TY  - JOUR
AB  - Transplanted organs are inevitably exposed to ischemia-reperfusion (IR) injury, which is known to cause graft dysfunction. Functional and structural changes that follow IR tissue injury are mediated by neutrophils through the production of oxygen-derived free radicals, as well as from degranulation which entails the release of proteases and other pro-inflammatory mediators. Neutrophil serine proteases (NSPs) are believed to be the principal triggers of post-ischemic reperfusion damage. Extended preservation times for the transplanted donor organ correlate with heightened occurrences of vascular damage and graft dysfunction. Preservation with α1-antitrypsin, an endogenous inhibitor of NSPs, improves primary graft function after lung or heart transplantation. Furthermore, pre-operative pharmacological targeting of NSP activation in the recipient using chemical inhibitors suppresses neutrophilic inflammation in transplanted organs. Hence, effective control of NSPs in the graft and recipient is a promising strategy to prevent IR injury. In this review, we describe the pathological functions of NSPs in IR injury and discuss their pharmacological inhibition to prevent primary graft dysfunction in lung or heart transplantation.
AU  - Korkmaz-Icöz, S.*
AU  - Szabo, G.*
AU  - Gieldon, A.*
AU  - McDonald, P.P.*
AU  - Dashkevich, A.*
AU  - Yildirim, A.Ö.
AU  - Korkmaz, B.*
C1  - 73163
C2  - 56939
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Protective effects of neutrophil serine protease inhibition against ischemia-reperfusion injury in lung or heart transplantation.
JO  - FEBS J.
PB  - Wiley
PY  - 2025
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - Vaspin is highly expressed not only in the skin but also in the liver and adipose tissue. It counteracts inflammation and oxidative stress in inflammatory skin diseases, obesity, and associated metabolic disorders, in part by inhibiting the kallikrein proteases KLK7 and KLK14. Vaspin binds the cell-surface low-density lipoprotein receptor-related protein 1 (LRP1) with nanomolar affinity, and is rapidly internalized into adipocytes and other cells. We found intracellular vaspin partially localized in the nucleus. Since vaspin binds heparin and inorganic polyphosphates, we investigated the DNA binding of vaspin. Using DNA-affinity chromatography and differential radial capillary action of ligand assays, we found high-affinity binding to random sequences of single- and double-stranded DNA for both vaspin and KLK7. Furthermore, KLK7 inhibition was accelerated fivefold in the presence of DNA molecules at least 40 bases in length. We previously identified the heparin-binding site at a basic patch on the central beta-sheet A of vaspin. In the current work, we determined the crystal structure of polyphosphate P45-bound vaspin, which confirmed previously identified residues mutated to generate a nonheparin-binding (NHB) vaspin variant. While NHB vaspin failed to bind heparin and polyP45, it still bound DNA with high affinity and accelerated protease inhibition. Mutation of closely spaced basic residues in helix A and helix G did not significantly alter DNA binding. In conclusion, we have identified vaspin as the second human DNA-binding serpin. While the exact mode of the nonspecific interaction remains unclear, it accelerates protease inhibition and likely contributes to the nuclear localization observed for internalized vaspin and may allow for intracellular effects.
AU  - Möhlis, K.
AU  - Useini, A.
AU  - Betat, H.*
AU  - Bonin, S.*
AU  - Broghammer, H.
AU  - Nuwayhid, R.*
AU  - Langer, S.*
AU  - Mörl, M.*
AU  - Sträter, N.*
AU  - Heiker, J.T.
C1  - 75602
C2  - 58244
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Vaspin identified as a DNA-binding serpin with functional consequences for protease inhibition.
JO  - FEBS J.
PB  - Wiley
PY  - 2025
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - The loss of pancreatic beta cell function leads to chronically high blood glucose levels, contributing to diabetes mellitus, one of the leading causes of morbidity and mortality worldwide. Understanding the molecular mechanisms that regulate beta cell function could pave the way for the development of more effective antidiabetic treatments. In this study, we identify the evolutionarily conserved transforming growth factor β-1 stimulated clone D1 (TSC22D1) protein as a previously unknown regulator of beta cell function. TSC22D1 depletion in INS-1E cells enhances the expression of key beta cell identity genes, including Ins1, Ins2, Pdx1, Slc2a2, and Nkx6.1, and promotes glucose-stimulated insulin secretion without altering intracellular insulin content. Mechanistically, TSC22D1 and Forkhead box protein O1 (FoxO1) interact and regulate each other in a reciprocal manner to control beta cell function. Our follow-up interactome and RNA-Seq analyses reveal that TSC22D1 is crucial for glucose-responsive cellular processes in beta cells, including mRNA processing, ribonucleoprotein complex biogenesis, and Golgi vesicle transport. Overall, our findings indicate that TSC22D1 plays a significant role in regulating beta cell function at multiple levels, with potential implications for metabolic diseases, such as diabetes.
AU  - Yıldırım, S.
AU  - Mhamane, A.
AU  - Lösch, S.
AU  - Wieder, A.
AU  - Ermis, E.
AU  - König, A.-C.
AU  - Yilmaz, S.
AU  - Hauck, S.M.
AU  - Kocabaş, F.*
AU  - Szendroedi, J.
AU  - Herzig, S.
AU  - Ekim Üstünel, B.
