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Institute
Genetic or pharmacological ablation of toll-like receptor 2 (TLR2) protects against myocardial ischemia/reperfusion injury (MI/R). However, the endogenous ligand responsible for TLR2 activation has not yet been detected. The objective of this study was to identify HMGB1 as an activator of TLR2 signalling during MI/R. C57BL/6 wild-type (WT) or TLR2(-/-)-mice were injected with vehicle, HMGB1, or HMGB1 BoxA one hour before myocardial ischemia (30 min) and reperfusion (24 hrs). Infarct size, cardiac troponin T, leukocyte infiltration, HMGB1 release, TLR4-, TLR9-, and RAGE-expression were quantified. HMGB1 plasma levels were measured in patients undergoing coronary artery bypass graft (CABG) surgery. HMGB1 antagonist BoxA reduced cardiomyocyte necrosis during MI/R in WT mice, accompanied by reduced leukocyte infiltration. Injection of HMGB1 did, however, not increase infarct size in WT animals. In TLR2(-/-)-hearts, neither BoxA nor HMGB1 affected infarct size. No differences in RAGE and TLR9 expression could be detected, while TLR2(-/-)-mice display increased TLR4 and HMGB1 expression. Plasma levels of HMGB1 were increased MI/R in TLR2(-/-)-mice after CABG surgery in patients carrying a TLR2 polymorphism (Arg753Gln). We here provide evidence that absence of TLR2 signalling abrogates infarct-sparing effects of HMGB1 blockade.
Background and study objective: Focused lung ultrasound (LUS) examinations are important tools in critical care medicine. There is evidence that LUS can be used for the detection of acute thoracic lesions. However, no validated training method is available. The goal of this study was to develop and assess an objective structured clinical examination (OSCE) curriculum for focused thorax, trachea, and lung ultrasound in emergency and critical care medicine (THOLUUSE).
Methods: 39 trainees underwent a one-day training course in a prospective educational study, including lectures in sonoanatomy and -pathology of the thorax, case presentations, and hands-on training. Trainees' pre- and posttest performances were assessed by multiple choice questionnaires, visual perception tests by interpretation video clips, practical performance of LUS, and identification of specific ultrasound findings.
Results: Trainees postcourse scores of correct MCQ answers increased from 56 ± 4% to 82 ± 2% (mean± SD; P < 0.001); visual perception skills increased from 54 ± 5% to 78 ± 3% (P < 0.001); practical ultrasound skills improved, and correct LUS was performed in 94%. Subgroup analysis revealed that learning success was independent from the trainees' previous ultrasound experience.
Conclusions: THOLUUSE significantly improves theoretical and practical skills for the diagnosis of acute thoracic lesions. We propose to implement THOLUUSE in emergency medicine training.
Smoking cigarettes throughout pregnancy is one of the single most important avoidable causes of adverse pregnancy outcomes and it represents the first major environmental risk of the unborn. If compared with other risk factors in the perinatal period, exposure to tobacco smoke is considered to be amongst the most harmful and it is associated with high rates of long and short term morbidity and mortality for mother and child. A variety of adverse pregnancy outcomes are linked with cigarette consumption before and during pregnancy. Maternal prenatal cigarette smoke disturbs the equilibrium among the oxidant and antioxidant system, has negative impact on the genetic and cellular level of both mother and fetus and causes a large quantity of diseases in the unborn child. These smoking-induced damages for the unborn offspring manifest themselves at various times in life and for most only a very limited range of causal treatment exists. Education, support and assistance are of high importance to decrease maternal and fetal morbidity and mortality, as there are few other avoidable factors which influence a child's health that profoundly throughout its life. It is imperative that smoking control should be seen as a public health priority.
