The Experts below are selected from a list of 309 Experts worldwide ranked by ideXlab platform
Joe W Ramos - One of the best experts on this subject based on the ideXlab platform.
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the Death Effector Domain protein pea 15 negatively regulates t cell receptor signaling
The FASEB Journal, 2010Co-Authors: Sandra Pastorino, Hemamalini Renganathan, Maisel J Caliva, Erin L Filbert, John Opokuansah, Florian J Sulzmaier, Joanna E Gawecka, Guy Werlen, Andrey S Shaw, Joe W RamosAbstract:PEA-15 is a Death Effector Domain-containing phosphoprotein that binds ERK and restricts it to the cytoplasm. PEA-15 also binds to FADD and thereby blocks apoptosis induced by Death receptors. Abnormal expression of PEA-15 is associated with type II diabetes and some cancers; however, its physiological function remains unclear. To determine the function of PEA-15 in vivo, we used C57BL/6 mice in which the PEA-15 coding region was deleted. We thereby found that PEA-15 regulates T-cell proliferation. PEA-15-null mice did not have altered thymic or splenic lymphocyte cellularity or differentiation. However, PEA-15 deficient T cells had increased CD3/CD28-induced nuclear translocation of ERK and increased activation of IL-2 transcription and secretion in comparison to control wild-type littermates. Indeed, activation of the T-cell receptor in wild-type mice caused PEA-15 release of ERK. In contrast, overexpression of PEA-15 in Jurkat T cells blocked nuclear translocation of ERK and IL-2 transcription. Finally, PEA-15-null T cells showed increased IL-2 dependent proliferation on stimulation. No differences in T cell susceptibility to apoptosis were found. Thus, PEA-15 is a novel player in T-cell homeostasis. As such this work may have far reaching implications in understanding how the immune response is controlled.—Pastorino, S., Renganathan, H., Caliva, M. J., Filbert, E. L., Opoku-Ansah, J., Sulzmaier, F. J., Gawecka, J. E., Werlen, G., Shaw, A. S., Ramos, J. W. The Death Effector Domain protein PEA-15 negatively regulates T-cell receptor signaling.
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Death Effector Domain containing proteins
Cellular and Molecular Life Sciences, 2009Co-Authors: Gudur M Valmiki, Joe W RamosAbstract:Death Effector Domains (DEDs) are protein-protein interaction structures that are found in proteins that regulate a variety of signal transduction pathways. DEDs are a part of the larger family of Death Domain structures that have been primarily described in the control of programmed cell Death. The seven standard DED-containing proteins are fas associated Death Domain protein (FADD), Caspase-8 and 10, cellular FLICE-like inhibitory protein (c-FLIP), Death Effector Domain containing DNA binding (DEDD), DEDD2 and phosphoprotein enriched in astrocytes 15-Kda (PEA-15). These proteins are particularly associated with the regulation of apoptosis and proliferation mediated by the tumor necrosis factor α (TNFα) receptor family. Consequently DED-containing proteins are reported to regulate transcription, migration, and proliferation, in addition to both pro and anti-apoptotic functions. Moreover, DED proteins are essential in embryonic development and homeostasis of the immune system. Here we focus on the role of DED-containing proteins in development and the pathologies arising from abnormal expression of these proteins.
