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Berlin Brandenburg

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  • 1
    Language: English
    In: Genes & development, 15 November 2002, Vol.16(22), pp.2829-42
    Description: So you thinkyou finally understand the regulation of your favorite gene? The transcriptional regulators have been identified; the signaling cascades that regulate syn- thesis and activity of the regulators have been found. Possibly you have found that the regulator is itself un- stable, and that instability is necessary for proper regu- lation. Time to lookfor a new project, or retire and rest on your laurels? Not so fast—there's more. It is rapidly becoming apparent that another whole level of regula- tion lurks, unsuspected, in both prokaryotic and eukary- otic cells, hidden from our notice in part by the tran- scription-based approaches that we usually use to study gene regulation, and in part because these regulators are very small targets for mutagenesis and are not easily found from genome sequences alone. These stealth regu- lators, operating below our radar, if not that of the cell, are small regulatory RNAs, acting to control the trans- lation and degradation of many messengers. These RNAs can be potent and multifunctional, allowing new signal- ing pathways to cross-regulate targets independently of the transcriptional signals for those targets, introducing polarity within operons, and explaining some puzzles in well-studied regulatory circuits. The importance of small regulatory RNAs was first appreciated in the elegant studies of plasmid-encoded an- tisense RNAs. The few apparently unusual cases of non- coding regulatory RNAs encoded in the bacterial chro- mosome has expanded over the last decade, and the role such RNA regulators play in both stimulating and inhib- iting gene expression has been firmly established. As ge- nome sequences have become available for many bacte- ria, it has become possible to search for additional mem- bers of this regulatory family, and, eventually, to begin to understand how they act at the molecular level. Simultaneously, researchers in eukaryotic systems were discovering the wonders of RNAi, a cellular strat- egy for protecting itself from RNA invaders, in which small double-stranded RNA molecules cause destruction of homologous messages. The discovery that develop- mental mutants in Caenorhabditis elegans define genes for two small RNA translational regulators, called small temporal RNAs (stRNAs) or microRNAs, and that these RNAs are processed by some of the same protein cofac- tors as is RNAi, have put regulatory RNAs in the spot- light in eukaryotes as well. Recent searches have con- firmed that flies, worms, plants, and humans all harbor significant numbers of small RNAs likely to play regu- latory roles. Along with the rapid expansion in RNAs doing inter- esting things, has come a proliferation of nomenclature. Noncoding RNAs (ncRNA) has been used recently, as the most general term (Storz 2002). Among the noncod- ing RNAs, the subclass of relatively small RNAs that frequently act as regulators have been called stRNAs (small temporal RNAs, eukaryotes) and sRNAs (small RNAs, prokaryotes), among others. Here, I will refer to the regulatory RNAs, which should be considered a sub- set of the ncRNAs. I review here the range of regulatory RNAs that have been identified and how they can be found, what we know about how they work, drawing lessons from the plasmid antisense molecules, and how they transduce regulatory signals. These stealthy RNAs may be the final level of unexpected regulatory circuitry in all of those systems we thought we were beginning to understand; now that we know they are there, we have some hope of understanding what it is they do and how they do it.
    Keywords: Micrornas -- Physiology
    ISSN: 0890-9369
    E-ISSN: 15495477
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  • 2
    Language: English
    In: Nature, Nov 3, 2016, Vol.539(7627), p.38(2)
    Keywords: Phosphates -- Health Aspects ; Microbial Colonies -- Health Aspects
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    Language: English
    In: Science, 03 December 1999, Vol.286(5446), pp.1888-1893
    Description: Polypeptides emerging from the ribosome must fold into stable three-dimensional structures and maintain that structure throughout their functional lifetimes. Maintaining quality control over protein structure and function depends on molecular chaperones and proteases, both of which can recognize hydrophobic regions exposed on unfolded polypeptides. Molecular chaperones promote proper protein folding and prevent aggregation, and energy-dependent proteases eliminate irreversibly damaged proteins. The kinetics of partitioning between chaperones and proteases determines whether a protein will be destroyed before it folds properly. When both quality control options fail, damaged proteins accumulate as aggregates, a process associated with amyloid diseases.
