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Search Results: 1 - 10 of 465460 matches for " Dieter A Wolf "
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The F-box protein SKP2 mediates androgen control of p27 stability in LNCaP human prostate cancer cells
Lifang Lu, Holger Schulz, Dieter A Wolf
BMC Cell Biology , 2002, DOI: 10.1186/1471-2121-3-22
Abstract: We show that androgen-induced G1 cell cycle arrest of LNCaP cells coincides with inhibition of cyclin-dependent kinase 2 activity and p27 accumulation caused by reduced p27 ubiquitylation activity. At the same time, androgen decreased expression of SKP2, but did not affect other components of SCFSKP2. Adenovirus-mediated overexpression of SKP2 led to ectopic down-regulation of p27 in asynchronous cells. Furthermore, SKP2 overexpression was sufficient to overcome p27 accumulation in androgen arrested cells by stimulating cellular p27 ubiquitylation activity. This resulted in transient activation of CDK2 activity, but was insufficient to override the androgen-induced G1 block.Our studies suggest that SKP2 is a major determinant of p27 levels in human prostate cancer cells. Based on our in vitro studies, we suggest that overexpression of SKP2 may be one of the mechanisms that allow prostate cancer cells to escape growth control mediated by p27. Consequently, the SKP2 pathway may be a suitable target for novel prostate cancer therapies.A plethora of circumstantial evidence implicates downregulation of the cyclin-dependent kinase (CDK) inhibitor p27 in prostate cancer. While greater than 85% of terminally differentiated secretory cells in normal human prostate display strong nuclear staining for p27, all cases of high-grade prostatic intraepithelial neoplasia, invasive carcinoma, and pelvic lymph node metastases studied by DeMarzo et al. showed down-regulation of p27 [1]. In addition, low p27 expression correlates with higher mean Gleason scores, a number of prognostic morphological features, and decreased survival [2-4]. Thus, p27 may be a prostate tumor suppressor.In support of this notion, the p27 protein has been identified as a target of viral oncoproteins [5,6]. However, unlike traditional tumor suppressors, the p27 gene rarely shows homozygous inactivation in cancer cells [7-9], a finding that points towards alternative mechanisms of p27 inactivation.p27 specifica
Conservation of the COP9/signalosome in budding yeast
Susan Wee, Bettina Hetfeld, Wolfgang Dubiel, Dieter A Wolf
BMC Genetics , 2002, DOI: 10.1186/1471-2156-3-15
Abstract: We show that disruption of four budding yeast genes, PCI8 and three previously uncharacterized ORFs, which encode proteins interacting with Rrr1p/Csn5p, each results in the accumulation of the cullin Cdc53p exclusively in the Rub1p-modified state. This phenotype, which resembles that of fission yeast csn mutants, is due to a biochemical defect in deneddylation that is complemented by wild-type cell lysate and by purified human CSN in vitro. Although three of the four genes encode proteins with PCI domains conserved in metazoan CSN proteins, their disruption does not confer the DNA damage sensitivity described in some fission yeast csn mutants.Our studies present unexpected evidence for the conservation of a functional homologue of the metazoan CSN, which mediates control of cullin neddylation in budding yeast.The COP9/signalosome (CSN) was first identified in Arabidopsis thaliana as an eight subunit complex involved in the suppression of light-dependent development [1]. Subsequent studies have led to the identification of similar complexes in other plant species, Drosophila melanogaster, human cells, and fission yeast [2-7], thus indicating a high degree of structural conservation during evolution. Cloning of CSN subunits revealed their structural similarities to the eight subunits of the lid complex of the 26S proteasome [3,8-10]. The similarity was most pronounced within the so-called MPN domains of CSN5 and 6 and the PCI domains of the remaining subunits [11].CSN has been implicated in multiple biological processes, many involving ubiquitin-mediated proteolysis (reviewed in [12,13]). For example, CSN is required for degradation of the plant transcription factor HY5 by the putative COP1 ubiquitin ligase [14]. In addition, CSN is involved in auxin-induced turn-over of the transcriptional repressor AUX/IAA [15]. This process is mediated by an ubiquitin ligase [15] related to SCF complexes first identified in budding yeast [16,17]. All SCF complexes share the core su
