UMLS:C0344329 - FACTA Search

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Query: UMLS:C0344329 (collapse)
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CTLs kill targets by inducing them to die through apoptosis. A number of morphological and biochemical events are now recognized as characteristic features of the apoptotic program. Among these, the disruption of the inner mitochondrial transmembrane potential (Delta Psi m) and the release of cytochrome c into the cytoplasm appear to be early events in many systems, leading to the activation of caspase-3 and, subsequently, nuclear apoptosis. We show here that, in Jurkat targets treated in vitro with purified granzyme B and perforin or granzyme B and adenovirus, Delta Psi m collapse, reactive oxygen species production, and cytochrome c release from mitochondria were observed. Loss of Delta Psi m was also detected in an in vivo system where green fluorescent protein-expressing targets were attacked by a cytotoxic T cell line that kills predominantly through the granzyme pathway. DNA fragmentation, phosphatidylserine externalization, and reactive oxygen species production were inhibited in the presence of the caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk) and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone (zDEVD-fmk) in our in vitro system. Importantly, in either the in vitro or in vivo systems, these inhibitors at concentrations up to 100 microM did not prevent Delta Psi m collapse. In addition, cytochrome c release was observed in the in vitro system in the absence or presence of zVAD-fmk. Thus the granzyme B-dependent killing pathway in Jurkat targets involves mitochondrial alterations that occur independently of caspases.
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PMID:Granzyme B-induced loss of mitochondrial inner membrane potential (Delta Psi m) and cytochrome c release are caspase independent. 1052 65

The plus-sense single-stranded RNA of tomato bushy stunt virus (TBSV) encodes a 19-kDa protein, which is translated from a 3' proximal open reading frame (p19) that is entirely nested within the cell-to-cell movement gene (p22). Expression of the cytosolic p19-protein induces either a systemic lethal collapse in Nicotiana benthamiana and N. clevelandii, or necrotic local lesions on resistant N. tabacum. In spinach, the p19-protein is required at high abundance for efficient systemic invasion. This study aimed to determine whether these seemingly different host-dependent biological activities are governed by the same or separate regions on the 172 amino acid p19-protein. For this purpose, codons for charged amino acids predicted to be exposed on the surface of the polypeptide and presumably available for host-specific interactions, were targeted for mutagenesis. A total of 12 mutants were generated, which had no deficiencies in replication or cell-to-cell movement, and substitution of amino acids at the extreme N-terminal end or within the carboxyl 70 amino acids failed to cause a noticeable biological effect on plants. However, mutations dispersed between positions 43 and 85 on the N-terminal half prevented the onset of a systemic lethal necrosis on N. benthamiana and N. clevelandii. With one exception, the same mutants elicited mostly chlorotic, rather than necrotic, local lesions on N. tabacum. Mutations in the central region, which substituted Arg with Gly at positions 72 or 75-78, impaired the ability of TBSV to systemically invade spinach plants. However, substitution with Ala instead of Gly at position 72 had minimal effects on systemic spread in spinach, suggesting the possible influence of protein structure effects. The implications are that regions on the N-terminal portion of the p19-protein mediate interactions in a host-dependent manner and that a central region is required for all activities either by a direct effect of the amino acids or through maintenance of structural integrity.
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PMID:Genetic dissection of tomato bushy stunt virus p19-protein-mediated host-dependent symptom induction and systemic invasion. 1061 62