    Keywords: Business -- Business economics -- Commercial production -- Protein refolding ; Biological sciences -- Biology -- Cytology -- Protein refolding ; Physical sciences -- Chemistry -- Chemical compounds -- Protein refolding ; Biological sciences -- Biology -- Cytology -- Protein refolding ; Philosophy -- Metaphysics -- Ontology -- Protein refolding ; Health sciences -- Medical treatment -- Emergency treatment -- Protein refolding ; Physical sciences -- Chemistry -- Chemical compounds -- Protein refolding ; Physical sciences -- Chemistry -- Chemical compounds -- Protein refolding ; Biological sciences -- Biology -- Genetics -- Protein refolding ; Physical sciences -- Chemistry -- Chemical compounds -- Protein refolding
    ISSN: 00368075
    E-ISSN: 10959203
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  • 4
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 01 December 1993, Vol.90(23), pp.11247-11251
    Description: We have cloned a human ATP-dependent protease that is highly homologous to members of the bacterial Lon protease family. The cloned gene encodes a protein of 963 amino acids with a calculated molecular mass of 106 kDa, slightly higher than that observed by Western blotting the protein from human tissues and cell lines (100 kDa). A single species of mRNA was found for this Lon protease in all human tissues examined. The protease is encoded in the nucleus, and the amino-terminal portion of the protein sequence contains a potential mitochondrial targeting presequence. Immunofluorescence microscopy suggested a predominantly mitochondrial localization for the Lon protease in cultured human cells. A truncated LON gene, in which translation was initiated at Met 118 of the coding sequence, was expressed in Escherichia coli and produced a protease that degraded α-casein in vitro in an ATP-dependent manner and had other properties similar to E. coli Lon protease.
    Keywords: Physical sciences -- Chemistry -- Chemical compounds -- KB cells ; Biological sciences -- Biology -- Cytology -- KB cells ; Physical sciences -- Chemistry -- Chemical compounds -- KB cells ; Biological sciences -- Biology -- Cytology -- KB cells ; Biological sciences -- Biology -- Cytology -- KB cells ; Physical sciences -- Chemistry -- Chemical compounds -- KB cells ; Biological sciences -- Biology -- Cytology -- KB cells ; Biological sciences -- Biology -- Cytology -- KB cells ; Biological sciences -- Biology -- Cytology -- KB cells ; Applied sciences -- Laboratory techniques -- Nucleic acid amplification techniques -- KB cells
    ISSN: 00278424
    E-ISSN: 10916490
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  • 5
    Language: English
    In: Molecular cancer research : MCR, March 2018, Vol.16(3), pp.361-377
    Description: Cyclin-dependent kinase 4/6 (CDK4/6)-specific inhibitors, such as palbociclib, have shown clinical efficacy, but primary or secondary resistance has emerged as a problem. To develop more effective therapeutic approaches, investigation is needed into the mechanisms of resistance or adaption. Here, it is demonstrated that CDK2 compensates for loss of CDK4 activity to rescue palbociclib-arrested breast cancer cells, suggesting that inhibition of both kinases is required to achieve durable response. In addition, a novel strategy is described to inhibit tyrosine phosphorylation of p27Kip1 (CDKN1B) and simultaneously inhibit both CDK2 and CDK4. p27Kip1 is a required assembly factor for cyclin-CDK4 complexes, but it must be phosphorylated on residue Y88 to open or activate the complex. The Brk-SH3 peptide, ALT, blocks p27 Y88 phosphorylation, inhibiting CDK4. Nonphosphorylated p27 is no longer a target for ubiquitin-mediated degradation and this stabilized p27 now also inhibits CDK2 activity. Thus, ALT induction inhibits both the kinase that drives proliferation (CDK4) and the kinase that mediates resistance (CDK2), causing a potent and long-lasting cell-cycle arrest. ALT arrests growth of all breast cancer subgroups and synergizes with palbociclib to increase cellular senescence and to cause tumor regression in breast cancer xenograft models. The use of ALT demonstrates that both CDK4 and CDK2 need to be inhibited if long-term efficacy is to be achieved and represents a novel modality to inhibit breast cancer cells. Modulating tyrosine phosphorylation of p27 impacts both proliferative (CDK4) and resistance (CDK2) mechanisms in breast cancer and suggests that phospho-p27 status may serve as a biomarker for patients that are responsive to CDK4/6 inhibition. .
