We found that, Fzd1, Fzd5, Fzd7, and Fzd8 are largely involved in Wnt/beta-catenin signaling of hMSCs. Moreover, the knockdown of Fzd5 can be compensated by the ectopic expression of Fzd7. Conversely, the ectopic expression of Fzd5 in Fzd7-knockdown hMSCs resulted in a rescue of Wnt/beta-catenin signaling, pointing to a functional redundancy of Fzd5 and Fzd7.
AU  - Kolben, T.*
AU  - Perobner, I.*
AU  - Fernsebner, K.
AU  - Lechner, F.*
AU  - Geissler, C.*
AU  - Ruiz-Heinrich, L.*
AU  - Capovilla, S.*
AU  - Jochum, M.*
AU  - Neth, P.*
C1  - 11435
C2  - 30675
SP  - 1433-1447
TI  - Dissecting the impact of Frizzled receptors in Wnt/β-catenin signaling of human mesenchymal stem cells.
JO  - Biol. Chem.
VL  - 393
IS  - 12
PB  - Walter De Gruyter & Co
PY  - 2012
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - Several members of the human kallikrein-related peptidase family, including KLK6, are up-regulated in ovarian cancer. High KLK6 mRNA or protein expression, measured by quantitative polymerase chain reaction and enzyme-linked immunoassay, respectively, was previously found to be associated with a shortened overall and progression-free survival (OS and PFS, respectively). In the present study, we aimed at analyzing KLK6 protein expression in ovarian cancer tissue by immunohistochemistry. Using a newly developed mono-specific polyclonal antibody, KLK6 immunoexpression was initially evaluated in normal tissues. We observed strong staining in the brain and moderate staining in the kidney, liver, and ovary, whereas the pancreas and the skeletal muscle were unreactive, which is in line with previously published results. Next, both tumor cell- and stromal cell-associated KLK6 immunoexpression were analyzed in tumor tissue specimens of 118 ovarian cancer patients. In multivariate Cox regression analysis, only stromal cell-associated expression, besides the established clinical parameters FIGO stage and residual tumor mass, was found to be statistically significant for OS and PFS [high vs. low KLK6 expression; hazard ratio (HR), 1.92; p=0.017; HR, 1.80; p=0.042, respectively]. These results indicate that KLK6 expressed by stromal cells may considerably contribute to the aggressiveness of ovarian cancer.
AU  - Seiz, L.*
AU  - Dorn, J.*
AU  - Kotzsch, M.*
AU  - Walch, A.K.
AU  - Grebenchtchikov, N.I.*
AU  - Gkazepis, A.*
AU  - Schmalfeldt, B.*
AU  - Kiechle, M.*
AU  - Bayani, J.*
AU  - Diamandis, E.P.*
AU  - Langer, R.*
AU  - Sweep, F.C.*
AU  - Schmitt, M.*
AU  - Magdolen, V.*
C1  - 7533
C2  - 29788
SP  - 391-401
TI  - Stromal cell-associated expression of kallikrein-related peptidase 6 (KLK6) indicates poor prognosis of ovarian cancer patients.
JO  - Biol. Chem.
VL  - 393
IS  - 5
PB  - Walter De Gruyter
PY  - 2012
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - Molecular chaperones of the heat shock protein 70 (Hsp70) family play a crucial role in the presentation of exogenous antigenic peptides by antigen-presenting cells (APCs). In a combined biochemical and immunological approach, we characterize the biochemical interaction of tumor-associated peptides with human Hsp70 and show that the strength of this interaction determines the efficacy of immunological cross-presentation of the antigenic sequences by APCs. A fluorescein-labeled cytosolic mammalian Hsc70 binding peptide is shown to interact with human Hsp70 molecules with high affinity (K-d=0.58 mu M at 25 degrees C). Competition experiments demonstrate weaker binding by Hsp70 of antigenic peptides derived from the tumor-associated proteins tyrosinase (K-d=32 mu M) and melanoma antigen recognized by T cells (MART-1) (K-d=2.4 mu M). Adding a peptide sequence (pep70) with high Hsp70 binding affinity (K-d=0.04 mu M) to the tumor-associated peptides enables them to strongly interact with Hsp70. Presentation of tumor-associated peptides by B cells resulting in T cell activation in vitro is enhanced by Hsp70 when the tumor-associated peptides contain the Hsp70 binding sequence. This observation has relevance for vaccine design, as augmented transfer of tumor-associated antigens to APCs is closely linked to the vaccine's efficacy of T cell stimulation.
AU  - Pandya, M.J.*
AU  - Bendz, H.
