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Berlin Brandenburg

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  • 1
    Language: English
    In: Plant physiology, March 2017, Vol.173(3), pp.1750-1762
    Description: Plants modify organ growth and tune morphogenesis in response to various endogenous and environmental cues. At the cellular level, organ growth is often adjusted by alterations in cell growth, but the molecular mechanisms underlying this control remain poorly understood. In this study, we identify the DNA BINDING WITH ONE FINGER (DOF)-type transcription regulator OBF BINDING PROTEIN4 (OBP4) as a repressor of cell growth. Ectopic expression of in Arabidopsis () inhibits cell growth, resulting in severe dwarfism and the repression of genes involved in the regulation of water transport, root hair development, and stress responses. Among the basic helix-loop-helix transcription factors known to control root hair growth, OBP4 binds the () promoter to repress its expression. The accumulation of OBP4 proteins is detected in expanding root epidermal cells, and its expression level is increased by the application of abscisic acid (ABA) at concentrations sufficient to inhibit root hair growth. ABA-dependent induction of is associated with the reduced expression of Furthermore, ectopic expression of or loss of function results in ABA-insensitive root hair growth. Taken together, our results suggest that OBP4-mediated transcriptional repression of contributes to the ABA-dependent inhibition of root hair growth in Arabidopsis.
    Keywords: Abscisic Acid -- Pharmacology ; Arabidopsis -- Genetics ; Arabidopsis Proteins -- Genetics ; DNA-Binding Proteins -- Genetics ; Gene Expression Regulation, Developmental -- Drug Effects ; Gene Expression Regulation, Plant -- Drug Effects ; Plant Roots -- Genetics
    ISSN: 00320889
    E-ISSN: 1532-2548
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  • 2
    In: Thewes, Verena; Orso, Francesca; Jäger, Richard; Eckert, Dawid; Schäfer, Sabine; Kirfel, Gregor; Garbe, Stephan; Taverna, Daniela; Schorle, Hubert (2010). Interference with activator protein-2 transcription factors leads to induction of apoptosis and an increase in chemo- and radiation-sensitivity in breast cancer cells. BMC Cancer 10 ,
    Description: Background: Activator Protein-2 (AP-2) transcription factors are critically involved in a variety of fundamental cellular processes such as proliferation, differentiation and apoptosis and have also been implicated in carcinogenesis. Expression of the family members AP-2 alpha and AP-2 gamma is particularly well documented in malignancies of the female breast. Despite increasing evaluation of single AP-2 isoforms in mammary tumors the functional role of concerted expression of multiple AP-2 isoforms in breast cancer remains to be elucidated. AP-2 proteins can form homo-or heterodimers, and there is growing evidence that the net effect whether a cell will proliferate, undergo apoptosis or differentiate is partly dependent on the balance between different AP-2 isoforms. Methods: We simultaneously interfered with all AP-2 isoforms expressed in ErbB-2-positive murine N202.1A breast cancer cells by conditionally over-expressing a dominant-negative AP-2 mutant. Results: We show that interference with AP-2 protein function lead to reduced cell number, induced apoptosis and increased chemo-and radiation-sensitivity. Analysis of global gene expression changes upon interference with AP-2 proteins identified 139 modulated genes (90 up-regulated, 49 down-regulated) compared with control cells. Gene Ontology (GO) investigations for these genes revealed Cell Death and Cell Adhesion and Migration as the main functional categories including 25 and 12 genes, respectively. By using information obtained from Ingenuity Pathway Analysis Systems we were able to present proven or potential connections between AP-2 regulated genes involved in cell death and response to chemo-and radiation therapy, (i.e. Ctgf, Nrp1, Tnfaip3, Gsta3) and AP-2 and other main apoptosis players and to create a unique network. Conclusions: Expression of AP-2 transcription factors in breast cancer cells supports proliferation and contributes to chemo-and radiation-resistance of tumor cells by impairing the ability to induce apoptosis. Therefore, interference with AP-2 function could increase the sensitivity of tumor cells towards therapeutic intervention.
    Keywords: Tissue Growth-Factor ; Smooth-Muscle-Cells ; Differential Expression ; Mammary-Carcinoma ; Ap-2 Family ; Proliferation ; Overexpression ; Ap-2-Gamma ; Tumor ; Lung
    ISSN: 1471-2407
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  • 3
    Language: English
    In: The American Journal of Pathology, November 2014, Vol.184(11), pp.2922-2935
    Description: Oxyphil cell transformation of epithelial cells due to the accumulation of mitochondria occurs often during cellular aging. To understand the pathogenic mechanisms, we studied mitochondrial DNA (mtDNA) alterations in the three cell types of the parathyroids using multiplex real-time PCR and next-generation sequencing. mtDNA was analyzed from cytochrome oxidase (COX)–positive and COX-negative areas of 19 parathyroids. Mitochondria-rich pre-oxyphil/oxyphil cells were more prone to develop COX defects than the mitochondria-poor clear chief cells (  〈 0.001). mtDNA increased approximately 2.5-fold from clear chief to oxyphil cells. In COX deficiency, the increase was even more pronounced, and COX-negative oxyphil cells had approximately two times more mtDNA than COX-positive oxyphil cells (  〈 0.001), illustrating the influence of COX deficiency on mtDNA biosynthesis, probably as a consequence of insufficient ATP synthesis. Next-generation sequencing revealed a broad spectrum of putative pathogenic mtDNA point mutations affecting NADH dehydrogenase and COX genes as well as regulatory elements of mtDNA. NADH dehydrogenase gene mutations preferentially accumulated in COX-positive pre-oxyphil/oxyphil cells and, therefore, could be essential for inducing oxyphil cell transformation by increasing mtDNA/mitochondrial biogenesis. In contrast, COX-negative cells predominantly harbored mutations in the and genes and in regulatory mtDNA elements, but only rarely NADH dehydrogenase mutations. Thus, multiple hits in NADH dehydrogenase and COX activity–impairing genes represent the molecular basis of oxyphil cell transformation in the parathyroids.