In the past century, scientists have realized that venoms are a source of a number of natural substances presenting a wide range of pharmacological properties and often displaying a high specificity for their targets. Thus, the field of toxinology came into being, which is defined as the study of toxic substances of biological origin. Toxins are found in a wide variety of animals, including fish, cone snails, scorpions, snakes, and even some mammals. To be classified as venom, these must contain substances, i.e. toxins, which disturb physiological processes and must be deliberately delivered to the target animal. Snakes have evolved one of the most sophisticated mechanisms for venom delivery. Envenomation by snakebite can induce and inhibit aggregation/agglutination of platelets as well as inhibit/activate hemostasis, but also disrupt other physiological functions via neurotoxins and angioneurin growth factors. Snake venoms contain a substantial amount of C-type lectin-related proteins (CLRPs) which are known to function, notably, as integrin inhibitors. CLRPs are heterodimers composed of homologous α and β subunits which can assemble either covalently or noncovalently to oligomers, resulting in αβ, (αβ)2 and (αβ)4 structures. Some of the main targets of CLRPs are membrane receptors, coagulation factors, and proteins essential to hemostasis. The platelet collagen receptors GPVI and α2β1 integrin as well as the von Willebrand factor receptor GPIb play important roles in platelet activation and aggregation and are considered main targets of antithrombotic drugs. In this thesis, the integrin α2β1 is particularly considered as it is the sole collagen-binding integrin on platelets. Reduced expression of this platelet receptor results in dysfunction of platelet responses. Equivalently, overexpression of α2β1 integrin results in an increased risk of thrombosis. As a result, selective inhibitors of the collagen-α2β1 interaction could give rise to effective antithrombotic drugs. Integrins are large receptors which mediate cell-cell contacts and the binding of cells to the extracellular matrix (ECM). Therefore, they play a role in physiological processes, e.g. hemostasis and immunity, as well as in pathological processes, e.g. tumor angiogenesis and atherosclerosis. 18 α and 8 β integrin subunits, with nine α subunits containing an additional A domain, associate non-covalently to form 24 heterodimers with distinct binding specificities. Integrin collagen receptors are a subclass of four receptors which all utilize the β1 subunit. The α2β1 integrin is a collagen-binding receptor expressed not only on platelets, but also on endothelial and epithelial cells. Consequently, this integrin is also essential for cell adhesion and migration playing a role in angiogenesis as well as tumor metastasis. To date, there are five known antagonists of α2β1 integrin: EMS16, rhodocetin, vixapatin, and most recently rhinocetin and flavocetin-A. The first four have been shown to be specific for the integrin α2A domain, the major collagen-binding domain. All these antagonists are CLRPs and present new leads for drug design. In the past few years, many insights into the structure and function of rhodocetin were obtained. Monoclonal antibodies proved to be advantageous in disclosing this information, making them not only useful as therapeutic agents, but also as tools for protein characterization. The venom of the Vipera palaestinae snake was recently shown to contain an α2β1 integrin inhibitor, which prevented the integrin from binding collagen. This inhibitor, called vixapatin, was the initial focus of this dissertation. Vixapatin’s interaction with the α2β1 integrin needed further characterization on a molecular and cellular level to assess its medical potential and monoclonal antibodies were to be used as a tool. Originally, vixapatin had been isolated by reversed-phase high-performance liquid chromatography. To avoid the stringency of this method, for this study, it was replaced with gentler chromatographic methods. First, the α2β1 integrin inhibitor was isolated from the crude snake venom with affinity chromatography using the α2A domain as bait, establishing a method to quickly screen venoms for α2β1-binding proteins which affect the collagenintegrin interaction. The applicability of this method to other snake venoms was shown by isolating an α2A domain-specific toxin from the venom of Trimeresurus flavoviridis. To allow further characterization of both these toxins, gel filtration and ion exchange chromatography were employed to purify the protein without the α2A domain. These