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Christian Kunz

Publications and source records attributed to Christian Kunz.

9 recordsLinked to original sources
PubMed2006

The biological functions of the versatile transcription factors STAT3 and STAT5 and new strategies for their targeted inhibition.

Signal transducers and activators of transcription (STATs) comprise a unique family of transcription factors, which transmit the interactions of cytokines, hormones and growth factors with their cell surface receptors into transcriptional programs. The mechanism of STAT activation has been well-established and comprises tyrosine phosphorylation, dimerization, nuclear translocation, binding to specific DNA response elements, recruitment of co-activators or co-repressors and transcriptional induction or repression of target genes. Gene deletion, microarrays, proteomics and chromatin immunoprecipitation experiments have revealed target genes with a broad range of functions regulated by STAT3 and STAT5. In the mammary gland, STAT5-induced genes contribute mainly to the prolactin dependent lobulo-alveolar development, whereas STAT3 induced genes control apoptosis during involution. Crucial effects have also been observed in other tissues. The germ line deletion of STAT3 or STAT5 causes early embryonal or perinatal lethality in mice. STAT5 is also required for proliferation of T- and B-cells and hematopoietic stem cell self-renewal. Deregulated STAT activity is often found associated with tumorigenesis and activated STATs seem to be limiting components in tumor cells. This review summarizes the functions of STAT3 and STAT5 in different cell types and the strategies that are used to counteract their action in tumor cells.

Animals↗
PubMed2006

Peptide aptamers with binding specificity for the intracellular domain of the ErbB2 receptor interfere with AKT signaling and sensitize breast cancer cells to Taxol.

The ErbB2 receptor tyrosine kinase is overexpressed in approximately 30% of breast tumor cases and its overexpression correlates with an unfavorable prognosis. A major contributor for this course of the disease is the insensitivity of these tumors toward chemotherapy. Monoclonal antibodies, inhibiting the ligand-induced activation of the receptor and tyrosine kinase inhibitors acting on the intrinsic enzymatic activity of the intracellular domain, have been developed as targeted drugs. Both have been shown to be beneficial for breast cancer patients. We targeted a third aspect of receptor function: its association with intracellular signaling components. For this purpose, we selected peptide aptamers, which specifically interact with defined domains of the intracellular part of the receptor. The peptide aptamers were selected from a random peptide library using a yeast two-hybrid system with the intracellular tyrosine kinase domain of ErbB2 as a bait construct. The peptide aptamer AII-7 interacts with high specificity with the ErbB2 receptor in vitro and in vivo. The aptamers colocalized with the intracellular domain of ErbB2 within cells. We investigated the functional consequences of the aptamer interaction with the ErbB2 receptor within tumor cells. The aptamer sequences were either expressed intracellularly or introduced into the cells as recombinant aptamer proteins. The phosphorylation of p42/44 mitogen-activated protein kinase was nearly unaffected and the activation of signal transducers and activators of transcription-3 was only modestly reduced. In contrast, they strongly inhibited the induction of AKT kinase in MCF7 breast cancer cells treated with heregulin, whereas AKT activation downstream of insulin-like growth factor I or epidermal growth factor receptor was not or only slightly affected. High AKT activity is responsible for the enhanced resistance of ErbB2-overexpressing cancer cells toward chemotherapeutic agents. Peptide aptamer interference with AKT activation resulted in the restoration of regular sensitivity of breast cancer cells toward Taxol.

Amino Acid Motifs↗
PubMed2005

Current strategies for the development of peptide-based anti-cancer therapeutics.