C1  - 75173
C2  - 57840
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - TSC22D1 is a newly identified inhibitor of insulin secretion in pancreatic beta cells.
JO  - FEBS J.
PB  - Wiley
PY  - 2025
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - Vaspin is a serine protease inhibitor that protects against adipose tissue inflammation and insulin resistance, two key drivers of adipocyte dysfunction and metabolic disorders in obesity. Inhibition of target proteases such as KLK7 has been shown to reduce adipose tissue inflammation in obesity, while vaspin binding to cell surface GRP78 has been linked to reduced obesity-induced ER stress and insulin resistance in the liver. However, the molecular mechanisms by which vaspin directly affects cellular processes in adipocytes remain unknown. Using fluorescently labeled vaspin, we found that vaspin is rapidly internalized by mouse and human adipocytes, but less efficiently by endothelial, kidney, liver, and neuronal cells. Internalization occurs by active, clathrin-mediated endocytosis, which is dependent on vaspin binding to the LRP1 receptor, rather than GRP78 as previously thought. This was demonstrated by competition experiments and RNAi-mediated knock-down in adipocytes and by rescuing vaspin internalization in LRP1-deficient Pea13 cells after transfection with a functional LRP1 minireceptor. Vaspin internalization is further increased in mature adipocytes after insulin-stimulated translocation of LRP1. Although vaspin has nanomolar affinity for LRP1 clusters II-IV, binding to cell surface heparan sulfates is required for efficient LRP1-mediated internalization. Native, but not cleaved vaspin, and also vaspin polymers are efficiently endocytosed, and ultimately targeted for lysosomal degradation. Our study provides mechanistic insight into the uptake and degradation of vaspin in adipocytes, thereby broadening our understanding of its functional repertoire. We hypothesize the vaspin-LRP1 axis to be an important mediator of vaspin effects not only in adipose tissue but also in other LRP1-expressing cells.
AU  - Tindall, C.A.
AU  - Möhlis, K.
AU  - Rapöhn, I.
AU  - Dommel, S.
AU  - Riedl, V.*
AU  - Schneekönig, M.
AU  - Höfling, C.*
AU  - Rosner, S.*
AU  - Stichel, J.*
AU  - Beck-Sickinger, A.G.*
AU  - Weiner, J.*
AU  - Heiker, J.T.
C1  - 68728
C2  - 54937
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - LRP1 is the cell-surface endocytosis receptor for vaspin in adipocytes.
JO  - FEBS J.
PB  - Wiley
PY  - 2023
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - The skin is home to an assortment of fibroblastic lineages that shape the wound repair response towards scars or regeneration. In this review, we discuss the distinct embryonic origins, anatomic locations, and functions of fibroblastic lineages, and how these distinct lineages of fibroblasts dictate the skin's wound response across injury depths, anatomic locations, and embryonic development to promote either scarring or regeneration. We highlight the supportive role of the fascia in dictating scarring outcomes, we then discuss recent findings that indicate fascia mobilization by its resident fibroblasts supersede the classical de novo deposition program of wound matrix formation. These recent findings reconfigure our traditional view of wound repair and presents exciting new therapeutic avenues to treat scarring and fibrosis across a range of medical settings.
AU  - Correa-Gallegos, D.
AU  - Rinkevich, Y.
C1  - 62334
C2  - 50775
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 5034-5048
TI  - Cutting into wound repair.
JO  - FEBS J.
VL  - 289
IS  - 17
PB  - Wiley
PY  - 2021
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - Fungal lipases are efficient and environment-friendly biocatalysts for many industrially relevant processes. One of the most widely applied lipases in the manufacturing industry is Candida antarctica lipase B (CALB). Here, we report the biochemical and structural characterization of a novel CALB-like lipase from an important human pathogen-Aspergillus fumigatus (AFLB), which has high sn-1,3-specificity toward triolein. AFLB crystal structure displays a CALB-like catalytic domain and hosts a unique tightly closed 'lid' domain that contains a disulfide bridge, as well as an extra N-terminal subdomain composed of residues 1-128 (including the helix alpha 1-alpha 5 located above the active site). To gain insight into the function of this novel lid and N-terminal subdomain, we constructed and characterized a series of mutants in these two domains. Deleting the protruding bulk lid's residues, replacing the bulk and tight lid with a small and loose lid from CALB, or breaking the disulfide bridge increased the affinity of CALB for glyceride substrates and improved its catalytic activity, along with the loss of enzyme fold stability and thermostability. N-terminal truncation mutants revealed that the N-terminal peptide (residues 1-59) is a strong inhibitor of AFLB binding to lipid films. This peptide thus limits AFLB's penetration power and specific activity, revealing a unique enzyme activity regulatory mechanism. Our findings on the functional and structural properties of AFLB provide a better understanding of the functions of the CALB-like lipases and pave the way for its future protein engineering. Database Structural data are available in the Protein Data Bank under the accession numbers .
AU  - Huang, W.*
AU  - Lan, D.*
AU  - Popowicz, G.M.
AU  - Zak, K.M.
AU  - Zhao, Z.*
AU  - Yuan, H.*
AU  - Yang, B.*
AU  - Wang, Y.*
C1  - 55743
C2  - 46505
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 2366-2380
TI  - Structure and characterization of Aspergillus fumigatus lipase B with a unique, oversized regulatory subdomain.