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vanishin is a novel ubiquitinylated Death Effector Domain protein that blocks erk activation
Biochemical Journal, 2005Co-Authors: Joe W RamosAbstract:The ERK (extracellular-signal regulated-kinase)/MAPK (mitogen-activated protein kinase) pathway can regulate transcription, proliferation, migration and apoptosis. The small DED (Death-Effector Domain) protein PEA-15 (phosphoprotein enriched in astrocytes-15) binds ERK and targets it to the cytoplasm. Other DED-containing proteins including cFLIP and DEDD can also regulate signal transduction events and transcription in addition to apoptosis. In the present study, we report the identification of a novel DED-containing protein called Vanishin. The amino acid sequence of Vanishin is closest in similarly to PEA-15 (61% identical). Vanishin mRNA is expressed in several mouse tissues and in both mouse and human cell lines. Interestingly, Vanishin is regulated by ubiquitinylation and subsequent degradation by the 26 S proteasome. The ubiquitinylation is complex and occurs at both the internal lysine residues and the N-terminus. We further show that Vanishin binds ERK/MAPK but not the DED proteins Fas-associated Death Domain, caspase 8 or PEA-15. Vanishin is present in both the nucleus and Golgi on overexpression and forces increased ERK accumulation in the nucleus in the absence of ERK stimulation. Moreover, Vanishin expression inhibits ERK activation and ERK-dependent transcription in cells, but does not alter MAPK/ERK activity. Therefore Vanishin is a novel regulator of ERK that is controlled by ubiquitinylation.
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RSK2 Activity Is Regulated by Its Interaction with PEA-15
Journal of Biological Chemistry, 2003Co-Authors: Hema Vaidyanathan, Joe W RamosAbstract:Abstract The ERK MAP (mitogen-activated protein) kinase cascade modulates many cellular processes including transcription, adhesion, growth, survival, and proliferation. One target substrate of ERK involved in regulating transcription is the p90 ribosomal S6 kinase (RSK) isozyme, RSK2. Here we demonstrate that a small Death Effector Domain-containing protein called PEA-15 binds RSK2. RSK2 and PEA-15 (phosphoprotein enriched in astrocytes, 15 kDa) co-precipitated from cells and were colocalized in the cytoplasm. Furthermore, purified PEA-15 bound in vitro translated RSK2, suggesting that these proteins interact directly. PEA-15 does not bind to RSK1 and therefore exhibits some binding specificity. RSK2 binds the COOH terminus of PEA-15 and does not interact with its NH2-terminal Death Effector Domain. We show that this interaction has functional consequences including the inhibition of RSK2-dependent CREB transcription. PEA-15 expression also blocks histone H3 phosphorylation, an RSK2-dependent event that may contribute to effects on gene expression. These results can be attributed to two effects of PEA-15 on RSK2. First, PEA-15 blocks nuclear accumulation of RSK2 after epidermal growth factor stimulation. Second, PEA-15 inhibits RSK2 kinase activity by 50%. A mutant of PEA-15 that binds RSK2 but is localized to the nucleus had no effect on RSK2-dependent transcription. Interestingly, this mutant also did not affect RSK2 kinase activity. This may indicate that cytoplasmic retention of RSK2 is also required for PEA-15 to impair kinase activity. PEA-15 does not alter ERK phosphorylation of RSK2 and is not itself a substrate of RSK2. Hence the effects of PEA-15 on RSK2 represent a novel mechanism for the regulation of RSK2-mediated signaling.
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recognition of erk map kinase by pea 15 reveals a common docking site within the Death Domain and Death Effector Domain
The EMBO Journal, 2002Co-Authors: Justine M Hill, Joe W Ramos, Mark H Ginsberg, Hema Vaidyanathan, Milton H WernerAbstract:PEA-15 is a multifunctional protein that modulates signaling pathways which control cell proliferation and cell Death. In particular, PEA-15 regulates the actions of the ERK MAP kinase cascade by binding to ERK and altering its subcellular localization. The three-dimensional structure of PEA-15 has been determined using NMR spectroscopy and its interaction with ERK defined by characterization of mutants that modulate ERK function. PEA-15 is composed of an N-terminal Death Effector Domain (DED) and a C-terminal tail of irregular structure. NMR ‘footprinting’ and mutagenesis identified elements of both the DED and tail that are required for ERK binding. Comparison of the DED-binding surface for ERK2 with the Death Domain (DD)-binding surface of Drosophila Tube revealed an unexpected similarity between the interaction modes of the DD and DED motifs in these proteins. Despite a lack of functional or sequence similarity between PEA-15 and Tube, these proteins utilize a common surface of the structurally similar DD and DED to recognize functionally diverse targets.