classical protein purification methods resulted in similar separation patterns of both the V. palaestinae and T. flavoviridis venom proteins. Purified proteins exhibiting the potential of inhibiting integrinbinding to collagen were analyzed by two-dimensional gel electrophoresis. Both VP-i and flavocetin-A, the integrin inhibitors from V. palaestinae and T. flavoviridis, respectively, were shown to have more complex structures than was evident from the purification. Each consisted of four low-molecular-weight proteins which assembled into two bands (for VP-i) or one single band (for flavocetin-A) under non-reducing conditions. Mass spectrometry analyses revealed VP-i to belong to the family of CLRPs, just like vixapatin does. However, these two proteins differed in their primary sequences and only showed homology to one another. The toxin purified from T. flavoviridis revealed this toxin to be flavocetin-A, a heterodimeric CLRP which had so far only been shown to have GPIb-binding activity. At the time of flavocetin-A’s purification, flavocetin-B was co-purified; flavocetin-B consists of the same two α and β subunits, plus an additional γ subunit. As no sequence information is known to date for the γ subunit, it may be one of the additional proteins purified here, along with an additional δ subunit. Therefore, the toxin isolated here may actually consist of four different subunits forming a tetramer of two different heterodimers, generating an (αβ)2(γδ)2 structure. This proposed (αβ)2(γδ)2 flavocetin-A structure has binding sites for both α2β1 integrin and GPIb, with no sterical overlap, as shown by affinity chromatography using the α2A domain and the extracellular domain of the GPIb receptor. The potential of VP-i and flavocetin-A to inhibit integrin-binding to type I collagen was shown during purification: Both toxins efficiently bind to the integrin α2A domain; also, VP-i and vixapatin bind to the A domain with the same affinity. Surface plasmon resonance showed the interaction of flavocetin-A with the α2β1 integrin to be extremely strong and association to be very fast. Furthermore, both toxins were shown to inhibit binding of the wildtype integrin to collagen: VP-i and flavocetin-A acted antagonistically on cell adhesion and cell migration. Initially, the interaction between VP-i and α2β1 integrin was to be further characterized with the help of monoclonal antibodies. However, this proved problematic, the procedure requiring various optimizations. Although, after expert consultation, some monoclonal antibodies could be obtained, the cells were extremely sensitive and gave unsatisfactory results when tested as detection tools in Western blot and immunoassays. Concluding, two novel α2β1 integrin inhibitors were discovered: VP-i and flavocetin-A, which were purified using the same procedure and which have similar functions. Both are Ctype lectin-related proteins which effectively inhibit cell adhesion and migration. This underlines that nature has instrumentalized CLRPs to specifically inhibit α2β1 integrin. Further characterization of VP-i and flavocetin-A will be able to provide leads for future drug development.
Persistent neuropathic pain is a frequent consequence of peripheral nerve injuries, particularly in the elderly. Using the IntelliCage we studied if sciatic nerve injury obstructed learning and memory in young and aged mice, each in wild type and progranulin deficient mice, which develop premature signs of brain aging. Both young and aged mice developed long-term nerve injury-evoked hyperalgesia and allodynia. In both genotypes, aged mice with neuropathic pain showed high error rates in place avoidance acquisition tasks. However, once learnt, these aged mice with neuropathic pain showed a significantly stronger maintenance of the aversive memory. Nerve injury did not affect place preference behavior in neither genotype, neither in young nor aged mice. However, nerve injury in progranulin deficient mice impaired the learning of spatial sequences of awarded places, particularly in the aged mice. This task required a discrimination of clockwise and anti-clockwise sequences. The chaining failure occurred only in progranulin deficient mice after nerve injury, but not in sham operated or wildtype mice, suggesting that progranulin was particularly important for compensatory adaptations after nerve injury. In contrast, all aged mice with neuropathic pain, irrespective of the genotype, had a long maintenance of aversive memory suggesting a negative alliance and possibly mutual aggravation of chronic neuropathic pain and aversive memory at old age.