JO  - FEBS J.
VL  - 286
IS  - 12
PB  - Wiley
PY  - 2019
SN  - 1742-464X
ER  - 

TY  - JOUR
AU  - Cristovao, J.S.*
AU  - Morris, V
AU  - Cardoso, I.*
AU  - Leal, S.S.*
AU  - Botelho, H.M.*
AU  - Goebl, C.*
AU  - Kierdorf, K.*
AU  - Madl, T.
AU  - Fritz, G.*
AU  - Reif, B.*
AU  - Gomes, C.M.*
C1  - 52137
C2  - 43773
CY  - Hoboken
SP  - 184-184
TI  - The neuronal S100B cytokine targeting amyloid-beta aggregation in Alzheimer's disease.
JO  - FEBS J.
VL  - 284
PB  - Wiley
PY  - 2017
SN  - 1742-464X
ER  - 

TY  - JOUR
AU  - Tretter, J.
AU  - Schorpp, K.K.
AU  - Luxenburger, E.*
AU  - Hadian, K.
AU  - Gires, O.*
AU  - Niessing, D.
C1  - 52136
C2  - 43774
CY  - Hoboken
SP  - 263-263
TI  - Innovative therapeutic modalities for solid EpCAM-positive tumours.
JO  - FEBS J.
VL  - 284
PB  - Wiley
PY  - 2017
SN  - 1742-464X
ER  - 

TY  - JOUR
AU  - Ben-Neriah, Y.*
AU  - Lasrey, A.*
AU  - Aran, D.*
AU  - Zinger, A.*
AU  - Finkin, S.*
AU  - Stein, I.*
AU  - Yuan, D.T.
AU  - Hellman, A.*
AU  - Heikenwälder, M.
AU  - Pikarsky, E.*
C1  - 50280
C2  - 42145
CY  - Hoboken
SP  - 24-24
TI  - A variety of cancer-associated inflammatory reactions.
JO  - FEBS J.
VL  - 283
PB  - Wiley-blackwell
PY  - 2016
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - Deletions at the C-terminus of the proto-oncogene protein c-Src kinase are characteristic of the viral oncogene protein v-Src and are present in some advanced human colon cancers. They are associated with increased kinase activity and elevated cellular invasiveness. Here, we analyzed the mRNA expression signature of a constitutively active C-terminal mutant of c-Src, c-Src(mt), in comparison to its wildtype protein, c-Src(wt), expressed in the human non-transformed breast epithelial cell line MCF-10A. We demonstrated previously that the mutant changed migratory and metastatic properties. Genome-wide transcriptome analysis revealed that c-Src(mt) deregulated the expression levels of about 430 mRNAs whose gene products are mainly involved in the cellular processes of migration and adhesion, apoptosis and protein synthesis. More than 80% of these genes have previously been linked to cellular migration, while the others play roles, for instance, in RNA transport and splicing processes. Consistent with the transcriptome data, c-Src(mt)-, but not c-Src(wt)-expressing cells showed the capacity to metastasize into mouse lung tissue in vivo. The mRNA expression profile of c-Src(mt)-expressing cells shows significant overlap with that of various primary human tumor samples, perhaps reflecting elevated Src activity in some cancerous cells. Expression of c-Src(mt) lead to elevated migratory potential. We used this model system to analyze the transcriptional changes associated with an invasive cellular phenotype. We identified genes and pathways deregulated by c-Src(mt) as biomarkers with potential interest for diagnostics or therapy of metastatic cells.
AU  - Broecker, F.*
AU  - Hardt, C.*
AU  - Herwig, R.*
AU  - Timmermann, B.*
AU  - Kerick, M.*
AU  - Wunderlich, A.*
AU  - Schweiger, M.R.*
AU  - Borsig, L.*
AU  - Heikenwälder, M.
AU  - Lehrach, H.*
AU  - Moelling, K.*
C1  - 48003
C2  - 39835
CY  - Hoboken
SP  - 1669-1688
TI  - Transcriptional signature induced by a C-terminal c-Src mutant in a human breast cell line.
JO  - FEBS J.
VL  - 283
IS  - 9
PB  - Wiley-blackwell
PY  - 2016
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - Papillon-Lefèvre syndrome (PLS; OMIM: 245000) is a rare disease characterized by severe periodontitis and palmoplantar keratoderma. It is caused by mutations in both alleles of the cathepsin C (CatC) gene CTSC which completely abrogate the proteolytic activity of this cysteine proteinase. A genetic analysis most often is unaffordable or unavailable to establish an early rapid diagnosis of PLS. In this study, we tested the hypothesis that active CatC is constitutively excreted and can be easily traced in the urine of normal subjects. If true, its absence in the urine of patients would be an early, simple, reliable, low cost and easy diagnostic technique. All 75 urine samples from healthy control subjects (aged 3 months to 80 years) contained proteolytically active CatC and its proform as revealed by kinetic analysis and immunochemical detection. From the urine samples of 31 patients with a PLS phenotype, 29 contained neither proteolytically active CatC nor the CatC antigen so that the PLS diagnosis was confirmed. CatC was detected in the urine of the other two patients and genetic analysis revealed no loss-of-function mutation in CTSC indicating that they suffer from a PLS-like condition but not from PLS. Screening the absence of urinary CatC activity soon after birth and early treatment before the onset of PLS manifestations will help to prevent aggressive periodontitis and loss of many teeth and should considerably improve the quality of life of PLS patients.
