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1.
Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination 总被引:43,自引:0,他引:43
Mutations in the Artemis protein in humans result in hypersensitivity to DNA double-strand break-inducing agents and absence of B and T lymphocytes (radiosensitive severe combined immune deficiency [RS-SCID]). Here, we report that Artemis forms a complex with the 469 kDa DNA-dependent protein kinase (DNA-PKcs) in the absence of DNA. The purified Artemis protein alone possesses single-strand-specific 5' to 3' exonuclease activity. Upon complex formation, DNA-PKcs phosphorylates Artemis, and Artemis acquires endonucleolytic activity on 5' and 3' overhangs, as well as hairpins. Finally, the Artemis:DNA-PKcs complex can open hairpins generated by the RAG complex. Thus, DNA-PKcs regulates Artemis by both phosphorylation and complex formation to permit enzymatic activities that are critical for the hairpin-opening step of V(D)J recombination and for the 5' and 3' overhang processing in nonhomologous DNA end joining. 相似文献
2.
Florian Neumann Antje Wurm Regina Linnertz Thomas Pannicke Ianors Iandiev Peter Wiedemann Andreas Reichenbach Andreas Bringmann 《Neurochemical research》2010,35(4):522-530
Osmotic swelling of glial cells may contribute to the development of retinal edema. We investigated whether sex steroids inhibit the swelling of glial somata in acutely isolated retinal slices and glial cells of the rat. Superfusion of retinal slices or cells from control animals with a hypoosmolar solution did not induce glial swelling, whereas glial swelling was observed in slices of postischemic and diabetic retinas. Progesterone, testosterone, estriol, and 17ß-estradiol prevented glial swelling with half-maximal effects at approximately 0.3, 0.6, 6, and 20 μM, respectively. The effect of progesterone was apparently mediated by transactivation of metabotropic glutamate receptors, P2Y1, and adenosine A1 receptors. The data suggest that sex steroids may inhibit cytotoxic edema in the retina. 相似文献
3.
Enders A Fisch P Schwarz K Duffner U Pannicke U Nikolopoulos E Peters A Orlowska-Volk M Schindler D Friedrich W Selle B Niemeyer C Ehl S 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(8):5060-5068
DNA ligase IV (LigIV) deficiency was identified as the molecular basis for a severe form of combined immunodeficiency in two microcephalic siblings with cellular radiosensitivity. In one patient the diagnosis was made directly after birth, allowing analysis of the role of LigIV in the development of specific immune cells. Absolute numbers of B cells were reduced 100-fold and alphabeta T cells 10-fold, whereas gammadelta T cells were normal. Spectratyping of all three cell populations showed a diverse repertoire, but sequencing of IgH V(D)J junctions revealed shorter CDR3 regions due to more extensive nucleotide deletions among D and J elements and fewer N nucleotide insertions. Clonal restriction of IgG-expressing, but not IgM-expressing, B cells and the lack of primary and secondary lymph node follicles indicated impaired class switch recombination. Observations in the older sibling showed that this rudimentary immune system was able to mount specific responses to infection. However, partial Ab responses and extensive amplification of gammadelta T cells could not prevent a life-threatening course of viral and bacterial infections, the development of an EBV-induced lymphoma, and immune dysregulation reflected by severe autoimmune cytopenia. Impaired generation of immune diversity under conditions of limited LigIV activity can cause a human SCID variant with a characteristic immunological phenotype. 相似文献
4.
Chao T. I Grosche J Biedermann B Francke M Pannicke T Reichelt W Wulst M Muhle C Pritz-Hohmeier S Kuhrt H Faude F Drommer W Kasper M Buse E Reichenbach A 《Brain Cell Biology》1997,26(7):439-454
Brain Cell Biology - Muller cells from 22 mammalian species were subjected to morphological and electrophysiological studies. In the ‘mid-periphery’ of retinae immunocytochemically... 相似文献
5.