The completion of the human genome sequence and the development of new techniques, which allow the visualisation of comprehensive gene expression patterns, has led to the identification of a large number of gene products differentially expressed in tumours and corresponding normal tissues. The task at hand is the sorting of these genes into correlative and causative ones. Correlative genes are merely changed as a consequence of transformation and have no decisive effects upon transformation. In contrast, causative genes play a direct role in the process of cellular transformation and the maintenance of the transformed state, which can be exploited for therapeutic purposes. Oncogenes and tumour suppressor genes are prime targets for the development of new inhibitors and gene therapeutic strategies. However, many target oncogene products do not exhibit enzymatic activity that can be inhibited by conventional small molecular weight compounds. They exert their functions through regulated protein-protein or protein-DNA interactions and might require other compounds for efficient interference with such functions. Peptides are emerging as a novel class of drugs for cancer therapy, which could fulfil these tasks. Peptide therapy aims at the specific inhibition of inappropriately activated oncogenes. This review will focus on the selection procedures, which can be employed to identify useful peptides for the treatment of cancer. Before peptide-based therapeutics can become useful, it will be necessary to increase their stability by modifications or the use of scaffolds. Additionally, various delivery methods including liposomes and particularly the use of protein transduction domains (PTDs) have to be explored. These strategies will yield highly specific and more effective peptides and improve the potential of peptide-based anti-cancer therapeutics.

Antineoplastic Agents↗
PubMed2005

The Golden Agers and Tick-borne encephalitis. Conference report and position paper of the International Scientific Working Group on Tick-borne encephalitis.

The 7th meeting of the ISW TBE had the main topic "Tick-borne encephalitis in the Golden Agers". Data from 14 European countries were presented about incidence and clinical course of Tick borne encephalitis (TBE) in general and especially in the population over 50 years of age. With age immunity is impaired quantitatively and qualitatively, the reactions to vaccinations are generally slower, antibody titres reach lower values and decrease earlier. The incidence of the disease is increasing with age, also the clinical course is more severe, they suffer significantly more sequelae, need a longer rehabilitation and have a higher case fatality. Vaccination as the only efficient protection is needed in endemic areas, considering that mobility has increased very much. For the age group over 50 years regular booster vaccinations according to the recommended vaccination intervals or even shorter intervals are most important.

Age Factors↗
PubMed2005

Peptide aptamers: recent developments for cancer therapy.

During the past two decades, our understanding of oncogenesis has advanced considerably and many new signalling pathways have been identified. Differences in signalling events that distinguish normal cells from tumour cells provide new targets for the development of anticancer agents. Peptide aptamers are small peptide sequences that have been selected to recognise a predetermined target protein domain and are potentially able to interfere with its function. They represent useful molecules for manipulating protein function in vivo. The isolation and use of specific peptide aptamers as inhibitors of individual signalling components, essential in cancer development and progression, provides a new challenge for drug development. Although peptides make up only a small fraction of current therapeutics, their potential is being enhanced by new developments affecting their modification, stability, delivery and their successful application in preclinical settings. This review summarises the methods that can be used for the isolation and delivery of peptide aptamers, as well as the important achievements that have been made using such peptide aptamers in different systems. The applicability of peptide aptamers as novel cancer therapeutics will be discussed.

Amino Acid Sequence↗
PubMed2003

Sequence-specific peptide aptamers, interacting with the intracellular domain of the epidermal growth factor receptor, interfere with Stat3 activation and inhibit the growth of tumor cells.

Receptor tyrosine kinases of the epidermal growth factor (EGF) receptor family regulate essential cellular functions such as proliferation, survival, migration, and differentiation but also play central roles in the etiology and progression of tumors. We have identified short peptide sequences from a random peptide library integrated into the thioredoxin scaffold protein, which specifically bind to the intracellular domain of the EGF receptor (EGFR). These molecules have the potential to selectively inhibit specific aspects of EGF receptor signaling and might become valuable as anticancer agents. Intracellular expression of the aptamer encoding gene construct KDI1 or introduction of bacterially expressed KDI1 via a protein transduction domain into EGFR-expressing cells results in KDI1.EGF receptor complex formation, a slower proliferation, and reduced soft agar colony formation. Aptamer KDI1 did not summarily block the EGF receptor tyrosine kinase activity but selectively interfered with the EGF-induced phosphorylation of the tyrosine residues 845, 1068, and 1148 as well as the phosphorylation of tyrosine 317 of p46 Shc. EGF-induced phosphorylation of Stat3 at tyrosine 705 and Stat3-dependent transactivation were also impaired. Transduction of a short synthetic peptide aptamer sequence not embedded into the scaffold protein resulted in the same impairment of EGF-induced Stat3 activation.

