Showing papers by "Ken-ichi Isobe published in 2007"
TL;DR: It is found that Abeta1-42 induces a high level of MMP3, MMP12 and MMP13 in the microglia, and the signal transduction pathway for the expression of these MMPs mRNA induced by Abeta 1-42 depends on PI3K/Akt.
78 citations
TL;DR: It is demonstrated that crosstalk between GADD34 and the mTOR signaling pathways contributes to the response of the protein synthetic machinery to environmental stress and may find clinical potential as a target drug for the treatment of mTOR-associated diseases.
Abstract: Cells regulate the rate of protein synthesis during conditions of cell stress to adapt to environmental changes. However, the molecular interactions between signaling pathways controlling translation and the cellular response to stress remain to be elucidated. Here, we show that the expression of growth arrest and DNA damage protein 34 (GADD34) is induced by energy depletion and that the expression of this protein protects cells from apoptotic cell death. During conditions of cell stress, GADD34 forms a stable complex with tuberous sclerosis complex (TSC) 1/2, causes TSC2 dephosphorylation, and inhibits signaling by mammalian target of the rapamycin (mTOR). These findings demonstrate that crosstalk between GADD34 and the mTOR signaling pathways contributes to the response of the protein synthetic machinery to environmental stress. GADD34 may find clinical potential as a target drug for the treatment of mTOR-associated diseases.
46 citations
TL;DR: GADD34 induced by vesicular stomatitis virus infection suppresses viral replication via mTOR pathway inhibition, indicating that cross talk between stress-inducible GADD34 and the mTOR signaling pathway plays a critical role in antiviral defense.
Abstract: GADD34 is a protein that is induced by a variety of stressors, including DNA damage, heat shock, nutrient deprivation, energy depletion, and endoplasmic reticulum stress. Here, we demonstrated that GADD34 induced by vesicular stomatitis virus (VSV) infection suppressed viral replication in wild-type (WT) mouse embryo fibroblasts (MEFs), whereas replication was enhanced in GADD34-deficient (GADD34-KO) MEFs. Enhanced viral replication in GADD34-KO MEFs was reduced by retroviral gene rescue of GADD34. The level of VSV protein expression in GADD34-KO MEFs was significantly higher than that in WT MEFs. Neither phosphorylation of eIF2α nor cellular protein synthesis was correlated with viral replication in GADD34-KO MEFs. On the other hand, phosphorylation of S6 and 4EBP1, proteins downstream of mTOR, was suppressed by VSV infection in WT MEFs but not in GADD34-KO MEFs. GADD34 was able to associate with TSC1/2 and dephosphorylate TSC2 at Thr1462. VSV replication was higher in TSC2-null cells than in TSC2-expressing cells, and constitutively active Akt enhanced VSV replication. On the other hand, rapamycin, an mTOR inhibitor, significantly suppressed VSV replication in GADD34-KO MEFs. These findings demonstrate that GADD34 induced by VSV infection suppresses viral replication via mTOR pathway inhibition, indicating that cross talk between stress-inducible GADD34 and the mTOR signaling pathway plays a critical role in antiviral defense.
36 citations
TL;DR: It is found that transduction of 7EJ-Ras cells with a retroviral vector expressing GADD34 suppressed their proliferation, and that it suppresses cellular proliferation through the induction of cellular senescence.
Abstract: We previously identified GADD34 (growth arrest and DNA damage protein 34) by screening for genes involved in oncogenic-transformation and/or cellular senescence in Ras-transformed rat F2408 fibroblasts (7EJ-Ras), which exhibit anchorage-independent growth and do not senesce. In the current study, we found that transduction of 7EJ-Ras cells with a retroviral vector expressing GADD34 suppressed their proliferation. Furthermore, we observed that fibroblasts derived from GADD34-knockout mice (GADD34-KO MEFs) did not undergo senescence. Whereas the expression of p21 was decreased in GADD34 KO MEFs, its expression was rescued in these cells by ectopic expression of GADD34 by retroviral transduction. These findings suggest that GADD34 contributes to the regulation of p21 expression, and that it suppresses cellular proliferation through the induction of cellular senescence.
10 citations
TL;DR: The findings imply that telomerase activity has a definitive impact on the type I allergic response by altering the character of effecter mast cells.
Abstract: Telomerase is critically important for the maintenance of a constant telomere length, which in turn, is related to the concepts of longev- ity and oncogenesis. In addition, it has been well documented that telomerase activity is expressed in immune cells in a highly regulated manner. We have studied systemic anaphylaxis in mouse telom- erase reverse transcriptase knockout (mTERT / ) mice to understand the significance of telomerase activity and telomere stability in mast cells, which induce a type I allergic response. Compared with wild-type mice, mTERT / mice displayed largely attenuated, IgE-mediated, passive anaphylactic re- sponses, which were observed even in the early generations of mTERT / mice, and had de- creased numbers of mast cells in vivo and impaired development of bone marrow-derived mast cells (BMMCs) induced by IL-3 or stem cell factor in vitro. Moreover, in mTERT / mice, BMMCs ex- hibited a large morphology and low proliferation rate, while they possessed a comparable degranu- lation capacity and cell surface expression level of c-kit and FcRI. These findings imply that telo- merase activity has a definitive impact on the type I allergic response by altering the character of effecter mast cells. J. Leukoc. Biol. 82: 429-435; 2007.
8 citations
TL;DR: Age-dependent changes in dopaminergic innervation of the neostriatum of rats suggest that DA neurons exhibit increased axonal branching in the aged brain.
6 citations