Regulation of transcriptome, translation, and proteome in response to environmental stress in fission yeast
Daniel H Lackner, Michael W Schmidt, Shuangding Wu, Dieter A Wolf, Jürg B?hler
Genome Biology , 2012, DOI: 10.1186/gb-2012-13-4-r25
Abstract: We observed a strong overall concordance between changes in mRNAs and co-directional changes in translation, for both induced and repressed genes, in response to three conditions: oxidative stress, heat shock, and DNA damage. However, approximately 200 genes each under oxidative and heat stress conditions showed discordant regulation with respect to mRNA and translation profiles, with genes and patterns of regulation being stress-specific. For oxidative stress, we also measured dynamic profiles for 2,147 proteins, comprising 43% of the proteome. The mRNAs induced during oxidative stress strongly correlated with increased protein expression, while repressed mRNAs did not relate to the corresponding protein profiles. Overall changes in relative protein expression correlated better with changes in mRNA expression than with changes in translational efficiency.These data highlight a global coordination and fine-tuning of gene regulation during stress that mostly acts in the same direction at the levels of transcription and translation. In the oxidative stress condition analyzed, transcription dominates translation to control protein abundance. The concordant regulation of transcription and translation leads to the expected adjustment in protein expression only for up-regulated mRNAs. These patterns of control might reflect the need to balance protein production for stress survival given a limited translational capacity.Cells adapt to stress or to changing environmental conditions by launching specialized gene expression programs that promote stress protection, homeostasis, and survival. Single-celled organisms like yeasts are particularly exposed to fluctuations in the environment that trigger a large common transcriptional response, called environmental stress response in budding yeast or core environmental stress response (CESR) in fission yeast [1,2]. The expression of hundreds of genes is either induced or repressed in response to different stress conditions in fissi
Chemical genetics approach to restoring p27Kip1 reveals novel compounds with antiproliferative activity in prostate cancer cells
Elizabeth Rico-Bautista, Chih-Cheng Yang, Lifang Lu, Gregory P Roth, Dieter A Wolf
BMC Biology , 2010, DOI: 10.1186/1741-7007-8-153
Abstract: We developed a cell-based assay for measuring the levels of endogenous nuclear p27 in a high throughput screening format employing LNCaP prostate cancer cells engineered to overexpress SKP2. The assay platform was optimized to Z' factors of 0.48 - 0.6 and piloted by screening a total of 7368 chemical compounds. During the course of this work, we discovered two small molecules of previously unknown biological activity, SMIP001 and SMIP004, which increase the nuclear level of p27 at low micromolar concentrations. SMIPs (small molecule inhibitors of p27 depletion) also upregulate p21Cip1, inhibit cellular CDK2 activity, induce G1 delay, inhibit colony formation in soft agar and exhibit preferential cytotoxicity in LNCaP cells relative to normal human fibroblasts. Unlike SMIP001, SMIP004 was found to downregulate SKP2 and to stabilize p27, although neither SMIP is a proteasome inhibitor. Whereas the screening endpoint - nuclear p27 - was robustly modulated by the compounds, SMIP-mediated cell cycle arrest and apoptosis were not strictly dependent on p27 and p21 - a finding that is explained by parallel inhibitory effects of SMIPs on positive cell cycle regulators, including cyclins E and A, and CDK4.Our data provide proof-of-principle that the screening platform we developed, using endogenous nuclear p27 as an endpoint, presents an effective means of identifying bioactive molecules with cancer selective antiproliferative activity. This approach, when applied to larger and more diverse sets of compounds with refined drug-like properties, bears the potential of revealing both unknown cellular pathways globally impinging on p27 and novel leads for chemotherapeutics targeting a prominent molecular defect of human cancers.p27 is a cyclin-dependent kinase (CDK) inhibitor (CKI) that controls cell proliferation, cell motility and apoptosis [1]. It regulates the progression of cells from G1 to S phase by binding and inhibiting the cyclin E-CDK2 complex. A plethora of evidence ha
