Details of a Researcher - Yoshimura, Akihiko

Papers - Yoshimura, Akihiko

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HTLV-1 Tax-mediated TAK1 activation involves TAB2 adapter protein

Yu Qingsheng, Minoda Yasumasa, Yoshida Ryoko, Yoshida Hideyuki, Iha Hidekatsu, Kobayashi Takashi, Yoshimura Akihiko, Takaesu Giichi

Biochemical and Biophysical Research Communications 365 ( 1 ) 189 - 194 2008.01

ISSN 0006-291X

Human T cell leukemia virus type 1 (HTLV-1) Tax is an oncoprotein that plays a crucial role in the proliferation and transformation of HTLV-1-infected T lymphocytes. It has recently been reported that Tax activates a MAPKKK family, TAK1. However, the molecular mechanism of Tax-mediated TAK1 activation is not well understood. In this report, we investigated the role of TAK1-binding protein 2 (TAB2) in Tax-mediated TAK1 activation. We found that TAB2 physically interacts with Tax and augments Tax-induced NF-κB activity. Tax and TAB2 cooperatively activate TAK1 when they are coexpressed. Furthermore, TAK1 activation by Tax requires TAB2 binding as well as ubiquitination of Tax. We also found that the overexpression of TRAF2, 5, or 6 strongly induces Tax ubiquitination. These results suggest that TAB2 may be critically involved in Tax-mediated activation of TAK1 and that NF-κB-activating TRAF family proteins are potential cellular E3 ubiquitin ligases toward Tax. © 2007 Elsevier Inc. All rights reserved.

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Prostaglandin E₂ is a major soluble factor produced by stromal cells for preventing inflammatory cytokine production from dendritic cells

Shiraishi Hiroshi, Yoshida Hideyuki, Saeki Kazuko, Miura Yoshiki, Watanabe Satoko, Ishizaki Takuma, Hashimoto Masayuki, Takaesu Giichi, Kobayashi Takashi, Yoshimura Akihiko

International Immunology 20 ( 9 ) 1219 - 1229 2008

ISSN 0953-8178

Dendritic cells (DCs) are specialized antigen-presenting cells that play pivotal roles in initiating immune responses. However, DC maturation is usually strongly restricted by the stromal microenvironment, especially in non-lymphoid tissues, such as skin and mucosa. Although suppression of DC maturation by stromal cells has been well documented, the molecular basis of this suppression has not been established. In this study, we examined the role of fibroblasts for DC maturation in vitro. The mouse embryonic fibroblasts (MEFs) strongly suppressed LPS-induced DC maturation. Although suppression of class II MHC and CD40 required DC-MEF contact, soluble factors in the culture supernatant of MEFs were sufficient for the suppression of IL-12 and tumor necrosis factor-α production. Using molecular-size selection and HPLC, we determined that prostaglandin E₂ (PGE₂) is a major soluble inhibitory factor secreted by MEFs. This was confirmed by the fact that cyclooxygenase inhibitors inhibited the production of the suppressive factor by MEFs. These results suggest that PGE₂ is a major soluble factor produced by MEFs for the suppression of inflammatory cytokine production from DCs, while a contact mechanism between MEFs and DCs is required for the suppression to induce T cell-stimulating molecules. © The Japanese Society for Immunology. 2008. All rights reserved.

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SOCS3 Protein Developmentally Regulates the Chemokine Receptor CXCR4-FAK Signaling Pathway during B Lymphopoiesis

Le Yi, Zhu Bing Mei, Harley Brendan, Park Shin Young, Kobayashi Takashi, Manis John P., Luo Hongbo R., Yoshimura Akihiko, Hennighausen Lothar, Silberstein Leslie E.