AU  - Hamon, Y.
AU  - Legowska, M.*
AU  - Fergelot, P.*
AU  - Dallet-Choisy, S.*
AU  - Newell, L.*
AU  - Vanderlynden, L.*
AU  - Kord Valeshabad, A.*
AU  - Acrich, K.*
AU  - Kord, H.*
AU  - Charalampos, T.*
AU  - Morice-Picard, F.*
AU  - Surplice, I.*
AU  - Zoidakis, J.*
AU  - David, K.*
AU  - Vlahou, A.*
AU  - Ragunatha, S.*
AU  - Nagy, N.*
AU  - Farkas, K.*
AU  - Széll, M.*
AU  - Goizet, C.*
AU  - Schacher, B.*
AU  - Battino, M.*
AU  - Al Farraj Aldosari, A.*
AU  - Wang, X.*
AU  - Liu, Y.*
AU  - Marchand-Adam, S.*
AU  - Lesner, A.*
AU  - Kara, E.*
AU  - Korkmaz-Icöz, S.*
AU  - Moss, C.*
AU  - Eickholz, P.*
AU  - Taïeb, A.*
AU  - Kavukcu, S.*
AU  - Jenne, D.
AU  - Gauthier, F.*
AU  - Korkmaz, B.*
C1  - 47474
C2  - 39370
CY  - Hoboken
SP  - 498-509
TI  - Analysis of urinary cathepsin C for diagnosing Papillon-Lefèvre syndrome.
JO  - FEBS J.
VL  - 283
IS  - 3
PB  - Wiley-blackwell
PY  - 2016
SN  - 1742-464X
ER  - 

TY  - JOUR
AU  - Gutmann, T.
AU  - Grzybek, M.
AU  - Pigino, G.*
AU  - Coskun, Ü.
C1  - 47199
C2  - 39175
SP  - 221
TI  - Allosteric regulation of insulin receptors by membrane lipids.
JO  - FEBS J.
VL  - 282
PY  - 2015
SN  - 1742-464X
ER  - 

TY  - JOUR
AU  - Kaszuba, K.*
AU  - Grzybek, M.
AU  - Simon, K.*
AU  - Vattulainen, I.*
AU  - Coskun, Ü.
C1  - 47200
C2  - 39174
SP  - 225
TI  - N-Glycosylation as determinant of epidermal growth factor receptor conformation in membranes.
JO  - FEBS J.
VL  - 282
PY  - 2015
SN  - 1742-464X
ER  - 

TY  - JOUR
AU  - Müller, G.
AU  - Tschöp, M.H.
C1  - 47198
C2  - 39176
SP  - 274-275
TI  - Biosensing of intact glycosylphosphatidylinositol-anchored proteins in serum as biomarkers for stress-induced diseases.
JO  - FEBS J.
VL  - 282
PY  - 2015
SN  - 1742-464X
ER  - 

TY  - JOUR
AU  - Ticha, T.*
AU  - Kubienova, L.*
AU  - Luhova, L.*
AU  - Sedlarova, M.*
AU  - Lochman, J.*
AU  - Lindermayr, C.
AU  - Petrivalsky, M.*
C1  - 47197
C2  - 39177
SP  - 306
TI  - Study of protein S-nitrosylation and its role in plant development and pathogenesis.
JO  - FEBS J.
VL  - 282
PY  - 2015
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - ADP-ribosylation is a post-translational modification that regulates various physiological processes, including DNA damage repair, gene transcription and signal transduction. Intracellular ADP-ribosyltransferases (ARTDs or PARPs) modify their substrates either by poly- or mono-ADP-ribosylation. Previously we identified ARTD10 (formerly PARP10) as a mono-ADP-ribosyltransferase, and observed that exogenous ARTD10 but not ARTD10-G888W, a catalytically inactive mutant, interferes with cell proliferation. To expand on this observation, we established cell lines with inducible ARTD10 or ARTD10-G888W. Consistent with our previous findings, induction of the wild-type protein but not the mutant inhibited cell proliferation, primarily by inducing apoptosis. During apoptosis, ARTD10 itself was targeted by caspases. We mapped the major cleavage site at EIAMD406S, a sequence that was preferentially recognized by caspase6. Caspase-dependent cleavage inhibited the pro-apoptotic activity of ARTD10, as ARTD10(1406) and ARTD10(4071025), either alone or together, were unable to induce apoptosis, despite catalytic activity of the latter. Deletion of the Nterminal RNA recognition motif in ARTD10(2571025) also resulted in loss of pro-apoptotic activity. Thus our findings indicate that the RNA recognition motif contributes to the pro-apoptotic effect, together with the catalytic domain. We suggest that these two domains must be physically linked to stimulate apoptosis, possibly targeting ARTD10 through the RNA recognition motif to specific substrates that control cell death. Moreover, we established that knockdown of ARTD10 reduced apoptosis in response to DNA-damaging agents. Together, these findings indicate that ARTD10 is involved in the regulation of apoptosis, and that, once apoptosis is activated, ARTD10 is cleaved as part of negative feedback regulation.