    Keywords: Breast Neoplasms -- Drug Therapy ; Cyclin-Dependent Kinase 2 -- Antagonists & Inhibitors ; Cyclin-Dependent Kinase 4 -- Antagonists & Inhibitors ; Cyclin-Dependent Kinase Inhibitor P27 -- Metabolism ; Neoplasm Proteins -- Pharmacology ; Peptide Fragments -- Pharmacology ; Protein-Tyrosine Kinases -- Pharmacology
    ISSN: 15417786
    E-ISSN: 1557-3125
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  • 6
    In: The American Journal of Surgical Pathology, 2013, Vol.37(9), pp.1407-1412
    Description: Adult T-cell leukemia/lymphoma (ATLL) is caused by the HTLV-1 virus, endemic to Japan and the Caribbean, and is likely derived from cells with the T-regulatory phenotype. The malignant cells express IL2 receptor α (CD25), and the majority express transcription factor Forkhead box P3 (Foxp3), in addition to T-cell markers. Occasional cases express CD30. Whereas Japanese cases are predominantly of the acute and chronic leukemic types, the less well-studied Caribbean cases are more often lymphomatous. We performed immunohistochemical analysis for CD25, Foxp3, and CD30 on samples from 42 US/Caribbean ATLL patients and correlated these markers with morphologic subtype and clinical characteristics. In the 16/42 patients who had successive biopsies, we determined the expression stability of these markers. Foxp3 was expressed in 26 of the 42 (62%) initial biopsies, and its intensity correlated with CD25 expression. It was more frequent in pleomorphic small-sized and medium-sized cell types than in large cell tumors but did not correlate with patients’ clinical attributes. Foxp3 expression and morphology were unchanged in successive biopsies in 13 of 16 patients. Four initial biopsies had features of anaplastic large cell T lymphomas, all of which were Foxp3. Successive biopsies from 2 patients with pleomorphic medium cell variant showed diminishing expression of originally weak Foxp3 expression and de novo CD30 expression, whereas they showed morphologic progression to the anaplastic cell variant. A third patient’s second biopsy revealed progression from pleomorphic medium to anaplastic large cell morphology with loss of Foxp3, but it remained CD30. Foxp3 expression correlates with pleomorphic small and medium cell types and may be lost with large cell transformation. The evolution of the latter type can be associated with the gain of CD30 expression; such ATLL tumors might respond to anti-CD30 monoclonal antibody therapies.
    Keywords: Molecular Targeted Therapy ; Antibodies -- Therapeutic Use ; Biomarkers, Tumor -- Analysis ; Forkhead Transcription Factors -- Analysis ; Ki-1 Antigen -- Analysis ; Leukemia-Lymphoma, Adult T-Cell -- Drug Therapy;
    ISSN: 0147-5185
    E-ISSN: 15320979
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  • 7
    Language: English
    In: mBio, 12/31/2013, Vol.4(6)
    Description: UNLABELLED: Bacterial FtsK plays a key role in coordinating cell division with the late stages of chromosome segregation. The N-terminal membrane-spanning domain of FtsK is required for cell division, whereas the C-terminal domain is a fast double-stranded DNA (dsDNA) translocase that brings the replication termination region of the chromosome to midcell, where it facilitates chromosome unlinking by activating XerCD-dif site-specific recombination. Therefore, FtsK coordinates the late stages of chromosome segregation with cell division. Although the translocase is known to act as a hexamer on DNA, it is unknown when and how hexamers form, as is the number of FtsK molecules in the cell and within the divisome. Using single-molecule live-cell imaging, we show that newborn Escherichia coli cells growing in minimal medium contain ~40 membrane-bound FtsK molecules that are largely monomeric; the numbers increase proportionately with cell growth. After recruitment to the midcell, FtsK is present only as hexamers. Hexamers are observed in all cells and form before any visible sign of cell constriction. An average of 7 FtsK hexamers per cell are present at midcell, with the N-terminal domain being able to hexamerize independently of the translocase. Detergent-solubilized and purified FtsK N-terminal domains readily form hexamers, as determined by in vitro biochemistry, thereby supporting the in vivo data. The hexameric state of the FtsK N-terminal domain at the division site may facilitate assembly of a functional C-terminal DNA translocase on chromosomal DNA.IMPORTANCE: In the rod-shaped bacterium Escherichia coli, more than a dozen proteins act at the cell center to mediate cell division, which initiates while chromosome replication and segregation are under way. The protein FtsK coordinates cell division with the late stages of chromosome segregation. The N-terminal part of FtsK is membrane embedded and acts in division, while the C-terminal part forms a hexameric ring on chromosomal DNA, which the DNA can translocate rapidly to finalize chromosome segregation. Using quantitative live-cell imaging, which measures the position and number of FtsK molecules, we show that in all cells, FtsK hexamers form only at the cell center at the initiation of cell division. Furthermore, the FtsK N-terminal portion forms hexamers independently of the C-terminal translocase.