Immunity 27 ( 5 ) 811 - 823 2007.11

ISSN 1074-7613

The chemokine CXCL12 induces prolonged focal adhesion kinase (FAK) phosphorylation and sustained proadhesive responses in progenitor bone-marrow (BM) B cells, but not in mature peripheral B cells. Here we demonstrate that suppressor of cytokine signaling 3 (SOCS3) regulated CXCL12-induced FAK phosphorylation through the ubiquitin-proteasome pathway. CXCL12 triggered increased FAK ubiquitination in mature B cells, but not in progenitor B cells. Accordingly, SOCS3 expression was low in progenitor B cells, increased in immature B cells, and highest in mature B cells. SOCS3 overexpression in pro-B cells impaired CXCL12-induced FAK phosphorylation and proadhesive responses. Conversely, SOCS3-deficient mature B cells from Cre^MMTVSocs3^fl/fl mice exhibited prolonged FAK phosphorylation and adhesion to VCAM-1. In contrast to wild-type mice, Cre^MMTVSocs3^fl/fl mice had a 2-fold increase in immature B cells, which were evenly distributed in endosteal and perisinusoidal BM compartments. We propose that the developmental regulation of CXCR4-FAK signaling by SOCS3 is an important mechanism to control the lodgement of B cell precursors in the BM microenvironment. © 2007 Elsevier Inc. All rights reserved.

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Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype

Brems Hilde, Chmara Magdalena, Sahbatou Mourad, Denayer Ellen, Taniguchi Koji, Kato Reiko, Somers Riet, Messiaen Ludwine, De Schepper Sofie, Fryns Jean Pierre, Cools Jan, Marynen Peter, Thomas Gilles, Yoshimura Akihiko, Legius Eric

Nature Genetics 39 ( 9 ) 1120 - 1126 2007.09

ISSN 1061-4036

We report germline loss-of-function mutations in SPRED1 in a newly identified autosomal dominant human disorder. SPRED1 is a member of the SPROUTY/SPRED family of proteins that act as negative regulators of RAS->RAF interaction and mitogen-activated protein kinase (MAPK) signaling. The clinical features of the reported disorder resemble those of neurofibromatosis type 1 and consist of multiple café-au-lait spots, axillary freckling and macrocephaly. Melanocytes from a café-au-lait spot showed, in addition to the germline SPRED1 mutation, an acquired somatic mutation in the wild-type SPRED1 allele, indicating that complete SPRED1 inactivation is needed to generate a café-au-lait spot in this syndrome. This disorder is yet another member of the recently characterized group of phenotypically overlapping syndromes caused by mutations in the genes encoding key components of the RAS-MAPK pathway. To our knowledge, this is the first report of mutations in the SPRY (SPROUTY)/SPRED family of genes in human disease. © 2007 Nature Publishing Group.

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Signal-transducing adaptor protein-2 regulates integrin-mediated T cell adhesion through protein degradation of focal adhesion kinase

Sekine Yuichi, Tsuji Satoshi, Ikeda Osamu, Sugiyma Kenji, Oritani Kenji, Shimoda Kazuya, Muromoto Ryuta, Ohbayashi Norihiko, Yoshimura Akihiko, Matsuda Tadashi

Journal of Immunology 179 ( 4 ) 2397 - 2407 2007.08

ISSN 0022-1767

Signal-transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that contains pleckstrin homology- and Src homology 2-like domains as well as a YXXQ motif in its C-terminal region. Our previous studies demonstrated that STAP-2 binds to STAT3 and STAT5, and regulates their signaling pathways. In the present study, we find that STAP-2-deficient splenocytes or T cells exhibit enhanced cell adhesion to fibronectin after PMA treatment, and that STAP-2-deficient T cells contain the increased protein contents of focal adhesion kinase (FAK). Furthermore, overexpression of STAP-2 induces a dramatic decrease in the protein contents of FAK and integrin-mediated T cell adhesion to fibronectin in Jurkat T cells via the degradation of FAK. Regarding the mechanism for this effect, we found that STAP-2 associates with FAK and enhances its degradation, proteasome inhibitors block FAK degradation, and STAP-2 recruits an endogenous E3 ubiquitin ligase, Cbl, to FAK. These results reveal a novel regulation mechanism for integrin-mediated signaling in T cells via STAP-2, which directly interacts with and degrades FAK. Copyright © 2007 by The American Association of Immunologists, Inc.