    Keywords: Medicine
    ISSN: 0002-9440
    E-ISSN: 1525-2191
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  • 4
    In: Plant Journal, October 2002, Vol.32(2), pp.243-253
    Description: To assist in the analysis of plant gene functions we have generated a new insertion mutant collection of 90 000 lines that carry the T‐DNA of gene fusion vector pPCV6NFHyg. Segregation analysis indicates that the average frequency of insertion sites is 1.29 per line, predicting about 116 100 independent tagged loci in the collection. The average T‐DNA copy number estimated by Southern DNA hybridization is 2.4, as over 50% of the insertion loci contain tandem T‐DNA copies. The collection is pooled in two arrays providing 40 PCR templates, each containing DNA from either 4000 or 5000 individual plants. A rapid and sensitive PCR technique using high‐quality template DNA accelerates the identification of T‐DNA tagged genes without DNA hybridization. The PCR screening is performed by agarose gel electrophoresis followed by isolation and direct sequencing of DNA fragments of amplified T‐DNA insert junctions. To estimate the mutation recovery rate, 39 700 lines have been screened for T‐DNA tags in 154 genes yielding 87 confirmed mutations in 73 target genes. Screening the whole collection with both T‐DNA border primers requires 170 PCR reactions that are expected to detect a mutation in a gene with at least twofold redundancy and an estimated probability of 77%. Using this technique, an family segregating a characterized gene mutation can be identified within 4 weeks.
    Keywords: T‐Dna ; Insertion Mutagenesis ; Arabidopsis ; Pcr Screening ; Functional Genomics
    ISSN: 0960-7412
    E-ISSN: 1365-313X
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  • 5
    Language: English
    In: Virology, 1991, Vol.184(2), pp.786-790
    Description: Replication of the single-stranded DNA genome of wheat dwarf virus (WDV) leads to the accumulation of covalently closed double-stranded DNA of genome length in infected cells. By studying the replication properties of a naturally occurring deletion mutant of WDV isolated from infected plants and of deletion mutants constructed in vitro, we have defined cis-acting regions required for viral DNA replication. The results show that two distinct regions are required in cis to yield the normal replicative forms of WDV-DNA.
    Keywords: Biology
    ISSN: 0042-6822
    E-ISSN: 1096-0341
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  • 6
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(2), p.e56625
    Description: The nuclear factor erythroid 2-related factor 2 (Nrf2) governs the expression of antioxidant and phase II detoxifying enzymes. Nrf2 activation can prevent or reduce cellular damage associated with several types of injury in many different tissues and organs. Dominant mutations in Cu/Zn-superoxide dismutase (SOD1) cause familial forms of amyotrophic lateral sclerosis (ALS), a fatal disorder characterized by the progressive loss of motor neurons and subsequent muscular atrophy. We have previously shown that Nrf2 activation in astrocytes delays neurodegeneration in ALS mouse models. To further investigate the role of Nrf2 in ALS we determined the effect of absence of Nrf2 or its restricted overexpression in neurons or type II skeletal muscle fibers on symptoms onset and survival in mutant hSOD1 expressing mice. We did not observe any detrimental effect associated with the lack of Nrf2 in two different mutant hSOD1 animal models of ALS. However, restricted Nrf2 overexpression in neurons or type II skeletal muscle fibers delayed disease onset but failed to extend survival in hSOD1(G93A) mice. These results highlight the concept that not only the pharmacological target but also the cell type targeted may be relevant when considering a Nrf2-mediated therapeutic approach for ALS.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: International Journal of Cancer, 15 March 2012, Vol.130(6), pp.1314-1318
    Description: Dysregulation of apoptosis plays an important role in carcinogenesis. Therefore, apoptosis‐associated genes like the () are interesting candidates for modifying the penetrance of breast and ovarian cancer in carriers of and mutations. The haplotype 626C–683C [626C〉G, Thr209Arg (rs4871857) and 683A〉C, Glu228Ala (rs17088993)] has recently been linked to an increased risk of breast cancer. To evaluate whether 626C〉G or 683A〉C modifies the risk of breast or ovarian cancer in carriers of and mutations, we undertook a national multicenter study including data of 840 carriers of breast cancer gene (BRCA) mutations. DNA samples were collected from 12 German research centers between 1996 and 2005 and were genotyped by the Taqman allelic discrimination assay. The association between genotypes and incidence of breast or ovarian cancer data was evaluated using a Cox proportional hazards regression model. We found evidence for a significant association of 683A〉C with a higher risk for ovarian cancer in carriers of mutations [ = 557, hazard ratio 1.78 (1.24–2.55), = 0.009]. Our results thus indicate that the 683A〉C variant modifies the risk of ovarian cancer in carriers of BRCA1 mutations.