AU  - Manzenrieder, F.*
AU  - Nößner, E.
AU  - Kessler, H.*
AU  - Buchner, J.*
AU  - Issels, R.D.
C1  - 885
C2  - 26198
SP  - 304-312
TI  - Interaction of human heat shock protein 70 with tumor-associated peptides.
JO  - Biol. Chem.
VL  - 390
IS  - 4
PB  - de Gruyter
PY  - 2009
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - The pro-apoptotic tumor necrosis factor (TNF)-receptor 1-associated death domain protein (TRADD) was initially identified as the central signaling adapter molecule of TNF-receptor 1 (TNFR1). Upon stimulation with the pro-inflammatory cytokine TNFalpha, TRADD is recruited to the activated TNFR1 by direct interaction between the death domains of both molecules. TRADD mediates TNFR1 activation of NF-kappaB and c-Jun N-terminal kinase (JNK), as well as caspase-dependent apoptosis. Surprisingly, TRADD is also recruited by latent membrane protein 1 (LMP1), the major oncoprotein of the human Epstein-Barr tumor virus. By mimicking a constitutively active receptor, LMP1 is essential for B-cell transformation by the virus, activating NF-kappaB, phosphatidylinositol 3-kinase, JAK/STAT and mitogen-activated protein kinase signaling. In contrast to TNFR1, LMP1's interaction with TRADD is independent of a functional death domain. The unique structure of the LMP1-TRADD complex dictates an unusual type of TRADD-dependent NF-kappaB signaling and subverts TRADD's potential to induce apoptosis. This article provides an overview of TNFR1 and LMP1 signal transduction with a focus on TRADD's functions in apoptotic and transforming signaling, incorporating recent results from TRADD RNAi and knockout studies.
AU  - Kieser, A.
C1  - 3457
C2  - 25792
SP  - 1261-1271
TI  - Pursuing different 'TRADDes': TRADD signaling induced by TNF-receptor 1 and the Epstein-Barr virus oncoprotein LMP1.
JO  - Biol. Chem.
VL  - 389
IS  - 10
PB  - de Gruyter
PY  - 2008
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - The redox enzyme phospholipid hydroperoxide glutathione peroxidase (PHGPx) has emerged as one of the most significant selenoenzymes in mammals, corroborated by early embryonic lethality of PHGPx null mice. PHGPx is one of five selenium-dependent glutathione peroxidases and the second glutathione peroxidase to be discovered in 1982. PHGPx has a particular position within this family owing to its peculiar structural and catalytic properties, its multifaceted roles during male gametogenesis, and its necessity for early mouse development. Interestingly, mice devoid of endogenous glutathione die at the same embryonic stage as PHGPx-deficient mice compatible with the hypothesis that a similar phenotype of embryonic lethality may be provoked by PHGPx deficiency and lack of its reducing substrate glutathione. Various gain- and loss-of-function approaches in mice have provided some insights into the physiological functions of PHGPx. These include a protective role for PHGPx in response to irradiation, increased resistance of transgenic PHGPx mice to toxin-induced liver damage, a putative role in various steps of embryogenesis, and a contribution to sperm chromatin condensation. The expression of three forms of PHGPx and early embryonic lethality call for more specific studies, such as tissue-specific disruption of PHGPx, to precisely understand the contribution of PHGPx to mammalian physiology and under pathological conditions.
AU  - Conrad, M.
AU  - Schneider, M.*
AU  - Seiler, A.
AU  - Bornkamm, G.W.
C1  - 3277
C2  - 24643
SP  - 1019-1025
TI  - Physiological role of phospholipid hydroperoxide glutathione peroxidase in mammals.
JO  - Biol. Chem.
VL  - 388
IS  - 10
PB  - de Gruyter
PY  - 2007
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - Thioredoxin reductases (Txnrds) are a group of selenoenzymes participating in cellular redox regulation. Three Txnrd isoforms are known, each of which exhibits distinct cellular localisation and tissue-specific expression pattern. Txnrd1 is found in the cytoplasm, expression of Txnrd2 is restricted to mitochondria and Txnrd3 shows testis-specific expression. Recently, it was shown that Txnrd2 strongly affects the development of blood cells, since mouse embryos deficient for Txnrd2 are severely anaemic, show increased apoptosis in foetal liver and possess haematopoietic liver stem cells of reduced capacity to proliferate in vitro. However, because Txnrd2-deficient mice die at embryonic day 13.5, it was not known how this enzyme affects blood cell function in the adult animal. In the present study we show that conditional Txnrd2 knockouts generated using CD4- and CD19Cre transgenic mice lack Txnrd2 expression in CD4-- and CD19-positive T- and B-lymphocytes, respectively. However, the development and differentiation of both cell types in thymus and bone marrow was not significantly impaired. In addition, B-cell proliferation and activation in response to CD40 and IL-4 was unaltered in Txnrd2-deficient B-cells.