Selective expansion of Foxp3-positive regulatory T cells and immunosuppression by suppressors of cytokine signaling 3-deficient dendritic cells

Matsumura Yumiko, Kobayashi Takashi, Ichiyama Kenji, Yoshida Ryoko, Hashimoto Masayuki, Takimoto Tomohito, Tanaka Kentaro, Chinen Takatoshi, Shichita Takashi, Wyss-Coray Tony, Sato Katsuaki, Yoshimura Akihiko

Journal of Immunology 179 ( 4 ) 2170 - 2179 2007.08

ISSN 0022-1767

Dendritic cells (DCs) induce immunity and immunological tolerance as APCs. It has been shown that DCs secreting IL-10 induce IL-10⁺ Tr1-type regulatory T (Treg) cells, whereas Foxp3-positive Treg cells are expanded from naive CD4⁺ T cells by coculturing with mature DCs. However, the regulatory mechanism of expansion of Foxp3⁺ Treg cells by DCs has not been clarified. In this study, we demonstrated that suppressors of cytokine signaling (SOCS)-3-deficient DCs have a strong potential as Foxp3⁺ T cell-inducing tolerogenic DCs. SOCS3^-/- DCs expressed lower levels of class II MHC, CD40, CD86, and IL-12 than wild-type (WT)-DCs both in vitro and in vivo, and showed constitutive activation of STAT3. Foxp3^- effector T cells were predominantly expanded by the priming with WT-DCs, whereas Foxp3⁺ Treg cells were selectively expanded by SOCS3^-/- DCs. Adoptive transfer of SOCS3^-/- DCs reduced the severity of experimental autoimmune encephalomyelitis. Foxp3⁺ T cell expansion was blocked by anti-TGF-β Ab, and SOCS3^-/- DCs produced higher levels of TGF-β than WT-DCs, suggesting that TGF-β plays an essential role in the expansion of Foxp3⁺ Treg cells. These results indicate an important role of SOCS3 in determining on immunity or tolerance by DCs. Copyright © 2007 by The American Association of Immunologists, Inc.

Suppression of SOCS3 expression in the pancreatic β-cell leads to resistance to type 1 diabetes

Mori Hiroyuki, Shichita Takashi, Yu Qingsheng, Yoshida Ryoko, Hashimoto Masayuki, Okamoto Fuyuki, Torisu Takahiro, Nakaya Mako, Kobayashi Takashi, Takaesu Giichi, Yoshimura Akihiko

Biochemical and Biophysical Research Communications 359 ( 4 ) 952 - 958 2007.08

ISSN 0006-291X

Type 1 diabetes results from the selective destruction of insulin-producing pancreatic β-cells during islet inflammation, which involves inflammatory cytokines and free radicals. However, mechanisms for protecting β-cells from destruction have not been clarified. In this study, we define the role of SOCS3 on β-cell destruction using β-cell-specific SOCS3-conditional knockout (cKO) mice. The β-cell-specific SOCS3-deficient mice were resistant to the development of diabetes caused by streptozotocin (STZ), a genotoxic methylating agent, which has been used to trigger β-cell destruction. The islets from cKO mice demonstrated hyperactivation of STAT3 and higher induction of Bcl-xL than did islets from WT mice, and SOCS3-deficient β-cells were more resistant to apoptosis induced by STZ in vitro than were WT β-cells. These results suggest that enhanced STAT3 signaling protects β-cells from destruction induced by a genotoxic stress and that STAT3/SOCS3 can be a potential therapeutic target for the treatment of type 1 diabetes. © 2007 Elsevier Inc. All rights reserved.