    Keywords: Biology;
    ISSN: mBio
    E-ISSN: 2150-7511
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  • 8
    Language: English
    In: mBio, 07/01/2013, Vol.4(3)
    Description: UNLABELLED: Previous work from our laboratory showed that the Gram-negative aquatic pathogen Vibrio cholerae can take up a much wider repertoire of fatty acids than other Gram-negative organisms. The current work elaborated on the ability of V. cholerae to exploit an even more diverse pool of lipid nutrients from its environment. We have demonstrated that the bacterium can use lysophosphatidylcholine as a metabolite for growth. Using a combination of thin-layer chromatography and mass spectrometry, we also showed that lysophosphatidylcholine-derived fatty acid moieties can be used for remodeling the V. cholerae membrane architecture. Furthermore, we have identified a lysophospholipase, VolA (Vibrio outer membrane lysophospholipase A), required for these activities. The enzyme is well conserved in Vibrio species, is coexpressed with the outer membrane fatty acid transporter FadL, is one of very few surface-exposed lipoprotein enzymes to be identified in Gram-negative bacteria and the first instance of a surface lipoprotein phospholipase. We propose a model whereby the bacterium efficiently couples the liberation of fatty acid from lysophosphatidylcholine to its subsequent metabolic uptake. An expanded ability to scavenge diverse environmental lipids at the bacterial surface increases overall bacterial fitness and promotes homeoviscous adaptation through membrane remodeling.IMPORTANCE: Our understanding of how bacteria utilize environmental lipid sources has been limited to lipids such as fatty acids and cholesterol. This narrow scope may be attributed to both the intricate nature of lipid uptake mechanisms and the diversity of lipid substrates encountered within an ecological niche. By examining the ability of the pathogen Vibrio cholerae to utilize exogenous lipids, we uncovered a surface-exposed lipoprotein (VolA) that is required for processing the prevalent host lipid lysophosphatidylcholine. VolA functions as a lipase liberating a fatty acid from exogenous lysophospholipids. The freed fatty acid is then transported into the cell, serving as a carbon source, or shunted into phospholipid synthesis for membrane assembly. A limited number of surface-exposed lipoproteins have been found in Gram-negative organisms, and few have enzymatic function. This work highlights the ability of bacteria to exploit exogenous lipids for both maintenance of the membrane and carbon source acquisition.
    Keywords: Biology;
    ISSN: mBio
    E-ISSN: 2150-7511
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  • 9
    Language: English
    In: Critical Reviews in Biochemistry and Molecular Biology, 01 January 2005, Vol.40(2), pp.93-113
    Description: Small regulatory RNAs can modify the activity of proteins and the stability and translation of mRNAs. They have now been found in a wide range of organisms, and can play previously unsuspected critical regulatory roles. The bacterial small RNAs include two major classes. The largest family...
    Keywords: Csra ; Csrb ; Dsra ; Hfq ; Rpos ; Anatomy & Physiology
    ISSN: 1040-9238
    E-ISSN: 1549-7798
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  • 10
    Language: English
    In: American Journal of Hematology, March 2001, Vol.66(3), pp.203-206
    Description: Approximately 3% of patients with B‐cell chronic lymphocytic leukemia (CLL) develop a high‐grade large‐cell lymphoma consistent with Richter's Syndrome. In most cases, these lymphomas are of B‐cell origin and are believed to arise by clonal evolution from the CLL cells. We present a case of a patient with a 10‐year history of B‐CLL who developed an aggressive large‐cell lymphoma, confirmed by immunophenotype to be of T‐cell origin. We suggest that in patients with CLL, immunodysregulation can result in the proliferation of T cells, which may mutate and result in the development of a new malignant clone. Am. J. Hematol. 66:203–206, 2001. © 2001 Wiley‐Liss, Inc.
    Keywords: T‐Cell Lymphoma ; Cll ; Richter'S Syndrome
    ISSN: 0361-8609
    E-ISSN: 1096-8652
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