AU  - Geisberger, R.
AU  - Kiermayer, C.
AU  - Hömig, C.
AU  - Conrad, M.
AU  - Schmidt, J.
AU  - Zimber-Strobl, U.
AU  - Brielmeier, M.
C1  - 2447
C2  - 24706
SP  - 1083-1090
TI  - B- and T-cell-specific inactivation of thioredoxin reductase 2 does not impair lymphocyte development and maintenance.
JO  - Biol. Chem.
VL  - 388
IS  - 10
PB  - de Gruyter
PY  - 2007
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - Thioredoxin reductase 1 (Txnrd1) and thioredoxin reductase 2 (Txnrd2) are selenoproteins whose expression and function depends on adequate supply of the trace element selenium (Se). As homozygous (-/-) knockout of both Txnrd1 and Txnrd2 is embryonically lethal, we investigated the effect of their hemizygosity (+/-) alone and in combination with dietary Se on enzymatic activity in various tissues. To assess the overall health of the corresponding mice, the growth, viability and fertility of the different experimental groups were also compared. Se depletion led to a marked decrease in Se organ contents. Se depletion was most prominent in lung, followed by liver, kidney, heart, muscle and brain. We found no major effect of Txnrd1 or Txnrd2 hemizygosity and/or Se on male fertility and the viability of offspring. A gene dose effect under Se-adequate conditions for Txnrd1 and Txnrd2 in all organs was observed. Haploid insufficiency decreased Txnrd activity to an extent that can be further decreased by Se deficiency, but not to levels below those observed for Se depletion alone. The only exception was Txnrd2 activity in kidney, heart and muscle, where we found an additive effect.
AU  - Kiermayer, C.
AU  - Michalke, B.
AU  - Schmidt, J.
AU  - Brielmeier, M.
C1  - 1791
C2  - 24708
SP  - 1091-1997
TI  - Effect of selenium on thioredoxin reductase activity in Txnrd1 or Txnrd2 hemizygous mice.
JO  - Biol. Chem.
VL  - 388
IS  - 10
PB  - de Gruyter
PY  - 2007
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - During tumor metastasis, a fine-tuned balance between the formation and loosening of adhesive cell contacts has to occur, a process based on the regulated expression of integrins. Human ovarian OV-MZ-6 cancer cells express the integrin αvβ3, which associates with vitronectin (VN) and correlates with ovarian cancer progression. Adhesion and spreading of OV-MZ-6 cells on VN was accompanied by the formation of focal adhesion contacts and the recruitment of activated tyrosine-phosphorylated focal adhesion kinase. Cultivation of OV-MZ-6 cells on VN resulted in a significantly induced cell proliferation. This VN effect could be mimicked by cultivating cells on the immobilized αvβ3-directed peptide cyclo-Arg-Gly-Asp-D-Phe-Val (cRGDfV). VN-dependent OV-MZ-6 cell adhesion and proliferation was significantly enhanced by overexpression of αvβ3, and was accompanied by rapid and transient tyrosinephosphorylation of p44erk 1/p42erk 2 mitogen-activated protein kinase. Moreover, overexpression of αvβ3 and OV-MZ-6 cell attachment to VN increased cell motility up to 5-fold accompanied by prominent changes in cytoskeletal organization and cell morphology. Upon αvβ3/VN interaction, by cDNA expression microarray analysis we identified altered mRNA levels of cmyc, epidermal growth factor receptor (EGF-R), transcription factor Fra-1, prothymosin-α (PTMA), integrin-linked kinase (ILK), and the cell adhesion molecule SQM-1, candidates which are possibly involved in changes of the adhesive, migratory, and proliferative phenotype of human ovarian cancer cells.
AU  - Hapke, S.*
AU  - Kessler, H.*
AU  - Luber, B.*
AU  - Benge, A.*
AU  - Hutzler, P.
AU  - Höfler, H.*
AU  - Schmitt, M.*
AU  - Reuning, U.*
C1  - 22333
C2  - 21179
SP  - 1073-1083
TI  - Ovarian Cancer Cell Proliferation and Motility is Induced by Engagement of Integrin alphavß3/ Vitronectin Interaction.
JO  - Biol. Chem.