3T3 Cells↗
PubMed2003

TBE vaccination and the Austrian experience.

In the pre-vaccination era, Austria had the highest recorded morbidity of tick-borne encephalitis (TBE) in Europe. The disease accounted for more than 50% of all viral meningoencephalitides in the eastern and southern parts of the country. This prompted us to start a cooperative vaccine development project in 1971 with J. Keppie from the Microbiological Research Establishment, Porton Down, England. After very satisfactory results of field studies, conducted in individuals for whom TBE was classified as occupational disease (forest workers, farmers, etc.), the killed virus vaccine (see chapter by N. Barrett in this issue), was made commercially available by Immuno AG Vienna (now Baxter Health-Care). The vaccine proved to be highly immunogenic and very well tolerated in both adults and children. After completing the series of three vaccinations seroconversion rates of >99% were recorded. In Austria, as in other European countries, TBE is now acquired for the most part during leisure activities. In view of this fact a mass vaccination campaign was initiated in 1981. Subsequently, the vaccination coverage of the Austrian population increased from 6% in 1980 to 86% in 2001, exceeding 90% in some of the high-risk areas. Data annually collected by our surveillance system show that the clinical effectiveness of the vaccine is excellent. Based on the assumption that the whole Austrian population is at risk of infection the calculated rate of protection after three doses of the vaccine is 96-98.7%. Breakthrough disease is rare and affects mainly higher age groups. Since the advent of TBE vaccination only one single case has been observed in the age group up to 20. The increasing vaccination coverage led to a more or less steady decline of TBE, drastically reducing the public health problem that the disease poses in Austria, especially in the provinces, where formerly the highest morbidity rates were observed. For example, in Carinthia, in the years 1973-1982 an average annual incidence of 155 was recorded, compared with only four annual cases in the last 4 years. The Austrian experience shows that containment of a tick-borne viral disease is feasible, provided a well-tolerated and effective vaccine is available that is widely accepted by the general population.

Austria↗
PubMed2003

Studies on the effects of a flanking repetitive sequence on the expression of single-copy transgenes in Nicotiana sylvestris and in N. sylvestris-N. tomentosiformis hybrids.

To test the influence of a Nicotiana tomentosiformis repetitive sequence (R8.3) on transgene expression in N. sylvestris and in N. sylvestris-N. tomentosiformis hybrids, the R8.3 sequence was placed upstream of a nopaline synthase promoter (NOSpro)-NPTII reporter gene in a T-DNA construct. A number of transgenic N. sylvestris lines were produced and in most, the NPTII gene was expressed. In one line, however, the NPTII gene became silenced and methylated in the NOSpro region. The silenced locus was able to trans-inactivate and induce methylation of two stably expressed transgene loci comprising a similar construct. Nucleotide sequence analyses of the three transgene loci revealed that they each contained a single incomplete copy of the T-DNA, which had sustained deletions of varying sizes in the R8.3 region. Paradoxically, the R8.3 DNA upstream of the two active, unmethylated NOSpro-NPTII genes was highly methylated, whereas the R8.3 DNA upstream of the silenced, methylated NOSpro-NPTII gene was less methylated. The methylated portions of the R8.3 sequence corresponded to retroelement remnants. An active NOSpro-NPTII gene downstream of a nearly intact R8.3 sequence did not become methylated in N. sylvestris-N. tomentosiformis hybrids. Thus, methylation in the R8.3 sequence did not spread into adjoining transgene promoters and the effect of the R8.3 dispersed repeat family on transgene expression was negligible. The silencing phenomena observed with the three single-copy transgene loci are discussed in the context of other possible triggers of silencing.

Amino Acid Oxidoreductases↗