Stefanie Vogler Antje Grosche Thomas Pannicke Peter Wiedemann Andreas Reichenbach Andreas Bringmann 《Neurochemical research》2016,41(10):2598-2606
Water accumulation in retinal glial (Müller) and neuronal cells resulting in cellular swelling contributes to the development of retinal edema and neurodegeneration. Here, we show that endothelin-1 (ET-1) dose-dependently inhibits the hypoosmotic swelling of Müller cells in freshly isolated retinal slices of control and diabetic rats, with a maximal inhibition at 100 nM. Osmotic Müller cell swelling was also inhibited by ET-2. The effect of ET-1 was mediated by activation of ETA and ETB receptors resulting in transactivation of metabotropic glutamate receptors, purinergic P2Y1, and adenosine A1 receptors. ET-1 (but not ET-2) also inhibited the osmotic swelling of bipolar cells in retinal slices, but failed to inhibit the swelling of freshly isolated bipolar cells. The inhibitory effect of ET-1 on the bipolar cell swelling in retinal slices was abrogated by inhibitors of the FGF receptor kinase (PD173074) and of TGF-β1 superfamily activin receptor-like kinase receptors (SB431542), respectively. Both Müller and bipolar cells displayed immunoreactivities of ETA and ETB receptor proteins. The data may suggest that neuroprotective effects of ETs in the retina are in part mediated by prevention of the cytotoxic swelling of retinal glial and bipolar cells. ET-1 acts directly on Müller cells, while the inhibitory effect of ET-1 on bipolar cell swelling is indirectly mediated, via stimulation of the release of growth factors like bFGF and TGF-β1 from Müller cells. 相似文献
6.
Lysann Wagner Thomas Pannicke Ina Frommherz Katja Sauer Ju Chen Antje Grosche 《Neurochemical research》2016,41(4):677-686
Glial cells in the diseased nervous system undergo a process known as reactive gliosis. Gliosis of retinal Müller glial cells is characterized by an upregulation of glial fibrillary acidic protein and frequently by a reduction of inward K+ current amplitudes. Purinergic signaling is assumed to be involved in gliotic processes. As previously shown, lack of the nucleotide receptor P2Y1 leads to an altered regulation of K+ currents in Müller cells of the ischemic retina. Here, we asked first whether this effect is mediated by the IP3 receptor subtype 2 (IP3R2) known as the major downstream signaling target of P2Y1 in Müller cells. The second question was whether lack of IP3R2 affects neuronal survival in the control and ischemic retina. Ischemia was induced in wild type and IP3R2-deficient (IP 3 R2 ?/?) mice by transient elevation of the intraocular pressure. Immunostaining and TUNEL labelling were used to quantify neuronal cell loss. The downregulation of inward K+ currents in Müller cells from ischemic IP 3 R2 ?/? retinae was less strong than in wild type animals. The reduction of the number of cells in the ganglion cell layer and of calretinin- and calbindin-positive cells 7 days after ischemia was similar in wild type and IP 3 R2 ?/? mice. However, IP3R2 deficiency led to an increased number of TUNEL-positive cells in the outer nuclear layer at 1 day and to an enhanced postischemic loss of photoreceptors 7 days after ischemia. This implies that IP3R2 is involved in some but not all aspects of signaling in Müller cells after an ischemic insult. 相似文献
7.
Iandiev I Wurm A Pannicke T Wiedemann P Reichenbach A Robson SC Zimmermann H Bringmann A 《Purinergic signalling》2007,3(4):423-433
Extracellular nucleotides mediate glia-to-neuron signalling in the retina and are implicated in the volume regulation of retinal
glial (Müller) cells under osmotic stress conditions. We investigated the expression and functional role of ectonucleotidases
in Müller cells of the rodent retina by cell-swelling experiments, calcium imaging, and immuno- and enzyme histochemistry.
The swelling of Müller cells under hypoosmotic stress was inhibited by activation of an autocrine purinergic signalling cascade.