VL  - 384
IS  - 7
PY  - 2003
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - The selenoprotein phospholipid hydroperoxide glutathione peroxidase (PHGPx) is present in at least three different isoforms in testis: as a cytosolic, as a mitochondrial, and as a nuclear protein. We have recently shown that a sperm nucleusspecific glutathione peroxidase (snGPx) is identical to the mitochondrial and cytosolic forms of PHGPx apart from its N-terminus. This argininerich N-terminus of snGPx, reminiscent of protamines, is encoded by an alternative exon located in the first intron of the PHGPx gene and is responsible for nuclear localisation and chromatin binding of snGPx [Pfeifer et al., FASEB J. 15 (2001), pp. 1236-1238]. By using a combination of techniques including selective cloning of mRNA 5'-ends, RT-PCR, and S1 analyses, we provide evidence that the transcript encoding the nuclear form is generated by transcription initiation at an alternative promoter and not by alternative splicing. We show that the major transcription start region is located at -12 to -14 upstream of the AUG translation initiation site of the sperm nucleusspecific exon and lacks a TATA box. Two minor TATA-less transcription initiation sites are located at around -30 and -45. We have shown by in situ hybridisation that snGPx expression in testis, like protamine expression, is restricted to late stages of spermatogenesis whereas PHGPx expression is only found in spermatocytes and early spermatids. These findings have to be taken into account when studying either the differential regulation of PHGPx and snGPx expression in testis or the impact of putative mutations in snGPx on male fertility in man.
AU  - Moreno, S.G.
AU  - Laux, G.
AU  - Brielmeier, M.
AU  - Bornkamm, G.W.
AU  - Conrad, M.
C1  - 1270
C2  - 21679
SP  - 635-643
TI  - Testis-Specific Expression of the Nuclear Form of Phospholipid Hydroperoxide Glutathione Peroxidase (PHGPx).
JO  - Biol. Chem.
VL  - 384
IS  - 4
PB  - de Gruyter 
PY  - 2003
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - In the human B cell line P493-6 two mitogenic signals, the Epstein-Barr virus nuclear antigen 2 (EBNA2) and myc, can be independently regulated by means of an estrogen receptor fusion construct or an inducible expression vector, respectively. Shut off of EBNA2, either in the presence or absence of myc, leads to a significant increase in enzymatic activity and surface expression of ecto-5'nucleotidase (CD73) as well as an increased adenosine receptor response in cyclic AMP formation. Shut off of myc expression has a small additional positive effect on CD73 activity. Among the four different subtypes of adenosine receptors, the A2a receptor exclusively is subject to regulation in this system, which is substantiated by pharmacologic data (specific agonists and inhibitors), as well as on the mRNA level. With upregulated CD73 and A2a, cells also respond to 5'-AMP with increased cyclic AMP formation. Turn on of EBNA2 has the reverse effect of repression of CD73 and A2a expression. The time course of both induction and repression of CD73 and A2a is rather slow.
AU  - Napieralski, R.*
AU  - Kempkes, B.
AU  - Gutensohn, W.*
C1  - 22247
C2  - 21005
SP  - 483-487
TI  - Evidence for Coordinated Induction and Repression of Ecto-5'-Nucleotidase (CD73) and the A2a Adenosine Receptor in a Human B Cell Line.
JO  - Biol. Chem.
VL  - 384
IS  - 3
PY  - 2003
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - Recently, gamma-glutamyl transpeptidase, which initiates cleavage of extracellular glutathione, has been shown to promote oxidative damage to cells. Here we examined a murine disease model of glomerulosclerosis, involving loss of the Mpv17 gene coding for a peroxisomal protein. In Mpv17-/- cells, enzyme activity and mRNA expression (examined by quantitative RT-PCR) of membrane-bound gamma-glutamyl transpeptidase were increased, while plasma glutathione peroxidase and superoxide dismutase levels were lowered. Superoxide anion production in these cells was increased as documented by electron spin resonance spectroscopy. In the presence of Mn(III)tetrakis(4-benzoic acid)porphyrin, the activities of gamma-glutamyl transpeptidase and plasma glutathione peroxidase were unchanged, suggesting a relationship between enzyme expression and the amount of reactive oxygen species. Inhibition of gamma-glutamyl transpeptidase by acivicin reverted the lowered plasma glutathione peroxidase and superoxide dismutase activities, indicating reciprocal control of gene expression for these enzymes.
AU  - Wagner, G.*
AU  - Stettmaier, K.
AU  - Bors, W.
AU  - Sies, H.*
AU  - Wagner, E.M.*
AU  - Reuter, A.*
AU  - Weiher, H.*
C1  - 21703
C2  - 19895
SP  - 1019-1025
TI  - Enhanced Gamma-Glutamyl Transpeptidase Expression and Superoxide Production in Mpv17-/- Glomerulosclerosis Mice.