AU  - Herzog, N.*
AU  - Hartkamp, J.D.H.*
AU  - Verheugd, P.*
AU  - Treude, F.*
AU  - Forst, A.H.*
AU  - Feijs, K.L.H.*
AU  - Lippok, B.E.*
AU  - Kremmer, E.
AU  - Kleine, H.*
AU  - Lüscher, B.*
C1  - 23615
C2  - 31234
SP  - 1330-1343
TI  - Caspase-dependent cleavage of the mono-ADP-ribosyltransferase ARTD10 interferes with its pro-apoptotic function.
JO  - FEBS J.
VL  - 280
IS  - 5
PB  - Wiley-Blackwell
PY  - 2013
SN  - 1742-464X
ER  - 

TY  - JOUR
AU  - Keller, I.E.
AU  - Takenaka, S.
AU  - Yildirim, A.Ö.
AU  - Eickelberg, O.
AU  - Meiners, S.
C1  - 47022
C2  - 40488
SP  - 458-458
TI  - Regulation of immunoproteasomes by cigarette smoke.
JO  - FEBS J.
VL  - 280
PY  - 2013
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - Inferring knowledge about biological processes by a mathematical description is a major characteristic of Systems Biology. To understand and predict system's behavior the available experimental information is translated into a mathematical model. Since the availability of experimental data is often limited and measurements contain noise, it is essential to appropriately translate experimental uncertainty to model parameters as well as to model predictions. This is especially important in Systems Biology because typically large and complex models are applied and therefore the limited experimental knowledge might yield weakly specified model components. Likelihood profiles have been recently suggested and applied in the Systems Biology for assessing parameter and prediction uncertainty. In this article, the profile likelihood concept is reviewed and the potential of the approach is demonstrated for a model of the erythropoietin (EPO) receptor.
AU  - Kreutz, C.*
AU  - Raue, A.
AU  - Kaschek, D.*
AU  - Timmer, J.*
C1  - 25149
C2  - 31834
SP  - 2564-2571
TI  - Profile likelihood in systems biology.
JO  - FEBS J.
VL  - 280
IS  - 11
PB  - Wiley-Blackwell
PY  - 2013
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - The cytochrome P450 (CYP) genes Cyp51, Cyp11a1, Cyp17a1, Cyb11b1, Cyp11b2 and Cyp21a1 are involved in the adrenal production of corticosteroids, whose circulating levels are circadian. cAMP signaling plays an important role in adrenal steroidogenesis. By using cAMP responsive element modulator (Crem) knockout mice, we show that CREM isoforms contribute to circadian expression of steroidogenic CYPs in the mouse adrenal gland. Most striking was the CREM-dependent hypomethylation of the Cyp17a1 promoter at zeitgeber time 12, which resulted in higher Cyp17a1 mRNA and protein expression in the knockout adrenal glands. The data indicate that products of the Crem gene control the epigenetic repression of Cyp17 in mouse adrenal glands.
AU  - Kosir, R.*
AU  - Zmrzljak, U.P.*
AU  - Bele, T.*
AU  - Acimovic, J.*
AU  - Perse, M.*
AU  - Majdic, G.*
AU  - Prehn, C.
AU  - Adamski, J.
AU  - Rozman, D.*
C1  - 6806
C2  - 29290
SP  - 1584-1593
TI  - Circadian expression of steroidogenic cytochromes P450 in the mouse adrenal gland - involvement of cAMP-responsive element modulator in epigenetic regulation of Cyp17a1.
JO  - FEBS J.
VL  - 279
IS  - 9
PB  - Wiley-Blackwell
PY  - 2012
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - Hematopoiesis is often pictured as a hierarchy of branching decisions, giving rise to all mature blood cell types from stepwise differentiation of a single cell, the hematopoietic stem cell. Various aspects of this process have been modeled using various experimental and theoretical techniques on different scales. Here we integrate the more common population-based approach with a single-cell resolved molecular differentiation model to study the possibility of inferring mechanistic knowledge of the differentiation process. We focus on a sub-module of hematopoiesis: differentiation of granulocyte-monocyte progenitors GMPs) to granulocytes or monocytes. Within a branching process model, we infer the differentiation probability of GMPs from the experimentally quantified heterogeneity of colony assays under permissive conditions where both granulocytes and monocytes can emerge. We compare the predictions with the differentiation probability in genealogies determined from single-cell time-lapse microscopy. In contrast to the branching process model, we found that the differentiation probability as determined by differentiation marker onset increases with the generation of the cell within the genealogy. To study this feature from a molecular perspective, we established a stochastic toggle switch model, in which the intrinsic lineage decision is executed using two antagonistic transcription factors. We identified parameter regimes that allow for both time-dependent and time-independent differentiation probabilities. Finally, we infer parameters for which the model matches experimentally observed differentiation probabilities via approximate Bayesian computing. These parameters suggest different timescales in the dynamics of granulocyte and monocyte differentiation. Thus we provide a multi-scale picture of cell differentiation in murine GMPs, and illustrate the need for single-cell time-resolved observations of cellular decisions.
AU  - Marr, C.
AU  - Strasser, M.
AU  - Schwarzfischer, M.
AU  - Schroeder, T.
AU  - Theis, F.J.