E C Twomey - One of the best experts on this subject based on the ideXlab platform.
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substantial conformational change mediated by charge triad residues of the Death Effector Domain in protein protein interactions
PLOS ONE, 2013Co-Authors: E C Twomey, Dana F Cordasco, Stephen D KozuchAbstract:Protein conformational changes are commonly associated with the formation of protein complexes. The non-catalytic Death Effector Domains (DEDs) mediate protein-protein interactions in a variety of cellular processes, including apoptosis, proliferation and migration, and glucose metabolism. Here, using NMR residual dipolar coupling (RDC) data, we report a conformational change in the DED of the phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) protein in the complex with a mitogen-activated protein (MAP) kinase, extracellular regulated kinase 2 (ERK2), which is essential in regulating ERK2 cellular distribution and function in cell proliferation and migration. The most significant conformational change in PEA-15 happens at helices α2, α3, and α4, which also possess the highest flexibility among the six-helix bundle of the DED. This crucial conformational change is modulated by the D/E-RxDL charge-triad motif, one of the prominent structural features of DEDs, together with a number of other electrostatic and hydrogen bonding interactions on the protein surface. Charge-triad motif promotes the optimal orientation of key residues and expands the binding interface to accommodate protein-protein interactions. However, the charge-triad residues are not directly involved in the binding interface between PEA-15 and ERK2.
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high definition nmr structure of ped pea 15 Death Effector Domain reveals details of key polar side chain interactions
Biochemical and Biophysical Research Communications, 2012Co-Authors: E C TwomeyAbstract:Death Effector Domain (DED) proteins constitute a subfamily of the large Death Domain superfamily that is primarily involved in apoptosis pathways. DED structures have characteristic side chain–side chain interactions among polar residues on the protein surface, forming a network of hydrogen bonds and salt bridges. The polar interaction network is functionally important in promoting protein–protein interactions by maintaining optimal side chain orientations. We have refined the solution DED structure of the PED/PEA-15 protein, a representative member of DED subfamily, using traditional NMR restraints with the addition of residual dipolar coupling (RDC) restraints from two independent alignment media, and employed the explicit solvent refinement protocol. The newly refined DED structure of PED/PEA-15 possesses higher structural quality as indicated by WHAT IF Z-scores, with most significant improvement in the backbone conformation normality quality factor. This higher quality DED structure of PED/PEA-15 leads to the identification of a number of key polar side chain interactions, which are not typically observed in NMR protein structures. The elucidation of polar side chain interactions is a key step towards the understanding of protein–protein interactions involving the Death Domain superfamily. The NMR structures with extensive details of protein structural features are thereby termed high-definition (HD) NMR structures.
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High-definition NMR structure of PED/PEA-15 Death Effector Domain reveals details of key polar side chain interactions
Biochemical and Biophysical Research Communications, 2012Co-Authors: E C TwomeyAbstract:Death Effector Domain (DED) proteins constitute a subfamily of the large Death Domain superfamily that is primarily involved in apoptosis pathways. DED structures have characteristic side chain–side chain interactions among polar residues on the protein surface, forming a network of hydrogen bonds and salt bridges. The polar interaction network is functionally important in promoting protein–protein interactions by maintaining optimal side chain orientations. We have refined the solution DED structure of the PED/PEA-15 protein, a representative member of DED subfamily, using traditional NMR restraints with the addition of residual dipolar coupling (RDC) restraints from two independent alignment media, and employed the explicit solvent refinement protocol. The newly refined DED structure of PED/PEA-15 possesses higher structural quality as indicated by WHAT IF Z-scores, with most significant improvement in the backbone conformation normality quality factor. This higher quality DED structure of PED/PEA-15 leads to the identification of a number of key polar side chain interactions, which are not typically observed in NMR protein structures. The elucidation of polar side chain interactions is a key step towards the understanding of protein–protein interactions involving the Death Domain superfamily. The NMR structures with extensive details of protein structural features are thereby termed high-definition (HD) NMR structures.