Gegenstand dieser Arbeit ist die Untersuchung der Genexpression der axonalen wachstumsassoziierten Proteine NAP-22, GAP-43 und CAP-23 in den dopaminergen Neuronen der Substantia nigra pars compacta (SNc), einer im Mesencephalon gelegenen Zellregion, relativ zu der Genexpression eines Referenzgens. Als Versuchstiere dienten sechs Monate alte, männliche CB6F1 Wildtypmäuse sowie sechs Monate alte, männliche CAP-23 transgene (CAP-23tg) Tiere, die das wachstumsassoziierte Protein CAP-23 überexprimieren. Die dopaminergen Zellen der SNc wurden zunächst morphologisch charakterisiert und ihre Ausdehnung im Mittelhirn durch alternierende Immunfärbungen der Tyrosinhydroxylase, einem Schlüsselenzym der Dopaminsynthese, sowie Toluidinblaufärbungen ermittelt. Anschließend wurden die Neurone durch die Methode der Lasermikrodissektion (LMD) im Zellverband isoliert. Hierfür war die Optimierung der Toluidinblaufärbung erforderlich, mit dem Ziel, sowohl eine gute Färbung der Neurone als auch eine hohe RNA-Nativität zu erzielen. Die RNA wurde isoliert und nach Integritätsprüfung in cDNA umgeschrieben. Daraufhin erfolgte die Analyse der Genexpression der beschriebenen Gene durch die quantitative Echtzeit-Polymerase-Kettenreaktion (qRT-PCR). Dabei war feststellbar, dass das Transgen Cap-23 in den transgenen Tieren stärker exprimiert wird als das Endogen Nap-22. Es zeigte sich jedoch kein signifikanter Unterschied der Expression von endogenem Nap-22 und endogenem Gap-43 in den CAP-23tg Tieren im Vergleich zu der Expression in den Wildtypmäusen. Das bedeutet, dass die Überexpression von Cap-23 in den transgenen Tieren die Expression der mRNA der beiden endogenen wachstumsassoziierten Proteine NAP-22 und GAP-43 nicht beeinflusst. Auf Grundlage der in dieser Arbeit vorgelegten Ergebnisse soll in Folgeexperimenten untersucht werden, inwieweit die Überexpression von CAP-23 die Reorganisationsfähigkeit dopaminerger Neuronen der SNc nach einer Schädigung beeinflusst, wie sie zum Beispiel beim Menschen im Verlauf des Morbus Parkinson beobachtet wird.
Abdominale Aortenaneurysmen sind in Industrienationen eine häufige Erkrankung der Personengruppe über 65 Jahre. Diese Dilatationen der abdominalen Aorta zeichnen sich durch eine lokale Inflammation aus, die mit der Infiltration von Immunzellen, dem Verlust von glatten vaskulären Muskelzellen und der Degeneration der extrazellulären Matrix einhergeht. Ursprünglich als Symptom einer Atherosklerose angesehen, sind die Ursachen dieser progressiv verlaufenden Erkrankung nach wie vor nicht vollständig verstanden; obwohl steigendes Alter, männliches Geschlecht, genetische Prädisposition, Rauchen und ein zuvor erlittener Myocardinfarkt als Risikofaktoren identifiziert werden konnten. Der lange Zeit asymptomatische Krankheitsverlauf, die Gefahr einer Ruptur mit häufig letalen Folgen und der Mangel einer effizienten pharmakologischen Therapie machen eine weitere Untersuchung dieser Erkrankung unabdingbar.
Diltiazem ist ein Inhibitor spannungssensitiver L Typ-Calciumkanäle, der seit über 25 Jahren zur Behandlung von arterieller Hypertonie, verschiedener Arrhythmien und Angina pectoris verwendet wird. Im Rahmen der vorliegenden Arbeit sollte untersucht werden, ob Diltiazem auch einen antianeurysmatischen Effekt besitzt. Eine vierwöchige subcutane Infusion des blutdrucksteigernden Hormons Angiotensin II führte nach vier Wochen zur Bildung abdominaler Aortenaneurysmen, sowie zu atherosklerotischen Gefäßveränderungen der thorakalen Aorta Apolipoprotein E (ApoE)-defizienter Mäuse. Eine parallele Therapie mit Diltiazem über das Trinkwasser konnte diese Entwicklung unabhängig vom arteriellen Blutdruck und damit unabhängig von der antihypertensiven Wirkung verhindern. Im Aortenbogen Diltiazem-behandelter Tiere konnte im Rahmen dieses in vivo-Modells nach sechs Tagen eine deutlich geringere lokale Expression proinflammatorischer Cytokine, wie Tumornekrosefaktor-a, Interleukin-1ß (IL1B) und Interleukin-6 (IL6), Chemokine, wie CCL2, und degenerativer Proteasen, wie der Matrix-Metalloprotease 9 (MMP9), festgestellt werden. Dies war die Folge einer reduzierten Anzahl von Macrophagen in der Gefäßwand. Zirkulierende proinflammatorische Cytokine, wie CCL12, konnten im Serum teilweise ebenfalls vermindert nachgewiesen werden.