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Ifi202, an IFN-inducible candidate gene for lupus susceptibility in NZB/ W F1 mice, is a positive regulator for NF-κB activation in dendritic cells

Yamauchi Moriyasu, Hashimoto Masayuki, Ichiyama Kenji, Yoshida Ryoko, Hanada Toshikatsu, Muta Tatsushi, Komune Shizuo, Kobayashi Takashi, Yoshimura Akihiko

International Immunology 19 ( 8 ) 935 - 942 2007.08

ISSN 0953-8178

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies and lupus nephritis. The [New Zealand black (NZB) × New Zealand white (NZW)]F1 (BWF1) mouse has been recognized as an important animal model of human SLE. The T_h1-prone phenotype of BWF1 mice has been shown to contribute to the development of the lupus. However, the molecular basis for T_h1 skewing in BWF1 mice has not been clarified. We noticed that IL-6, IL-12 and other proinflammatory cytokines as well as IκB-ζ induction were higher in mature bone marrow-derived dendritic cells (BMDCs) from NZB and BWF1 mice than those from NZW mice. The expression of an IFN-inducible gene Ifi202, a candidate gene for lupus, was almost undetectable in NZW BMDCs. Thus, we hypothesized that Ifi202 is involved in elevated IL-12 production from BWF1 BMDCs. Overexpression of Ifi202 enhanced the LPS-induced IκB-ζ, IL-12p40 and NF-κB promoter activities, while anti-sense (AS) RNA against Ifi202 strongly suppressed them in a monocytic cell line, RAW 264.7. Furthermore, overexpression of Ifi202 enhanced LPS-induced IL-12p40 and IκB-ζ mRNA induction while Ifi202 AS RNA suppressed these in RAW 264.7 cells. In addition, forced expression of Ifi202 enhanced IL-12p40 mRNA induction in NZW BMDCs. Thus, Ifi202 is an important NF-κB activator in DCs and involved in IL-12 production, which may account for a T_h1-prone phenotype of BWF1 mice. © The Japanese Society for Immunology. 2007. All rights reserved.

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STAP-2 regulates c-Fms/M-CSF receptor signaling in murine macrophage Raw 264.7 cells

Ikeda Osamu, Sekine Yuichi, Kakisaka Michinori, Tsuji Satoshi, Muromoto Ryuta, Ohbayashi Norihiko, Oritani Kenji, Yoshimura Akihiko, Matsuda Tadashi

Biochemical and Biophysical Research Communications 358 ( 3 ) 931 - 937 2007.07

ISSN 0006-291X

Signal-transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein as a c-Fms/M-CSF receptor-interacting protein and constitutively expressed in macrophages. Our previous studies also revealed that STAP-2 binds to MyD88 and IKK-α/β, and modulates NF-κB signaling in macrophages. In the present study, we examined physiological roles of the interaction between STAP-2 and c-Fms in Raw 264.7 macrophage cells. Our immunoprecipitation has revealed that c-Fms directly interacts with the PH domain of STAP-2 independently on M-CSF-stimulation. Ectopic expression of STAP-2 markedly suppressed M-CSF-induced tyrosine phosphorylation of c-Fms as well as activation of Akt and extracellular signal regulated kinase. In addition, Raw 264.7 cells over-expressing STAP-2 showed impaired migration in response to M-CSF and wound-healing process. Taken together, our findings demonstrate that STAP-2 directly binds to c-Fms and interferes with the PI3K signaling, which leads to macrophage motility, in Raw 264.7 cells. © 2007 Elsevier Inc. All rights reserved.

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Potentiation of astrogliogenesis by STAT3-mediated activation of bone morphogenetic protein-Smad signaling in neural stem cells

Fukuda Shinji, Abematsu Masahiko, Mori Hiroyuki, Yanagisawa Makoto, Kagawa Tetsushi, Nakashima Kinichi, Yoshimura Akihiko, Taga Tetsuya