Toru Miyazaki - One of the best experts on this subject based on the ideXlab platform.
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Death Effector Domain containing protein dedd is required for uterine decidualization during early pregnancy in mice
Journal of Clinical Investigation, 2011Co-Authors: Mayumi Mori, Satoko Arai, Jun Kurokawa, Miwako Kitazume, Kaori Koga, Yutaka Osuga, Toru MiyazakiAbstract:During intrauterine life, the mammalian embryo survives via its physical connection to the mother. The uterine decidua, which differentiates from stromal cells after implantation in a process known as decidualization, plays essential roles in supporting embryonic growth before establishment of the placenta. Here we show that female mice lacking Death Effector Domain–containing protein (DEDD) are infertile owing to unsuccessful decidualization. In uteri of Dedd–/– mice, development of the decidual zone and the surrounding edema after embryonic implantation was defective. This was subsequently accompanied by disintegration of implantation site structure, leading to embryonic Death before placentation. Polyploidization, a hallmark of mature decidual cells, was attenuated in DEDD-deficient cells during decidualization. Such inefficient decidualization appeared to be caused by decreased Akt levels, since polyploidization was restored in DEDD-deficient decidual cells by overexpression of Akt. In addition, we showed that DEDD associates with and stabilizes cyclin D3, an important element in polyploidization, and that overexpression of cyclin D3 in DEDD-deficient cells improved polyploidization. These results indicate that DEDD is indispensable for the establishment of an adequate uterine environment to support early pregnancy in mice.
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Death Effector Domain–containing protein (DEDD) is required for uterine decidualization during early pregnancy in mice
Journal of Clinical Investigation, 2010Co-Authors: Mayumi Mori, Satoko Arai, Jun Kurokawa, Miwako Kitazume, Kaori Koga, Yutaka Osuga, Toru MiyazakiAbstract:During intrauterine life, the mammalian embryo survives via its physical connection to the mother. The uterine decidua, which differentiates from stromal cells after implantation in a process known as decidualization, plays essential roles in supporting embryonic growth before establishment of the placenta. Here we show that female mice lacking Death Effector Domain–containing protein (DEDD) are infertile owing to unsuccessful decidualization. In uteri of Dedd–/– mice, development of the decidual zone and the surrounding edema after embryonic implantation was defective. This was subsequently accompanied by disintegration of implantation site structure, leading to embryonic Death before placentation. Polyploidization, a hallmark of mature decidual cells, was attenuated in DEDD-deficient cells during decidualization. Such inefficient decidualization appeared to be caused by decreased Akt levels, since polyploidization was restored in DEDD-deficient decidual cells by overexpression of Akt. In addition, we showed that DEDD associates with and stabilizes cyclin D3, an important element in polyploidization, and that overexpression of cyclin D3 in DEDD-deficient cells improved polyploidization. These results indicate that DEDD is indispensable for the establishment of an adequate uterine environment to support early pregnancy in mice.
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Death Effector Domain containing protein dedd is an inhibitor of mitotic cdk1 cyclin b1
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Satoko Arai, Katsuhisa Miyake, Renate Voit, Shino Nemoto, Edward K Wakeland, Ingrid Grummt, Toru MiyazakiAbstract:Accumulating evidence has shown that many molecules, including some cyclin-dependent kinases (Cdks) and cyclins, as well as the Death-Effector Domain (DED)-containing FADD, function for both apoptosis and cell cycle. Here we identified that DEDD, which also possesses the DED Domain, acts as a novel inhibitor of the mitotic Cdk1/cyclin B1 complex. DEDD associates with mitotic Cdk1/cyclin B1 complexes via direct binding to cyclin B1 and reduces their function. In agreement, kinase activity of nuclear Cdk1/cyclin B1 in DEDD-null (DEDD−/−) embryonic fibroblasts is increased compared with that in DEDD+/+ cells, which results in accelerated mitotic progression, thus exhibiting a shortened G2/M stage. Interestingly, DEDD−/− cells also demonstrated decreased G1 duration, which perhaps enhanced the overall reduction in rRNA amounts and cell volume, primarily caused by the rapid termination of rRNA synthesis before cell division. Likewise, DEDD−/− mice show decreased body and organ weights relative to DEDD+/+ mice. Thus, DEDD is an impeder of cell mitosis, and its absence critically influences cell and body size via modulation of rRNA synthesis.