Obwohl die antihypertensive Wirkung von Diltiazem in glatten vaskulären Muskelzellen vermittelt wird, war es nicht möglich, die Angiotensin II-induzierte Produktion von promigratorischem CCL2 und proinflammatorischem IL6 in isolierten Aortenringen ApoE-defizienter Mäuse oder in glatten vaskulären Muskelzellen der Ratte zu reduzieren. Diltiazem war zudem nicht in der Lage, die CCL2-induzierte Migration proinflammatorischer Ly6C+-Monocyten in vivo zu unterbinden. In isolierten peritonealen Macrophagen ApoE-defizienter Mäuse dagegen, konnte die IL6 induzierte Expression von IL1B- und CCL12-mRNA durch eine Inkubation mit Diltiazem verhindert werden. In der RAW264.7-Zelllinie, die morphologische und funktionelle Merkmale von Monocyten und Macrophagen aufweist, konnte die Dilitiazem-sensitive IL6-induzierte Expression von IL1B-mRNA in vitro ebenfalls nachgewiesen werden. Eine Stimulation mit IL6 war in diesen Zellen jedoch nicht ausreichend, um die Sekretion von IL1B-Protein auszulösen.
Thorakales Aortengewebe wies im Vergleich mit RAW264.7-Zellen eine veränderte Ausstattung spannungssensitiver Calciumkanäle auf. In letzteren fanden sich keine muskelzellspezifischen L-Typ-Calciumkanäle (CACNA1C), aber eine relevante Expression neuronaler P/Q-Typ-Calciumkanäle (CACNA1A). Mittels fluorimetrischer Bestimmung mit Fura-2AM konnte jedoch festgestellt werden, dass die intrazelluläre Calciumkonzentration Diltiazem-behandelter RAW264.7-Zellen unverändert war und der antiinflammatorische Effekt somit calciumunabhängig vermittelt wurde.
Diltiazem war nicht in der Lage, eine Lipopolysaccharid (LPS)-bedingte Inflammation in RAW264.7-Zellen zu unterbinden. Weder die LPS-induzierte Sekretion von IL1B Protein, noch die nucleäre Translokation des Transkriptionsfaktors NF-?B oder die Aktivierung des NF-?B-Promotors konnten durch eine Inkubation der Zellen mit Diltiazem verhindert werden. Diltiazem reduzierte jedoch, die IL6-induzierte Aktivierung des AP 1-Promotors unabhängig von der MAPK1-Phosphorylierung oder der Phosphorylierung und nucleären Translokation des Transkriptionsfaktors STAT3 zu unterbinden. Eine Unterdrückung von c-Jun N-terminale Kinase JNK- oder p38 Proteinkinase-vermittelten Signalwegen ist damit wahrscheinlich.
Das Pirinixinsäurederivat LP105 ist ein neuer Inhibitor der Arachidonat-5-Lipoxygenase (LOX5), der im Rahmen dieser Arbeit erstmals in vivo auf seine antianeurysmatischen Eigenschaften hin untersucht wurde. LOX5 katalysiert die Reaktion von Arachidonsäure zu Leukotrien A4 und kontrolliert damit einen wichtigen Schritt in der Synthese proinflammatorischer Leukotriene. LP105 war im Tiermodell nicht in der Lage die Angiotensin II-induzierte Bildung abdominaler Aortenaneurysmen in ApoE-defizienten Mäusen komplett zu unterbinden, führte aber über die Reduktion der vaskulären Inflammation zu einer deutlich verringerten Krankheitslast. LP105 selbst beeinflusste die mRNA-Expression verschiedener Enzyme des Arachidonsäuremetabolismus nicht, verstärkte jedoch durch die Blockade von LOX5 die Metabolisierung von Arachidonsäure über Arachidonat-15-Lipoxygenase und Cytochrom P450-Enzyme.