    Keywords: Brca ; Ovarian Cancer ; Breast Cancer ; Death Receptor 4 ; Snp
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 8
    Language: English
    In: Genes & development, 15 May 2010, Vol.24(10), pp.1045-58
    Description: Ultraviolet (UV) B irradiation can severely damage the skin and even induce tumorigenesis. It exerts its effects by direct DNA modification and by formation of reactive oxygen species (ROS). We developed a strategy to genetically activate target gene expression of the transcription factor NF-E2-related factor 2 (Nrf2) in keratinocytes in vivo based on expression of a constitutively active Nrf2 mutant. Activation of Nrf2 target genes strongly reduced UVB cytotoxicity through enhancement of ROS detoxification. Remarkably, the protective effect was extended to neighboring cells. Using different combinations of genetically modified mice, we demonstrate that Nrf2 activates the production, recycling, and release of glutathione and cysteine by suprabasal keratinocytes, resulting in protection of basal cells in a paracrine, glutathione/cysteine-dependent manner. Most importantly, we found that endogenous Nrf2 controls selective protection of suprabasal keratinocytes from UVB-induced apoptosis through activation of cytoprotective genes. This finding explains the preferential UVB-induced apoptosis of basal cells, which is important for elimination of mutated stem cells as well as for preservation of skin integrity. Taken together, our results identify Nrf2 as a key regulator in the UV response of the skin.
    Keywords: Ultraviolet Rays ; Cytoprotection -- Physiology ; Glutathione -- Metabolism ; Keratinocytes -- Metabolism ; Nf-E2-Related Factor 2 -- Genetics
    ISSN: 08909369
    E-ISSN: 1549-5477
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  • 9
    Language: English
    In: EMBO Molecular Medicine, July 2012, Vol.4(7), pp.647-659
    Description: Here, we describe a novel missense mutation in the amyloid precursor protein (APP) causing a lysine‐to‐asparagine substitution at position 687 (APP770; herein, referred to as K16N according to amyloid‐β (Aβ) numbering) resulting in an early onset dementia with an autosomal dominant inheritance pattern. The K16N mutation is located exactly at the α‐secretase cleavage site and influences both APP and Aβ. First, due to the K16N mutation APP secretion is affected and a higher amount of Aβ peptides is being produced. Second, Aβ peptides carrying the K16N mutation are unique in that the peptide itself is not harmful to neuronal cells. Severe toxicity, however, is evident upon equimolar mixture of wt and mutant peptides, mimicking the heterozygous state of the subject. Furthermore, Aβ42 K16N inhibits fibril formation of Aβ42 wild‐type. Even more, Aβ42 K16N peptides are protected against clearance activity by the major Aβ‐degrading enzyme neprilysin. Thus the mutation characterized here harbours a combination of risk factors that synergistically may contribute to the development of early onset Alzheimer disease.
    Keywords: Aggregation ; Alzheimer Disease ; Amyloid‐Beta Toxicity ; App Processing ; Neprilysin
    ISSN: 1757-4676
    E-ISSN: 1757-4684
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  • 10
    Language: English
    In: American Journal of Ophthalmology, August 2015, Vol.160(2), pp.364-372.e1
    Description: To describe a series of patients with Bardet-Biedl syndrome (BBS) and predominantly retinal cone dysfunction, a previously only rarely reported association. Retrospective observational case series. Seven patients with clinically proven Bardet-Biedl syndrome had undergone detailed ocular phenotyping, which included fundus examination, Goldmann visual fields, fundus autofluorescence imaging (FAF), optical coherence tomography (OCT), and electroretinography (ERG). Mutational screening in the BBS genes was performed either by direct Sanger sequencing or targeted next-generation sequencing. All 7 patients had proven BBS mutations; 1 had a cone dystrophy phenotype on ERG and 6 had a cone-rod pattern of dysfunction. Macular atrophy was present in all patients, usually with central hypofluorescence surrounded by a continuous hyperfluorescent ring on fundus autofluorescence imaging. OCT confirmed loss of outer retinal structure within the atrophic areas. No clear genotype-phenotype relationship was evident. Patients with Bardet-Biedl syndrome usually develop early-onset retinitis pigmentosa. In contrast, the patients described herein, with molecularly confirmed Bardet-Biedl syndrome, developed early cone dysfunction, including the first reported case of a cone dystrophy phenotype associated with the disorder. The findings significantly expand the phenotype associated with Bardet-Biedl syndrome.
    Keywords: Medicine
    ISSN: 0002-9394
    E-ISSN: 1879-1891
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