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Death-Effector Domain-containing protein DEDD is an inhibitor of mitotic Cdk1/cyclin B1
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Satoko Arai, Katsuhisa Miyake, Renate Voit, Shino Nemoto, Edward K Wakeland, Ingrid Grummt, Toru MiyazakiAbstract:Accumulating evidence has shown that many molecules, including some cyclin-dependent kinases (Cdks) and cyclins, as well as the Death-Effector Domain (DED)-containing FADD, function for both apoptosis and cell cycle. Here we identified that DEDD, which also possesses the DED Domain, acts as a novel inhibitor of the mitotic Cdk1/cyclin B1 complex. DEDD associates with mitotic Cdk1/cyclin B1 complexes via direct binding to cyclin B1 and reduces their function. In agreement, kinase activity of nuclear Cdk1/cyclin B1 in DEDD-null (DEDD−/−) embryonic fibroblasts is increased compared with that in DEDD+/+ cells, which results in accelerated mitotic progression, thus exhibiting a shortened G2/M stage. Interestingly, DEDD−/− cells also demonstrated decreased G1 duration, which perhaps enhanced the overall reduction in rRNA amounts and cell volume, primarily caused by the rapid termination of rRNA synthesis before cell division. Likewise, DEDD−/− mice show decreased body and organ weights relative to DEDD+/+ mice. Thus, DEDD is an impeder of cell mitosis, and its absence critically influences cell and body size via modulation of rRNA synthesis.
Marcus E Peter - One of the best experts on this subject based on the ideXlab platform.
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Fusing DEDD with ubiquitin changes its intracellular localization and apoptotic potential
Apoptosis, 2005Co-Authors: Gary X. Wang, Olaf Schickling, Marcus E PeterAbstract:DEDD, a highly conserved and ubiquitous Death Effector Domain containing protein, exists in non, mono, and diubiquitinated forms. We previously reported that endogenous unmodified DEDD is only found in nucleoli and that mono- and diubiquitinated DEDD associate with caspase-3 in the cytosol suggesting that ubiquitination may be important to the apoptosis regulating functions of DEDD in the cytosol. We now demonstrate that many of its 16 lysine residues can serve as alternative acceptors for ubiquitination to maintain the monoubiquitination status of DEDD. A central region in DEDD (amino acids 109–305) outside the Death Effector Domain was found to be essential for ubiquitination and/or the docking of the ubiquitination machinery. Fusion of ubiquitin to the C-terminus of DEDD to mimic monoubiquitinated DEDD relocated DEDD from nucleoli to the cytosol. This fusion protein also demonstrated a greater apoptosis potential than unmodified DEDD. Finally, we show that both mono- and polyubiquitination of DEDD can be achieved by the cellular inhibitor of apoptosis proteins 1 and 2 (cIAP-1/2). In addition, the cotransfection of DEDD with cIAP-1 or cIAP-2 results in the relocalization of the IAPs to the nucleoli. Our data suggest that monoubiquitination of DEDD regulates both its cytoplasmic localization and its proapoptotic potential and that IAP proteins can regulate DEDD's ubiquitination status.