Eine Infektion mit dem Hepatitis B Virus (HBV) kann bei 5-10 % der infizierten Erwachsenen und 70-90 % der infizierten Kinder chronisch verlaufen. Trotz einer verfügbaren Impfung gegen die Erkrankung sind heute nach Angaben der WHO weltweit etwa 350 Mio. Menschen chronisch HBV-infiziert [Lupberger and Hildt, 2007, Hollinger and Liang, 2001]. In 5-10 % der Fälle führt eine chronische Infektion zu einer Leberfibrose und Zirrhose, welche letztlich zur Ausbildung eines hepatozellulären Karzinoms (HCC) führen kann. HCCs sind die dritthäufigste karzinomassoziierte Todesursache weltweit [Blum, 2005]. Um Therapien gegen eine HBV-Infektion und das damit erhöhte Risiko einer HCC-Entstehung entwickeln zu können, müssen die einzelnen Schritte des HBV-Replikationszyklus verstanden sein. Wesentliche Schritte der frühen Infektionsphase, insbesondere der Rezeptor bzw. Rezeptorkomplex, welcher den Zelleintritt des Virus vermittelt sowie der Transport des Virusgenoms in den Zellkern, sind bisher noch unklar. Auch der Exportprozess und die Freisetzung der Viruspartikel ist bisher noch nicht im Detail verstanden. Es ist jedoch bekannt, dass die Viruspartikel unter Nutzung der zellulären ESCRT (endosomal sorting complex required for transport)-Maschinerie aus der Zelle freigesetzt werden [Lambert et al., 2007]. Auf der Suche nach Faktoren, die in diese Vorgänge involviert sind, konnte in dieser Arbeit das vesikeltransportassoziierte Protein α-Taxilin identifiziert werden. Der Einfluss von HBV auf die α-Taxilin-Bildung und seine mögliche Beteiligung am viralen Export wurden dabei näher charakterisiert. In HBV-positiven Zellen konnte in vivo und in vitro eine signifikante Steigerung der α-Taxilin-Expression nachgewiesen werden. Diese wird hierbei durch die HBV-Proteine HBx und LHBs über den Raf/Mek/Erk-Signalweg induziert [Glatzel, 2011]. Mithilfe von knockdown-Experimenten konnte beobachtet werden, dass α-Taxilin für den Export der Viruspartikel, nicht aber für den Export subviraler Partikel (SVPs) essentiell ist. Der Export der Virionen findet hierbei über das ESCRT-System statt. Den HBV-Strukturproteinen fehlen jedoch die für die Interaktion mit dem ESCRT-System essentiellen late-Domänen. Die Proteinstruktur von α-Taxilin dagegen weist diese late-Domänen auf. In dieser Arbeit konnte diese interaktionsvermittelnde Funktion von α-Taxilin zwischen dem Virus und dem ESCRT-System charakterisiert werden. Über eine Interaktion von α-Taxilin mit dem viralen LHBs-Protein auf der einen Seite und der tsg101-Komponente des ESCRT-I-Komplexes auf der anderen Seite agiert α-Taxilin als eine Art Linker zwischen dem ESCRT-System und HBV.
Darüber hinaus wurde Annexin A5 als zellulärer Interaktionspartner für α-Taxilin identifiziert [Röttger, 2011]. Es dirigiert α-Taxilin in einer Art shuttle-Funktion auf die Zellmembran suszeptibler Zellen und bindet es an deren Zelloberfläche. Diese Exposition von α-Taxilin nimmt während der Dedifferenzierung in Korrelation mit dem Suszeptibilitätsverlust primärer Hepatozyten ab. Eine Maskierung von α-Taxilin durch eine vorherige Inkubation der Zellen mit α-Taxilin-spezifischen Antikörpern konnte die Bindung und die Aufnahme der Viren inhibieren. Überexpressionsstudien bestätigten die essentielle Rezeptorfunktion von α-Taxilin. Die verstärkte Produktion von α-Taxilin führte zur Suszeptibilität der Zellen. Auch die Speziesspezifität der Bindung zwischen humanem α-Taxilin und HBV konnte in einem Co-Immunpräzipitationsexperiment mit den rezeptorbindenden Domänen von HBV, WHV und DHBV identifiziert werden.