This cascade is initiated by exogenous glutamate and involves the consecutive activation of P2Y1 and adenosine A1 receptors, the action of ectoadenosine 5′-triphosphate (ATP)ases, and a nucleoside-transporter-mediated
release of adenosine. Inhibition of ectoapyrases increased the ATP-evoked calcium responses in Müller cell endfeet. Müller
cells were immunoreactive for nucleoside triphosphate diphosphohydrolases (NTPDase)2 (but not NTPDase1), ecto-5′-nucleotidase,
P2Y1, and A1 receptors. Enzyme histochemistry revealed that ATP but not adenosine 5′-diphosphate (ADP) is extracellularly metabolised
in retinal slices of NTPDase1 knockout mice. NTPDase1 activity and protein is restricted to blood vessels, whereas activity
of alkaline phosphatase is essentially absent at physiological pH. The data suggest that NTPDase2 is the major ATP-degrading
ectonucleotidase of the retinal parenchyma. NTPDase2 expressed by Müller cells can be implicated in the regulation of purinergic
calcium responses and cellular volume. 相似文献
8.
Glial cells in (patho)physiology 总被引:1,自引:0,他引:1
Parpura V Heneka MT Montana V Oliet SH Schousboe A Haydon PG Stout RF Spray DC Reichenbach A Pannicke T Pekny M Pekna M Zorec R Verkhratsky A 《Journal of neurochemistry》2012,121(1):4-27
Neuroglial cells define brain homeostasis and mount defense against pathological insults. Astroglia regulate neurogenesis and development of brain circuits. In the adult brain, astrocytes enter into intimate dynamic relationship with neurons, especially at synaptic sites where they functionally form the tripartite synapse. At these sites, astrocytes regulate ion and neurotransmitter homeostasis, metabolically support neurons and monitor synaptic activity; one of the readouts of the latter manifests in astrocytic intracellular Ca(2+) signals. This form of astrocytic excitability can lead to release of chemical transmitters via Ca(2+) -dependent exocytosis. Once in the extracellular space, gliotransmitters can modulate synaptic plasticity and cause changes in behavior. Besides these physiological tasks, astrocytes are fundamental for progression and outcome of neurological diseases. In Alzheimer's disease, for example, astrocytes may contribute to the etiology of this disorder. Highly lethal glial-derived tumors use signaling trickery to coerce normal brain cells to assist tumor invasiveness. This review not only sheds new light on the brain operation in health and disease, but also points to many unknowns. 相似文献
9.
Slezak M Grosche A Niemiec A Tanimoto N Pannicke T Münch TA Crocker B Isope P Härtig W Beck SC Huber G Ferracci G Perraut M Reber M Miehe M Demais V Lévêque C Metzger D Szklarczyk K Przewlocki R Seeliger MW Sage-Ciocca D Hirrlinger J Reichenbach A Reibel S Pfrieger FW 《Neuron》2012,74(3):504-516
Glial cells release molecules that influence brain?development, function, and disease. Calcium-dependent exocytosis has been proposed as potential release mechanism in astroglia, but the physiological relevance of "gliotransmission" in?vivo remains controversial. We focused on the impact of glial exocytosis on sensory transduction in the retina.?To this end, we generated transgenic mice to block exocytosis by Cre recombinase-dependent expression of the clostridial botulinum neurotoxin serotype?B light chain, which cleaves vesicle-associated membrane protein 1-3. Ubiquitous and neuronal toxin expression caused perinatal lethality and?a reduction of synaptic transmission thus validating transgene function. Toxin expression in Müller cells inhibited vesicular glutamate release and impaired glial volume regulation but left retinal histology and visual processing unaffected. Our model to study gliotransmission in?vivo reveals specific functions of exocytotic glutamate release in retinal glia. 相似文献
10.
Schwarz K Ma Y Pannicke U Lieber MR 《BioEssays : news and reviews in molecular, cellular and developmental biology》2003,25(11):1061-1070
Human severe combined immune deficiency (SCID) is the most serious inherited immunological deficit. Recent work has revealed defects in the predominant pathway for double-strand break repair called nonhomologous DNA end joining, or NHEJ. Progress in the biochemistry and genetics of NHEJ and of human SCID has proven to be synergistic between these two fields in a manner that covers the range from biochemical etiology to considerations about possible gene therapy for the B- SCID patients. 相似文献