C1  - 10633
C2  - 30321
SP  - 3488-3500
TI  - Multi-scale modeling of GMP differentiation based on single-cell genealogies.
JO  - FEBS J.
VL  - 279
IS  - 18
PB  - Wiley-Blackwell
PY  - 2012
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - Many fields of science and industry depend on efficient production of active protein using heterologous expression in Escherichia coli. The solubility of proteins upon expression is dependent on their amino acid sequence. Prediction of solubility from sequence is therefore highly valuable. We present a novel machine-learning-based model called PROSO II which makes use of new classification methods and growth in experimental data to improve coverage and accuracy of solubility predictions. The classification algorithm is organized as a two-layered structure in which the output of a primary Parzen window model for sequence similarity and a logistic regression classifier of amino acid k-mer composition serve as input for a second-level logistic regression classifier. Compared with previously published research our model is trained on five times more data than used by any other method before (82 000 proteins). When tested on a separate holdout set not used at any point of method development our server attained the best results in comparison with other currently available methods: accuracy 75.4%, Matthews correlation coefficient 0.39, sensitivity 0.731, specificity 0.759, gain (soluble) 2.263. In summary, due to utilization of cutting edge machine learning technologies combined with the largest currently available experimental data set the PROSO II server constitutes a substantial improvement in protein solubility predictions. PROSO II is available at .
AU  - Smialowski, P.
AU  - Doose, G.*
AU  - Torkler, P.*
AU  - Kaufmann, S.*
AU  - Frishman, D.
C1  - 7550
C2  - 30132
SP  - 2192-2200
TI  - PROSO II - a new method for protein solubility prediction.
JO  - FEBS J.
VL  - 279
IS  - 12
PB  - Wiley-Blackwell
PY  - 2012
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - High-throughput metabolomics is a dynamically developing technology that enables the mass separation of complex mixtures at very high resolution. Metabolic profiling has begun to be widely used in clinical research to study the molecular mechanisms of complex cell disorders. Similar to transcriptomics, which is capable of detecting genes at differential states, metabolomics is able to deliver a list of compounds differentially present between explored cell physiological conditions. The bioinformatics challenge lies in a statistically valid interpretation of the functional context for identified sets of metabolites. Here, we present TICL, a web tool for the automatic interpretation of lists of compounds. The major advance of TICL is that it not only provides a model of possible compound transformations related to the input list, but also implements a robust statistical framework to estimate the significance of the inferred model. The TICL web tool is freely accessible at http://mips.helmholtz-muenchen.de.
AU  - Antonov, A.V.
AU  - Dietmann, S.
AU  - Wong, P.
AU  - Mewes, H.-W.
C1  - 1564
C2  - 27008
SP  - 2084-2094
TI  - TICL - a web tool for network-based interpretation of compound lists inferred by high-throughput metabolomics.
JO  - FEBS J.
VL  - 276
IS  - 7
PB  - Wiley-Blackwell Publishing, Inc
PY  - 2009
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - The pathway of riboflavin (vitamin B2) biosynthesis is significantly different in archaea, eubacteria, fungi and plants. Specifically, the first committed intermediate, 2,5-diamino-6-ribosylamino-4(3H)-pyrimidinone 5'-phosphate, can either undergo hydrolytic cleavage of the position 2 amino group by a deaminase (in plants and most eubacteria) or reduction of the ribose side chain by a reductase (in fungi and archaea). We compare 2,5-diamino-6-ribitylamino-4(3H)-pyrimidinone 5'-phosphate synthases from the yeast Candida glabrata, the archaeaon Methanocaldococcus jannaschii and the eubacterium Aquifex aeolicus. All three enzymes convert 2,5-diamino-6-ribosylamino-4(3H)-pyrimidinone 5'-phosphate into 2,5-diamino-6-ribitylamino-4(3H)-pyrimidinone 5'-phosphate, as shown by 13C-NMR spectroscopy using [2,1',2',3',4',5'-13C6]2,5-diamino-6-ribosylamino-4(3H)-pyrimidinone 5'-phosphate as substrate. The beta anomer was found to be the authentic substrate, and the alpha anomer could serve as substrate subsequent to spontaneous anomerisation. The M. jannaschii and C. glabrata enzymes were shown to be A-type reductases catalysing the transfer of deuterium from the 4(R) position of NADPH to the 1' (S) position of the substrate. These results are in agreement with the known three-dimensional structure of the M. jannaschii enzyme.
AU  - Römisch-Margl, W.
AU  - Eisenreich, W.*
AU  - Haase, I.*
AU  - Bacher, A.*
AU  - Fischer, M.*
C1  - 6155
C2  - 27768
CY  - Oxford
SP  - 4403-4414
TI  - 2,5-diamino-6-ribitylamino-4(3H)-pyrimidinone 5'-phosphate synthases of fungi and archaea.
JO  - FEBS J.