JO  - Biol. Chem.
VL  - 382
IS  - 7
PY  - 2001
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - A burst of active oxygen species (AOS) is known to be involved in local cell death as part of plant defence against pathogens. It is, however, under dispute to what extent AOS can induce pathogen resistance and immunity throughout the plant. Three experimental strategies that reveal a primary role for AOS and a surprisingly low chemical and spatial specificity are now described for tobacco and Arabidopsis thaliana plants. Ozone is a gaseous AOS that was applied to non-transgenic plants. Hydrogen peroxide or singlet oxygen are AOS that were induced by high-light treatment of transgenic plants that contained antisense constructs inhibiting catalase activity or chlorophyll biosynthetic enzymes. In all cases, activated oxygen species, cellular lesions, ethylene and salicylic acid, and components of major plant defence systems (systemic acquired resistance, hypersensitive response) were induced, as was resistance towards pathogens (tobacco mosaic virus, Pseudomonas syringae or Peronospora parasitica). It is concluded that active oxygen species can act as mediators of plant immunity so that new non-pesticidal plant protection strategies could be developed.
AU  - Sandermann, H.
C1  - 21812
C2  - 20015
SP  - 649-653
TI  - Active Oxygen Species as Mediators of Plant Immunity : Three Case Studies.
JO  - Biol. Chem.
VL  - 381
IS  - 8
PY  - 2000
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - The crystallins were discovered as the structural proteins of the vertebrate eye lens in the last century by C.T. Mörner (Z. Physiol. Chem. 18, 1893, 61-106). Since that time the mammalian crystallins referred to as alpha-, beta-, and gamma-crystallins have been characterized with respect to their genetic organization, the regulation of their expression pattern and their participation in several diseases. Moreover, some crystallins have also been discovered outside the eye. Evolutionary analysis has demonstrated the relationship of crystallins to proteins involved in protection against stress. The alpha-crystallins are considered to be molecular chaperones and members of the small heat shock protein family; they have autokinase activity and are involved in the gamma-crystallin gene activation. The alpha-crystallins are associated with a broad variety of neurological disorders. The beta/gamma-crystallin superfamily is characterized by four greek key motifs. The various N- and C-terminal extensions of the beta/gamma-crystallins are mainly responsible for their distinct biophysical and biochemical properties. Modifications in the beta/gamma-crystallins or mutations in their genes lead to opacification of the eye lens (cataract). Other proteins found to be expressed at relatively high levels in the lens are characterized bytheir strong relationship to well-known enzymes. They are referred to as enzyme-crystallins, and as one example, the xi-crystallin will be discussed. It has evolved from a quinone oxidoreductase using a lens-specific promoter, and a mutation in xi-crystallin is involved in cataract formation.
AU  - Graw, J.
C1  - 24303
C2  - 32742
SP  - 1331-1348
TI  - The crystallins: Genes, proteins and diseases.
JO  - Biol. Chem.
VL  - 378
IS  - 11
PB  - De Gryter
PY  - 1997
SN  - 1431-6730
ER  - 

TY  - JOUR
AB  - In a mouse/human chimeric IgG1 Ab with a deletion of the CH1 domain the disulfide bridges between H and L chain cannot be formed, although the corresponding cysteine residues are present. We show that the kappa chains are non-covalently associated to H chain dimers and that they can dissociate from the H chains. Therefore different populations of Ab can be distinguished according to the number of associated kappa chains. Only the molecules with two kappa chains can bind to the target cell. Since this Ab was derived from a T cell depleting anti-Thy-1.2 Ab, we can assess the implications of this conformational alteration as to binding avidity, effector functions and immunosuppression in vivo.
AU  - Mocikat, R.
AU  - Mysliwietz, J.
AU  - Lang, P.
AU  - Thierfelder, S.S.
C1  - 40294
C2  - 13840
SP  - 461-465
TI  - Antigen binding and effector functions of a chimeric antibody with a deletion of the CH1 domain and non-covalently associated kappa chains.
JO  - Biol. Chem.
VL  - 374
IS  - 7
PY  - 1993
SN  - 1431-6730
ER  - 

TY  - JOUR
AU  - Eulitz, M.
C1  - 20258
C2  - 13444
SP  - 629-633
TI  - Amyloid Formation from Immunoglobulin Chains.
JO  - Biol. Chem.
VL  - 373
IS  - 7
PY  - 1992
SN  - 1431-6730
ER  -