Molecular and Cellular Biology 27 ( 13 ) 4931 - 4937 2007.07

ISSN 0270-7306

Astrocytes play important roles in brain development and injury response. Transcription factors STAT3 and Smadl, activated by leukemia inhibitory factor (LIF) and bone morphogenetic protein 2 (BMP2), respectively, form a complex with the coactivator p300 to synergistically induce astrocytes from neuroepithelial cells (NECs) (K. Nakashima, M. Yanagisawa, H. Arakawa, N. Kimura, T. Hisatsune, M. Kawabata, K. Miyazono, and T. Taga, Science 284:479-482, 1999). However, the mechanisms that govern astrogliogenesis during the determination of the fate of neural stem cells remain elusive. Here we found that LIF induces expression of BMP2 via STAT3 activation and leads to the consequent activation of Smad1 to efficiently promote astrogliogenic differentiation of NECs. The BMP antagonist Noggin abrogated LIF-induced Smadl activation and astrogliogenesis by inhibiting BMPs produced by NECs. NECs deficient in suppressor of cytokine signaling 3 (SOCS3), a negative regulator of STAT3, readily differentiated into astrocytes upon activation by LIF not only due to sustained activation of STAT3 but also because of the consequent activation of Smadl. Our study suggests a novel LIF-triggered positive regulatory loop that enhances astrogliogenesis. Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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Intracellular negative signals and allergy

Yoshimura Akihiko, Tanaka Kentaro, Okamoto Fuyuki, Kobayashi Takashi

Arerugī = [Allergy] 56 ( 6 ) 563 - 569 2007.06

ISSN 0021-4884

SOCS proteins, cytokine signalling and immune regulation

Yoshimura Akihiko, Naka Tetsuji, Kubo Masato

Nature Reviews Immunology 7 ( 6 ) 454 - 465 2007.06

ISSN 1474-1733

Suppressor of cytokine signalling (SOCS) proteins are inhibitors of cytokine signalling pathways. Studies have shown that SOCS proteins are key physiological regulators of both innate and adaptive immunity. These molecules positively and negatively regulate macrophage and dendritic-cell activation and are essential for T-cell development and differentiation. Evidence is also emerging of the involvement of SOCS proteins in diseases of the immune system. In this Review we bring together data from recent studies on SOCS proteins and their role in immunity, and propose a cohesive model of how cytokine signalling regulates immune-cell function. © 2007 Nature Publishing Group.

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Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling

Taniguchi Koji, Kohno Ri Ichiro, Ayada Toranoshin, Kato Reiko, Ichiyama Kenji, Morisada Tohru, Oike Yuichi, Yonemitsu Yoshikazu, Maehara Yoshihiko, Yoshimura Akihiko

Molecular and Cellular Biology 27 ( 12 ) 4541 - 4550 2007.06

ISSN 0270-7306

Spred/Sprouty family proteins negatively regulate growth factor-induced ERK activation. Although the individual physiological roles of Spred-1 and Spred-2 have been investigated using gene-disrupted mice, the overlapping functions of Spred-1 and Spred-2 have not been clarified. Here, we demonstrate that the deletion of both Spred-1 and Spred-2 resulted in embryonic lethality at embryonic days 12.5 to 15.5 with marked subcutaneous hemorrhage, edema, and dilated lymphatic vessels filled with erythrocytes. This phenotype resembled that of Syk^-/- and SLP-76^-/- mice with defects in the separation of lymphatic vessels from blood vessels. The number of LYVE-1-positive lymphatic vessels and lymphatic endothelial cells increased markedly in Spred-1/2-deficient embryos compared with WT embryos, while the number of blood vessels was not different. Ex vivo colony assay revealed that Spred-1/2 suppressed lymphatic endothelial cell proliferation and/or differentiation. In cultured cells, the overexpression of Spred-1 or Spred-2 strongly suppressed vascular endothelial growth factor-C (VEGF-C)/VEGF receptor (VEGFR)-3-mediated ERK activation, while Spred-1/2-deficient cells were extremely sensitive to VEGFR-3 signaling. These data suggest that Spreds play an important role in lymphatic vessel development by negatively regulating VEGF-C/VEGFR-3 signaling. Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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Robustness of the signal transduction system of the mammalian JAK/STAT pathway and dimerization steps