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the Death Effector Domain protein family
Oncogene, 2003Co-Authors: Bryan C Barnhart, Elizabeth C Alappat, Marcus E PeterAbstract:Apoptosis signaling is regulated and executed by specialized proteins that often carry protein/protein interaction Domains. One of these Domains is the Death Effector Domain (DED) that is predominantly found in components of the Death-inducing signaling complex, which forms at the members of the Death receptor family following their ligation. Both proapoptotic- and antiapoptotic-DED-containing proteins have been identified, which makes these proteins exquisitely suited to the regulation of apoptosis. Aside from their pivotal role in the control of the apoptotic program, DED-containing proteins have recently been demonstrated to exert their influence on other cellular processes as well, including cell proliferation. These data highlight the multiple roles for the members of this family, suggesting that they are suited to control both life and Death decisions of cells. Additionally, because they can act proapoptotically, antiapoptotically, or in the regulation of the cell cycle, this family of proteins may be excellent candidates for cancer therapy targets.
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DEDD regulates degradation of intermediate filaments during apoptosis.
Journal of Cell Biology, 2002Co-Authors: Olaf Schickling, Alexander H Stegh, Robert G. Oshima, David Dinsdale, Gerald M. Cohen, Marcus E PeterAbstract:Apoptosis depends critically on regulated cytoskeletal reorganization events in a cell. We demonstrate that Death Effector Domain containing DNA binding protein (DEDD), a highly conserved and ubiquitous Death Effector Domain containing protein, exists predominantly as mono- or diubiquitinated, and that diubiquitinated DEDD interacts with both the K8/18 intermediate filament network and pro–caspase-3. Early in apoptosis, both cytosolic DEDD and its close homologue DEDD2 formed filaments that colocalized with and depended on K8/18 and active caspase-3. Subsequently, these filamentous structures collapsed into intracellular inclusions that migrated into cytoplasmic blebs and contained DEDD, DEDD2, active caspase-3, and caspase-3–cleaved K18 late in apoptosis. Biochemical studies further confirmed that DEDD coimmunoprecipitated with both K18 and pro–caspase-3, and kinetic analyses placed apoptotic DEDD staining prior to caspase-3 activation and K18 cleavage. In addition, both caspase-3 activation and K18 cleavage was inhibited by expression of DEDDΔNLS1-3, a cytosolic form of DEDD that cannot be ubiquitinated. Finally, siRNA mediated DEDD knockdown cells exhibited inhibition of staurosporine-induced DNA degradation. Our data suggest that DEDD represents a novel scaffold protein that directs the Effector caspase-3 to certain substrates facilitating their ordered degradation during apoptosis.
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nuclear localization of dedd leads to caspase 6 activation through its Death Effector Domain and inhibition of rna polymerase i dependent transcription
Cell Death & Differentiation, 2001Co-Authors: Olaf Schickling, Alexander H Stegh, J Byrd, Marcus E PeterAbstract:Nuclear localization of DEDD leads to caspase-6 activation through its Death Effector Domain and inhibition of RNA polymerase I dependent transcription
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the Death Effector Domain associated factor plays distinct regulatory roles in the nucleus and cytoplasm
Journal of Biological Chemistry, 2001Co-Authors: Lixin Zheng, Marcus E Peter, Olaf Schickling, Michael J LenardoAbstract:Abstract Homophilic interactions of Death Effector Domains (DEDs) are crucial for the signaling pathways of Death receptor-mediated apoptosis. The machinery that regulates proper oligomerization and autoactivation of procaspase-8 and/or procaspase-10 during T lymphocyte activation determines whether the cells will undergo caspase-mediated apoptosis or proliferation. We screened a yeast two-hybrid library by using the DEDs contained in the proDomains of procaspase-8 and procaspase-10 and isolated a DED-associated factor (DEDAF) that interacts with several DED-containing proteins but does not itself contain a DED. DEDAF is highly conserved between human and mouse (98% amino acid identity) and is homologous to a nuclear regulatory protein YAF-2. DEDAF is expressed at the highest levels in lymphoid tissues and placenta. DEDAF interacts with FADD, procaspase-8, and procaspase-10 in the cytosol as well as with the DED-containing DNA-binding protein (DEDD) in the nucleus. At the cell membrane, DEDAF augmented the formation of CD95-FADD-caspase-8 complexes and enhanced Death receptor- as well as DED-mediated apoptosis. In the nucleus, DEDAF caused the DEDD protein to relocalize from subnuclear structures to a diffuse distribution in the nucleoplasm. Our data therefore suggest that DEDAF may be involved in the regulation of both cytoplasmic and nuclear events of apoptosis.