We previously identified Rho-associated protein kinase (Rho-kinase) as a specific effector of Rho. In this study, we identified collapsin response mediator protein-2 (CRMP-2), as a novel Rho-kinase substrate in the brain. CRMP-2 is a neuronal protein whose expression is up-regulated during development. Rho-kinase phosphorylated CRMP-2 at Thr-555 in vitro. We produced an antibody that specifically recognizes CRMP-2 phosphorylated at Thr-555. Using this antibody, we found that Rho-kinase phosphorylated CRMP-2 downstream of Rho in COS7 cells. Phosphorylation of CRMP-2 was observed in chick dorsal root ganglion neurons during lysophosphatidic acid (LPA)-induced growth cone collapse, whereas the phosphorylation was not detected during semaphorin-3A-induced growth cone collapse. Both LPA-induced CRMP-2 phosphorylation and LPA-induced growth cone collapse were inhibited by Rho-kinase inhibitor HA1077 or Y-32885. LPA-induced growth cone collapse was also blocked by a dominant negative form of Rho-kinase. On the other hand, semaphorin-3A-induced growth cone collapse was not inhibited by a dominant negative form of Rho-kinase. Furthermore, overexpression of a mutant CRMP-2 in which Thr-555 was replaced by Ala significantly inhibited LPA-induced growth cone collapse. These results demonstrate the existence of Rho-kinase-dependent and -independent pathways for growth cone collapse and suggest that CRMP-2 phosphorylation by Rho-kinase is involved in the former pathway.
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PMID:Phosphorylation of collapsin response mediator protein-2 by Rho-kinase. Evidence for two separate signaling pathways for growth cone collapse. 1081 93

Tumor necrosis factor-alpha (TNFalpha) mediates cytochrome c release from mitochondria, loss of mitochondrial membrane potential (DeltaPsim) and apoptosis in sensitive leukemic cells. In the present study, by using the human leukemic U937 cell line, we demonstrate that the cytochrome c release is caspase-8-dependent and can be blocked by an inhibitor of caspase-8, Z-Ile-Glu (OMe)-Thr-Asp(OMe)-fluoromethyl ketone (Z-IETD.fmk), or a pan caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (Z-VAD.fmk). However, TNFalpha-mediated loss of DeltaPsim was not inhibited by caspase inhibitors. The apoptotic process was blocked by either Z-IETD.fmk or Z-VAD.fmk in cells with lower DeltaPsim. U937 cells with stable transfection of the cellular inhibitor of apoptosis protein 1 (c-IAP1) are resistant to TNFalpha-induced activation of caspases, Bid cleavage, cytochrome c release and DeltaPsim collapse. In addition, both c-IAP1 and XIAP were not up-regulated upon prolonged exposure to TNFalpha. In contrast, there was a caspase-dependent cleavage of XIAP, but not c-IAP1, during treatment with TNFalpha for 7 days. These results demonstrate that c-IAP1 blocks TNFalpha signaling at a level controlling both activation of caspase-8 and a signal to cause loss of DeltaPsim. The sensitive U937 cell line failed to acquire resistance and gain a self-protecting advantage against apoptosis, upon induction of c-IAP1 expression.
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PMID:c-IAP1 blocks TNFalpha-mediated cytotoxicity upstream of caspase-dependent and -independent mitochondrial events in human leukemic cells. 1154 72

Keratin 8 (K8) serine 73 occurs within a relatively conserved type II keratin motif ((68)NQSLLSPL) and becomes phosphorylated in cultured cells and organs during mitosis, cell stress, and apoptosis. Here we show that Ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. In cells, Ser-73 phosphorylation occurs in association with p38 kinase activation and is inhibited by SB203580 but not by PD98059. Transfection of K8 Ser-73 --> Ala or K8 Ser-73 --> Asp with K18 generates normal-appearing filaments. In contrast, exposure to okadaic acid results in keratin filament destabilization in cells expressing wild-type or Ser-73 --> Asp K8, whereas Ser-73 --> Ala K8-expressing cells maintain relatively stable filaments. p38 kinase associates with K8/18 immunoprecipitates and binds selectively with K8 using an in vitro overlay assay. Given that K1 Leu-160 --> Pro ((157)NQSLLQPL --> (157)NQSPLQPL) leads to epidermolytic hyperkeratosis, we tested and showed that the analogous K8 Leu-71 --> Pro leads to K8 hyperphosphorylation by p38 kinase in vitro and in transfected cells, likely due to Ser-70 neo-phosphorylation, in association with significant keratin filament collapse upon cell exposure to okadaic acid. Hence, K8 Ser-73 is a physiologic phosphorylation site for p38 kinase, and its phosphorylation plays an important role in keratin filament reorganization. The Ser-73 --> Ala-associated filament reorganization defect is rescued by a Ser-73 --> Asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.
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PMID:Keratin 8 phosphorylation by p38 kinase regulates cellular keratin filament reorganization: modulation by a keratin 1-like disease causing mutation. 1178 83