VL  - 275
IS  - 17
PB  - Wiley-Blackwell
PY  - 2008
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - Cells of the innate immune system play important roles in the progression of prion disease after peripheral infection. It has been found in vivo and in vitro that the expression of the cellular prion protein (PrP(c)) is up-regulated on stimulation of immune cells, also indicating the functional importance of PrP(c) in the immune system. The aim of our study was to investigate the impact of cytosine-phosphate-guanosine- and lipopolysaccharide-induced PrP(c) up-regulation on the uptake and processing of the pathological prion protein (PrP(Sc)) in phagocytic innate immune cells. For this purpose, we challenged the macrophage cell line J774, the microglial cell line BV-2 and primary bone marrow-derived macrophages in a resting or stimulated state with various prion strains, and monitored the uptake and clearance of PrP(Sc). Interestingly, stimulation led either to a transient increase in the level of PrP(Sc) relative to unstimulated cells or to a decelerated degradation of PrP(Sc). These features were dependent on cell type and prion strain. Our data indicate that the stimulation of innate immune cells may be able to support transient prion propagation, possibly explained by an increased PrP(c) cell surface expression in stimulated cells. We suggest that stimulation of innate immune cells can lead to an imbalance between the propagation and degradation of PrP(Sc).
AU  - Gilch, S.*
AU  - Schmitz, F.*
AU  - Aguib, Y.*
AU  - Kehler, C.*
AU  - Bülow, S.*
AU  - Bauer, S.*
AU  - Kremmer, E.
AU  - Schatzl, H.M.*
C1  - 2927
C2  - 24804
SP  - 5834-5844
TI  - CpG and LPS can interfere negatively with prion clearance in macrophage and microglial cells.
JO  - FEBS J.
VL  - 274
IS  - 22
PB  - Wiley-Blackwell
PY  - 2007
SN  - 1742-464X
ER  - 

TY  - JOUR
AU  - Altschuh, J.
AU  - Walcher, S.*
AU  - Sandermann, H.
C1  - 3353
C2  - 22659
SP  - 2399-2406
TI  - The lipid/protein interface as xenobiotic target site : Kinetic analysis of tadpole narcosis.
JO  - FEBS J.
VL  - 272
PY  - 2005
SN  - 1742-464X
ER  - 

TY  - JOUR
AU  - Kaffarnik, F.
AU  - Heller, W.
AU  - Hertkorn, N.
AU  - Sandermann, H.
C1  - 1365
C2  - 22586
SP  - 1415-1424
TI  - Flavonol 3-O-glycoside hydroxycinnamoyltransferases from Scots pine (Pinus sylvestris L.).
JO  - FEBS J.
VL  - 272
PY  - 2005
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - Epstein–Barr virus nuclear antigen 2 (EBNA2) and the Notch protein both function within the nucleus as transcriptional adaptor proteins. EBNA2 plays a key role during the immortalization of primary B-cells by Epstein–Barr virus (EBV). Notch proteins are involved in lymphomagenesis as well as in multiple cell fate decisions during tissue differentiation and development. Both, EBNA2 and Notch interact with the DNA binding protein RBP-J and thereby gain access to the promoter of their target genes. In order to identify regions within the J recombination signal sequence binding protein (RBP-J), that are relevant for either the Notch or the EBNA2 interaction, we have performed a mutational analysis of RBP-J. A library of RBP-J mutants was screened by a reverse two-hybrid system for alleles that fail to bind to either EBNA2 or Notch. The sequence analysis of these alleles reveals that a limited and particularly distinct number of amino-acid positions are relevant for either interaction only. Given the important role of RBP-J in B-cell immortalization, the EBNA2/RBP-J protein–protein interaction
AU  - Fuchs, K.P.
AU  - Bommer, G.
AU  - Dumont, E.
AU  - Christoph, B.
AU  - Vidal, M.*
AU  - Kremmer, E.
AU  - Kempkes, B.*
C1  - 21862
C2  - 20059
SP  - 4639-4646
TI  - Mutational analysis of the J recombination signal sequence binding protein (RBP-J)/Epstein-Barr virus nuclear antigen 2 (EBNA2) and RBP-J/Notch interaction.
JO  - FEBS J.
VL  - 268
IS  - 17
PY  - 2001
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - Phorbol esters reactivate Epstein-Barr virus (EBV) from latently infected cells via transcriptional activation of the viral immediate-early gene BZLF1. BZLF1 is a member of the extended AP-1 family of transcription factors that binds to specific BZLF1-binding motifs within early EBV promoters and to consensus AP-1 sites. Regulation of BZLF1's activity is achieved at the transcriptional level as well as through post-translational modifications. Recently, we reported that the transcriptional activity of BZLF1 is augmented by TPA [Baumann, M., Mischak, H., Dammeier, S., Kolch, W., Gires, O., Pich, D., Zeidler, R., Delecluse, H. J. & Hammerschmidt, W., (1998) J. Virol. 72, 8105-8114]. The increase of BZLF1's activity depends on a single serine residue (S186) that is phosphorylated by protein kinase C (PKC) in vitro and in vivo after stimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA). Here, we identified RACK1 as a binding partner of BZLF1 in a yeast interaction trap assay. RACK stands for receptor of activated C-kinase and is involved in targeting activated PKCs and other signaling proteins. In vivo, RACK1 binds directly to the transactivation domain of BZLF1. Although a functional relationship between BZLF1 and PKC could be mediated by RACKs, RACK1 did not have a detectable effect on the phosphorylation status of BZLF1 in in vitro or in vivo phosphorylation assays. We suggest that RACK1 may act as a scaffolding protein on BZLF1 independently of activated PKCs.
AU  - Baumann, M.