Satoko Arai - One of the best experts on this subject based on the ideXlab platform.
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Death Effector Domain containing protein dedd is required for uterine decidualization during early pregnancy in mice
Journal of Clinical Investigation, 2011Co-Authors: Mayumi Mori, Satoko Arai, Jun Kurokawa, Miwako Kitazume, Kaori Koga, Yutaka Osuga, Toru MiyazakiAbstract:During intrauterine life, the mammalian embryo survives via its physical connection to the mother. The uterine decidua, which differentiates from stromal cells after implantation in a process known as decidualization, plays essential roles in supporting embryonic growth before establishment of the placenta. Here we show that female mice lacking Death Effector Domain–containing protein (DEDD) are infertile owing to unsuccessful decidualization. In uteri of Dedd–/– mice, development of the decidual zone and the surrounding edema after embryonic implantation was defective. This was subsequently accompanied by disintegration of implantation site structure, leading to embryonic Death before placentation. Polyploidization, a hallmark of mature decidual cells, was attenuated in DEDD-deficient cells during decidualization. Such inefficient decidualization appeared to be caused by decreased Akt levels, since polyploidization was restored in DEDD-deficient decidual cells by overexpression of Akt. In addition, we showed that DEDD associates with and stabilizes cyclin D3, an important element in polyploidization, and that overexpression of cyclin D3 in DEDD-deficient cells improved polyploidization. These results indicate that DEDD is indispensable for the establishment of an adequate uterine environment to support early pregnancy in mice.
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Death Effector Domain–containing protein (DEDD) is required for uterine decidualization during early pregnancy in mice
Journal of Clinical Investigation, 2010Co-Authors: Mayumi Mori, Satoko Arai, Jun Kurokawa, Miwako Kitazume, Kaori Koga, Yutaka Osuga, Toru MiyazakiAbstract:During intrauterine life, the mammalian embryo survives via its physical connection to the mother. The uterine decidua, which differentiates from stromal cells after implantation in a process known as decidualization, plays essential roles in supporting embryonic growth before establishment of the placenta. Here we show that female mice lacking Death Effector Domain–containing protein (DEDD) are infertile owing to unsuccessful decidualization. In uteri of Dedd–/– mice, development of the decidual zone and the surrounding edema after embryonic implantation was defective. This was subsequently accompanied by disintegration of implantation site structure, leading to embryonic Death before placentation. Polyploidization, a hallmark of mature decidual cells, was attenuated in DEDD-deficient cells during decidualization. Such inefficient decidualization appeared to be caused by decreased Akt levels, since polyploidization was restored in DEDD-deficient decidual cells by overexpression of Akt. In addition, we showed that DEDD associates with and stabilizes cyclin D3, an important element in polyploidization, and that overexpression of cyclin D3 in DEDD-deficient cells improved polyploidization. These results indicate that DEDD is indispensable for the establishment of an adequate uterine environment to support early pregnancy in mice.