We report on the unexpected structural changes caused by substitution of acidic amino acids in the Q(B) binding pocket of the bacterial photosynthetic reaction center by alanines. The mutations targeted key residues L212Glu and L213Asp of this transmembrane protein-cofactor complex. The amino acid substitutions in the L212Ala-L213Ala mutant reaction center ("AA") were known to affect the delivery of protons after the light-induced generation of Q(B)(-), which renders the AA strain incapable of photosynthetic growth. The AA structure not only revealed side chain rearrangements but also showed movement of the main chain segments that are contiguous with the mutation sites. The alanine substitutions caused an expansion of the cavity rather than its collapse. In addition, Q(B) is found mainly in the binding site that is proximal to the iron-ligand complex (closest to Q(A)) as opposed to its distal binding site (furthest from Q(A)) in the structure of the wild-type reaction center. The observed rearrangements in the structure of the AA reaction center establish a new balance between charged residues of an interactive network near Q(B). This structurally and electrostatically altered complex forms the basis for future understanding of the structural basis for proton transfer in active reaction centers which retain the alanine substitutions but carry a distant compensatory mutation.
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PMID:The structure of a mutant photosynthetic reaction center shows unexpected changes in main chain orientations and quinone position. 1199 94

Various anticancer drugs cause mitochondrial perturbations in association with apoptosis. Here we investigated the involvement of caspase- and Bcl-2-dependent pathways in doxorubicin-induced mitochondrial perturbations and apoptosis. For this purpose, we set up a novel three-color flow cytometric assay using rhodamine 123, annexin V-allophycocyanin, and propidium iodide to assess the involvement of the mitochondria in apoptosis caused by doxorubicin in the breast cancer cell line MTLn3. Doxorubicin-induced apoptosis was preceded by up-regulation of CD95 and CD95L and a collapse of mitochondrial membrane potential (Deltapsi) occurring prior to phosphatidylserine externalization. This drop in Deltapsi was independent of caspase activity, since benzyloxycarbonyl-Val-Ala-dl-Asp-fluoromethylketone did not inhibit it. Benzyloxycarbonyl-Val-Ala-dl-Asp-fluoromethylketone also blocked activation of caspase-8, thus excluding an involvement of the death receptor pathway in Deltapsi dissipation. Furthermore, although overexpression of Bcl-2 in MTLn3 cells inhibited apoptosis, dissipation of Deltapsi was still observed. No decrease in Deltapsi was observed in cells undergoing etoposide-induced apoptosis. Immunofluorescent analysis of Deltapsi and cytochrome c localization on a cell-to-cell basis indicates that the collapse of Deltapsi and cytochrome c release are mutually independent in both normal and Bcl-2-overexpressing cells. Together, these data indicate that doxorubicin-induced dissipation of the mitochondrial membrane potential precedes phosphatidylserine externalization and is independent of a caspase- or Bcl-2-controlled checkpoint.
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PMID:Differential regulation of doxorubicin-induced mitochondrial dysfunction and apoptosis by Bcl-2 in mammary adenocarcinoma (MTLn3) cells. 1210 57

Triply mutated MATalpha2 protein, alpha2-3A, in which all three major groove-contacting residues are mutated to alanine, is defective in binding DNA alone or in complex with Mcm1 yet binds with MATa1 with near wild-type affinity and specificity. To gain insight into this unexpected behavior, we determined the crystal structure of the a1/alpha2-3A/DNA complex. The structure shows that the triple mutation causes a collapse of the alpha2-3A/DNA interface that results in a reorganized set of alpha2-3A/DNA contacts, thereby enabling the mutant protein to recognize the wild-type DNA sequence. Isothermal titration calorimetry measurements reveal that a much more favorable entropic component stabilizes the a1/alpha2-3A/DNA complex than the alpha2-3A/DNA complex. The combined structural and thermodynamic studies provide an explanation of how partner proteins influence the sequence specificity of a DNA binding protein.
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PMID:Structural and thermodynamic characterization of the DNA binding properties of a triple alanine mutant of MATalpha2. 1212 51