AU  - Gires, O.*
AU  - Kolch, W.*
AU  - Mischak, H.*
AU  - Zeidler, R.*
AU  - Pich, D.
AU  - Hammerschmidt, W.
C1  - 27638
C2  - 32779
SP  - 3891-3901
TI  - The PKC targeting protein RACK1 interacts with the Epstein-Barr virus activator protein BZLF1.
JO  - FEBS J.
VL  - 267
IS  - 12
PY  - 2000
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - Fetuins are among the major plasma proteins, yet their biological role has remained elusive. Here we report the molecular cloning of rat fetuin and the sequence analysis of a full-length clone, RF619 of 1456 bp with an open reading frame of 1056 bp encoding 352 amino acid residues. The coding part of RF619 was identical with the cDNA sequence of the natural inhibitor of the insulin receptor tyrosine kinase from rat (pp63) except for four substitutions and a single base insertion causing divergence of the predicted protein sequences. Partial amino acid sequences of rat plasma fetuin were in agreement with the predictions based on the RF619 cDNA. Purified rat fetuin inhibited the insulin receptor tyrosine kinase in vitro. Therefore, we conclude that RF619 and pp63 cDNA encode the same protein, i.e. authentic rat fetuin which is a functional tyrosine kinase inhibitor.
AU  - Rauth, G.
AU  - Pöschke, O.
AU  - Fink, E.
AU  - Eulitz, M.
AU  - Tippmer, S.
AU  - Kellerer, M.
AU  - Häring, H.-U.
AU  - Nawratil, P.
AU  - Haasemann, M.
AU  - Jahnen-Dechent, W.
AU  - Müller-Esterl, W.
C1  - 20000
C2  - 13168
SP  - 523-529
TI  - The Nucleotide and Partial Amino Acid Sequences of Rat Fetuin. Identity with the Natural Tyrosine Kinase Inhibitor of the Rat Insulin Receptor.
JO  - FEBS J.
VL  - 204
IS  - 2
PY  - 1992
SN  - 1742-464X
ER  - 

TY  - JOUR
AU  - Beck-Speier, I.
AU  - Luippold, G.B.
AU  - Godleski, J.J.
C1  - 18176
C2  - 11040
TI  - Effect of Sulfite and Human Neutrophils.
JO  - FEBS J.
PY  - 1989
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - 1. Diacylglycerol kinase apoprotein was purified from membranes of Escherichia coli K12 by a six-step procedure that included HPLC. The proposed assignment of the enzyme to the dgkA gene [Lightner et al. (1983) J. Biol. Chen. 258, 10856-10861] could be supported by molecular mass determination (~ 14 kDa), N-terminal sequencing (Met-Ala-Asn), cyanogen bromide fragmentation and amino acid analysis. As predicted, proline was absent. 2. The membrane-associated as well as the butan-1-ol-dissolved enzyme survived heating to 100°C. 3. Alkylglycoside detergents were found to constitute an additional class of lipid activators. 4. The enzyme apoprotein in a non-activating substrate/detergent solution was capable of autocatalytic self-activation which was attributed to a novel feedback activation mechanism involving phosphatidic acid (diacylglycerol 3-phosphate).
AU  - Russ, E.
AU  - Kaiser, U.
AU  - Sandermann, H.J.
C1  - 34012
C2  - 36199
SP  - 335-342
TI  - Lipid-dependent membrane enzymes : Purification to homogeneity and further characterization of diacylglycerol kinase from Escherichia coli.
JO  - FEBS J.
VL  - 171
IS  - 1-2
PY  - 1988
SN  - 1742-464X
ER  - 

TY  - JOUR
AB  - Human blood platelet aggregation and the formation of icosanoids were studied in response to triethyl lead chloride (Et3PbCl). Concentrations higher than 75 μM stimulate platelets to aggregate, whereas low concentrations (≦ 20 μM) caused platelet hypersensitivity to aggregating agents such as collagen or arachidonic acid. Incubation of suspensions of washed platelets with Et3PbCl resulted in a stimulated liberation and subsequent metabolism of arachidonic acid. This response was dependent on the concentration of Et3PbCl and the incubation time. Using low concentrations of Et3PbCl and up to 3 h of incubation, the lipoxygenase product 12-hydroxy-5,8,10,14-icosatetraenoic acid was the major metabolite. Under normal conditions, however, stimulation of platelets with collagen, thrombin, or arachidonic acid leads to higher amounts of the cyclooxygenase products 12-hydroxy-5,8,10-heptadecatrienoic acid and thromboxane B2.The aggregation of human platelets induced by Et3PbCl was inhibited by three different drugs: acetylsalicylic acid, forskolin and quinacrine; but only quinacrine could prevent the liberation of arachidonic acid and the appearance of its metabolites. These specific effects of the inhibitors on Et3PbCl-stimulated platelets as well as the differences in the pattern of arachidonic acid metabolites and phosphatidic acid suggest a direct stimulatory action of Et3PbCl on platelet phospholipase A2.  
AU  - Krug, H.F.
AU  - Berndt, J.
C1  - 33535
C2  - 38391
SP  - 293-298
TI  - Stimulation of arachidonic acid metabolism via phospholipase A2 by triethyl lead.
JO  - FEBS J.
VL  - 162
IS  - 2
PY  - 1987
SN  - 1742-464X
ER  -