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the Death Effector Domain containing dedd supports s6k1 activity via preventing cdk1 dependent inhibitory phosphorylation
Journal of Biological Chemistry, 2009Co-Authors: Nobuya Kurabe, Satoko Arai, Akemi Nishijima, Naoto Kubota, Futoshi Suizu, Mayumi Mori, Jun Kurokawa, Miki Kondomiyazaki, Kouji Murakami, Katsuhisa MiyakeAbstract:Cell cycle regulation and biochemical responses upon nutrients and growth factors are the major regulatory mechanisms for cell sizing in mammals. Recently, we identified that the Death Effector Domain-containing DEDD impedes mitotic progression by inhibiting Cdk1 (cyclin-dependent kinase 1) and thus maintains an increase of cell size during the mitotic phase. Here we found that DEDD also associates with S6 kinase 1 (S6K1), downstream of phosphatidylinositol 3-kinase, and supports its activity by preventing inhibitory phosphorylation of S6K1 brought about by Cdk1 during the mitotic phase. DEDD-/- cells showed reduced S6K1 activity, consistently demonstrating decreased levels in activating phosphorylation at the Thr-389 site. In addition, levels of Cdk1-dependent inhibitory phosphorylation at the C terminus of S6K1 were enhanced in DEDD-/- cells and tissues. Consequently, as in S6K1-/- mice, the insulin mass within pancreatic islets was reduced in DEDD-/- mice, resulting in glucose intolerance. These findings suggest a novel cell sizing mechanism achieved by DEDD through the maintenance of S6K1 activity prior to cell division. Our results also suggest that DEDD may harbor important roles in glucose homeostasis and that its deficiency might be involved in the pathogenesis of type 2 diabetes mellitus.
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Death Effector Domain containing protein dedd is an inhibitor of mitotic cdk1 cyclin b1
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Satoko Arai, Katsuhisa Miyake, Renate Voit, Shino Nemoto, Edward K Wakeland, Ingrid Grummt, Toru MiyazakiAbstract:Accumulating evidence has shown that many molecules, including some cyclin-dependent kinases (Cdks) and cyclins, as well as the Death-Effector Domain (DED)-containing FADD, function for both apoptosis and cell cycle. Here we identified that DEDD, which also possesses the DED Domain, acts as a novel inhibitor of the mitotic Cdk1/cyclin B1 complex. DEDD associates with mitotic Cdk1/cyclin B1 complexes via direct binding to cyclin B1 and reduces their function. In agreement, kinase activity of nuclear Cdk1/cyclin B1 in DEDD-null (DEDD−/−) embryonic fibroblasts is increased compared with that in DEDD+/+ cells, which results in accelerated mitotic progression, thus exhibiting a shortened G2/M stage. Interestingly, DEDD−/− cells also demonstrated decreased G1 duration, which perhaps enhanced the overall reduction in rRNA amounts and cell volume, primarily caused by the rapid termination of rRNA synthesis before cell division. Likewise, DEDD−/− mice show decreased body and organ weights relative to DEDD+/+ mice. Thus, DEDD is an impeder of cell mitosis, and its absence critically influences cell and body size via modulation of rRNA synthesis.
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Death-Effector Domain-containing protein DEDD is an inhibitor of mitotic Cdk1/cyclin B1
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Satoko Arai, Katsuhisa Miyake, Renate Voit, Shino Nemoto, Edward K Wakeland, Ingrid Grummt, Toru MiyazakiAbstract:Accumulating evidence has shown that many molecules, including some cyclin-dependent kinases (Cdks) and cyclins, as well as the Death-Effector Domain (DED)-containing FADD, function for both apoptosis and cell cycle. Here we identified that DEDD, which also possesses the DED Domain, acts as a novel inhibitor of the mitotic Cdk1/cyclin B1 complex. DEDD associates with mitotic Cdk1/cyclin B1 complexes via direct binding to cyclin B1 and reduces their function. In agreement, kinase activity of nuclear Cdk1/cyclin B1 in DEDD-null (DEDD−/−) embryonic fibroblasts is increased compared with that in DEDD+/+ cells, which results in accelerated mitotic progression, thus exhibiting a shortened G2/M stage. Interestingly, DEDD−/− cells also demonstrated decreased G1 duration, which perhaps enhanced the overall reduction in rRNA amounts and cell volume, primarily caused by the rapid termination of rRNA synthesis before cell division. Likewise, DEDD−/− mice show decreased body and organ weights relative to DEDD+/+ mice. Thus, DEDD is an impeder of cell mitosis, and its absence critically influences cell and body size via modulation of rRNA synthesis.