Transposición corregida de los grandes vasos: aspectos clínicos y angiográficos Corrected transposition of the great vessels
Odette Farru A,Ignacio Hernández N,Mauricio O'Connell J,Dieter Wolf
Revista chilena de pediatría , 1986,
Abstract:
Molecular mechanism of protrusion formation during cell-to-cell spread of Listeria
Keith Ireton,Luciano A. Rigano,Lilia Polle,Wolf-Dieter Schubert
Frontiers in Cellular and Infection Microbiology , 2014, DOI: 10.3389/fcimb.2014.00021
Abstract: The bacterial pathogen Listeria monocytogenes spreads within human tissues using a motility process dependent on the host actin cytoskeleton. Cell-to-cell spread involves the ability of motile bacteria to remodel the host plasma membrane into protrusions, which are internalized by neighboring cells. Recent results indicate that formation of Listeria protrusions in polarized human cells involves bacterial antagonism of a host signaling pathway comprised of the scaffolding protein Tuba and its effectors N-WASP and Cdc42. These three human proteins form a complex that generates tension at apical cell junctions. Listeria relieves this tension and facilitates protrusion formation by secreting a protein called InlC. InlC interacts with a Src Homology 3 (SH3) domain in Tuba, thereby displacing N-WASP from this domain. Interaction of InlC with Tuba is needed for efficient Listeria spread in cultured human cells and infected animals. Recent structural data has elucidated the mechanistic details of InlC/Tuba interaction, revealing that InlC and N-WASP compete for partly overlapping binding surfaces in the Tuba SH3 domain. InlC binds this domain with higher affinity than N-WASP, explaining how InlC is able to disrupt Tuba/N-WASP complexes.
The Angular Momentum Structure of the Nucleon
Nowak, Wolf-Dieter
High Energy Physics - Phenomenology , 2008, DOI: 10.1063/1.3013084
Abstract: The proton spin budget is discussed. Results are presented from inclusive and semi-inclusive deep inelastic scattering and from deeply virtual Compton scattering. They permit interpretations towards the determination of various contributions to the proton spin.
Single Spin Asymmetries in Proton-Proton and Proton-Neutron Scattering at 820 GeV
Wolf-Dieter Nowak
Physics , 1995, DOI: 10.1063/1.48918
Abstract: The physics case is summarised for the investigation of high energy spin phenomena by placing an internal polarised target into HERA's unpolarised proton beam. The luminosity and experimental sensitivity are discussed. Estimating the physics reach of single spin asymmetries in different final states reveals a considerable physics potential in testing the spin sector of perturbative QCD.
Measurement of Singly Polarized p + N(pol) Collisions at HERA
Wolf-Dieter Nowak
Physics , 1995,
Abstract: A summary is given on the physics potential of measuring singly polarized proton--nucleon collisions using a polarized internal target in the 820 GeV HERA proton beam. This summary is based upon talks given at the 2nd Meeting on 'Possible Measurements of Singly Polarized p + p(pol) and p + n(pol) Collisions at HERA' which was held at DESY Zeuthen from August 31 to September 2, 1995 as a follow-up to the 'Workshop on the Prospects of Spin Physics at HERA.
Possible Measurements of Single and Double Spin Asymmetries with HERA--$\vec{N}$
Wolf-Dieter Nowak
Physics , 1996,
Abstract: The physics scope of a possible future experiment utilizing an internal polarized nucleon target in the HERA proton beam is discussed. By measuring single spin asymmetries in inclusive particle production at 820~GeV beam energy the higher-twist sector of perturbative QCD can be probed with good statistical sensitivity. To support the physics case for proton polarization at HERA, we consider the measurement of double spin asymmetries in photon plus jet production. It appears possible to determine the polarized gluon distribution in the range 0.1~$\leq x_{gluon} \leq$~0.4 with good accuracy.
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