Proteins extracted from the cuticle of pharate larvae and pupae of the mealworm Tenebrio molitor are more soluble at low temperatures than at higher temperatures, a behaviour characteristic of hydrophobic proteins. When the temperature of an unfractionated cuticular extract is raised from 4 to 25 degrees C the solution becomes turbid, droplets of a heavy, protein-rich phase are formed, which gradually settles, leaving an upper protein-poor phase, indicating that the aggregation process is a coacervation. The aggregation of the dissolved cuticular proteins is influenced by changes in temperature, pH, and ionic strength. The process has been studied by measuring development of turbidity in unfractionated cuticular extracts and in solutions of three purified proteins from Tenebrio pharate larvae and pupae (TmLPCP-A1a, TmLPCP-E1a, and TmLPCP-G1a), while temperature, pH or ionic strength of the solutions were varied. Protein aggregation was also studied by determination of changes in fluorescence intensity, when the hydrophobicity probe, 8-anilinonaphthalenesulfonic acid (ANS) was added to solutions of the cuticular proteins. Only when the protein solutions had developed a measurable turbidity was an increase in ANS-fluorescence observed, indicating formation of tightly packed clusters of hydrophobic amino acid residues during aggregation. The temperature range for aggregation depends upon protein concentration: the higher the concentration the lower and more narrow is the temperature range within which aggregation occurs. The tendency for the individual cuticular proteins to aggregate is most pronounced near their isoelectric points, and most of the cuticular proteins have alkaline isoelectric points. The influence of salts on the tendency of the proteins to aggregate varies among the proteins and depends upon how close they are to their isoelectric point. A solution containing both protein TmLPCP-A1a and TmLPCP-E1a becomes more turbid and develops a more intense ANS-fluorescence when warmed from 10 to 30 degrees C than corresponding to the sum of measurements performed on separate solutions of the two proteins, indicating that the two proteins interact during aggregation. The Tenebrio larval/pupal cuticular proteins are characterized by an abundance of hydrophobic amino acid residues, and especially their contents of alanine and proline are high. The behaviour of the cuticular proteins in solution resembles that of another hydrophobic protein, tropoelastin, and it seems reasonable to suggest that similar interactions govern the folding and aggregation of the peptide chains in the two types of proteins. The proline and alanine rich chain segments in the pharate cuticular proteins are suggested to form a series of beta-turns and to fold into a relatively open structure at low temperatures, giving water access to the hydrophobic residues and making the proteins water soluble. At increased temperatures the structure of the ordered water layer surrounding the hydrophobic groups breaks down, and the peptide chains tend to collapse into a more closed structure and to interact more tightly with hydrophobic regions in neighbouring molecules. In dilute solutions in the test tube this results in aggregation and precipitation of the proteins; in intact, pharate cuticle at ambient temperatures the proteins will preferably be in an aggregated, easily dissociated state. Accordingly, small changes in intercuticular pH and ionic strength can produce pronounced changes in the mechanical properties of unsclerotized solid cuticle by interference with protein interactions, in agreement with reports that some cuticles undergo plasticization during and/or immediately after ecdysis.
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PMID:Characteristic properties of proteins from pre-ecdysial cuticle of larvae and pupae of the mealworm Tenebrio molitor. 1221 44

Semaphorin-3A (Sema3A), a member of class 3 semaphorins, regulates axon and dendrite guidance in the nervous system. How Sema3A and its receptors plexin-As and neuropilins regulate neuronal guidance is unknown. We observed that in fyn- and cdk5-deficient mice, Sema3A-induced growth cone collapse responses were attenuated compared to their heterologous controls. Cdk5 is associated with plexin-A2 through the active state of Fyn. Sema3A promotes Cdk5 activity through phosphorylation of Tyr15, a phosphorylation site with Fyn. A Cdk5 mutant (Tyr15 to Ala) shows a dominant-negative effect on the Sema3A-induced collapse response. The sema3A gene shows strong interaction with fyn for apical dendrite guidance in the cerebral cortex. We propose a signal transduction pathway in which Fyn and Cdk5 mediate neuronal guidance regulated by Sema3A.
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PMID:Fyn and Cdk5 mediate semaphorin-3A signaling, which is involved in regulation of dendrite orientation in cerebral cortex. 1237 85

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