In der vorliegenden Arbeit konnte somit zum ersten Mal eine Rezeptorfunktion von α-Taxilin bei der Aufnahme von HBV in die Wirtszelle nachgewiesen werden. Darüber hinaus schreiben die in dieser Arbeit gemachten Beobachtungen α-Taxilin eine essentielle Funktion für die Vermittlung des ESCRT-abhängigen Exports der Virionen aus der Zelle zu. Die hierbei gewonnen Erkenntnisse sind von hoher Relevanz für die weitere Erforschung der HBV-assoziierten Pathogenese und die Etablierung eines in vivo Infektions-Modells.
Die phylogenetisch hochkonservierte Jak/Stat‐Signaltransduktionskaskade repräsentiert eines der zentralen Säulen zellulärer Signalübertragung eukaryotischer Organismen. Ubiquitär im Organismus exprimiert und über eine Vielzahl von Zytokinen, Hormonen und Wachstumsfaktoren aktiviert, sind Stat‐Transkriptionsfaktoren maßgeblich an dem Erhalt der Physiologie und Homöostase von Organen und Geweben beteiligt. So sind die Mitglieder Stat5A und Stat5B (als homologe Proteine im Verbund als Stat5 bezeichnet) entscheidende Regulatoren des Immunsystems und der Hämatopoese, der Funktion und Entwicklung des Prostata‐ und Brustdrüsengewebes (Mammogenese) oder bestimmter Funktionen der Leber. Wie auch Stat3, konnten Stat5 Proteine in aberrant aktiver Form in verschiedensten Typen und Stadien humaner Tumore nachgewiesen werden, wo sie über die Expression ihrer Zielgene sowie über weitere nicht‐kanonische Funktionen im Zytoplasma und im Zellkern einer fortschreitend malignen Entartung entscheidend beitragen. Als Folge der Unterstützung essentieller Tumorgenese‐
Mechanismen, wie gesteigertes Zellwachstum, Apoptosehemmung, Migration und Metastasierung, Sauerstoff‐unabhängiger Energiestoffwechsel, Angiogenese oder Umgehung der Immunabwehr, entwickeln Tumore häufig eine Abhängigkeit gegenüber der gesteigerten Aktivität dieser Vertreter der Stat‐Proteinfamilie und reagieren mit einem Wachstumsstopp und Apoptoseinduktion auf ihre Inhibierung. Perspektivisch stellt die gezielte Interferenz mit aberranten, Tumortyp‐spezifischen Stat5‐Aktivitäten einen relevanten Ansatz in der personalisierten Therapie Stat5‐abhängiger Tumore, vorrangig leukämischen Ursprungs, dar. ...
The signal transducer and activator of transcription Stat5 is transiently activated by growth factor and cytokine signals in normal cells, but its persistent activation has been observed in a wide range of human tumors. Aberrant Stat5 activity was initially observed in leukemias, but subsequently also found in carcinomas. We investigated the importance of Stat5 in human tumor cell lines. shRNA mediated downregulation of Stat5 revealed the dependence of prostate and breast cancer cells on the expression of this transcription factor. We extended these inhibition studies and derived a peptide aptamer (PA) ligand, which directly interacts with the DNA-binding domain of Stat5 in a yeast-two-hybrid screen. The Stat5 specific PA sequence is embedded in a thioredoxin (hTRX) scaffold protein. The resulting recombinant protein S5-DBD-PA was expressed in bacteria, purified and introduced into tumor cells by protein transduction. Alternatively, S5-DBD-PA was expressed in the tumor cells after infection with a S5-DBD-PA encoding gene transfer vector. Both strategies impaired the DNA-binding ability of Stat5, suppressed Stat5 dependent transactivation and caused its intracellular degradation. Our experiments describe a peptide based inhibitor of Stat5 protein activity which can serve as a lead for the development of a clinically useful compound for cancer treatment.