Shudo Emi, Yang Jin, Yoshimura Akihiko, Iwasa Yoh

Journal of Theoretical Biology 246 ( 1 ) 1 - 9 2007.05

ISSN 0022-5193

In the interferon-γ (IFNγ)-activated Janus Kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) pathway, multiple steps of STAT1 dimerization are required prior to gene expression that produce antiviral molecules. By interpreting experimental results, an existing mathematical model suggested that only phosphorylated STAT1 dimers could translocate to the nucleus and activate gene transcription. In this paper, we examine the role of STAT1 dimerization steps by studying the dynamic behaviors of four alternative models. By analyzing several system properties at low input IFNγ signal including the steady-state antiviral molecule production, to the input, the delay of responses triggered by input, and the parameter sensitivity, we found that the mice JAK/STAT1 system identified by experiments (1) suppresses antiviral molecule production at low input signal, (2) has slow kinetics of antiviral molecule production and (3) has low parameter sensitivity of antiviral molecule production at steady state. We conclude that the observed structure of the JAK/STAT1 pathway is responsible for the robust system behavior. © 2007 Elsevier Ltd. All rights reserved.

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Leukemia inhibitory factor-induced phosphorylation of STAP-2 on tyrosine-250 is involved in its STAT3-enhancing activity

Sekine Yuichi, Tsuji Satoshi, Ikeda Osamu, Kakisaka Michinori, Sugiyama Kenji, Yoshimura Akihiko, Matsuda Tadashi

Biochemical and Biophysical Research Communications 356 ( 2 ) 517 - 522 2007.05

ISSN 0006-291X

Signal transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that contains Pleckstrin and Src homology 2 (SH2)-like domains as well as a YXXQ motif in its C-terminal region. Our previous studies revealed that STAP-2 binds to signal transducer and activator of transcription 3 (STAT3) and STAT5, and regulates their signaling pathways. In the present study, we identified tyrosine-250 (Tyr250) in STAP-2 as a major site of phosphorylation by v-src and Jak2, using a phospho-specific antibody against STAP-2 phosphorylated at Tyr250. Mutational analyses revealed that Tyr250 was involved in the STAT3-enhancing activity of STAP-2. We further found that leukemia inhibitory factor (LIF) stimulated STAP-2 Tyr250 phosphorylation in 293T and Hep3B cells. Moreover, endogenous STAP-2 was phosphorylated at Tyr250 following LIF stimulation of murine M1 cell line. Taken together, our findings demonstrate that endogenous STAP-2 is phosphorylated at Tyr250 and that this phosphorylation is involved in its function. © 2007 Elsevier Inc. All rights reserved.

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An RNA-binding protein αCP-1 is involved in the STAT3-mediated suppression of NF-κB transcriptional activity

Nishinakamura Hitomi, Minoda Yasumasa, Saeki Kazuko, Koga Keiko, Takaesu Giichi, Onodera Masafumi, Yoshimura Akihiko, Kobayashi Takashi

International Immunology 19 ( 5 ) 609 - 619 2007.05

ISSN 0953-8178

Signal transducer and activator of transcription 3 (STAT3) has been shown to mediate the anti-inflammatory effect of IL-10. Activated STAT3 suppresses LPS-induced IL-6, tumor necrosis factor-α and IL-12 gene expression in macrophages and dendritic cells. However, the mechanism of Toll-like receptor (TLR) signal suppression by STAT3 has not been clarified. In this study, we investigated the effect of constitutively activated STAT3 (STAT3C) on LPS-induced nuclear factor-κB (NF-κB) activation. The forced expression of STAT3C in HEK293/TLR4 cells, but neither wild-type STAT3 nor dominant-negative form of STAT3, suppressed LPS-TLR4-mediated NF-κB reporter activation. The over-expression of STAT3C did not affect the signal transduction of TLR4, such as the phosphorylation of inhibitory nuclear factor-κBα and mitogen-activated protein kinases and the DNA-binding activity of NF-κB. Thus, STAT3C could suppress the transcriptional and/or translational activity of NF-κB. To define the molecular mechanism, we searched STAT3C-binding proteins by using a proteomic approach and found that a novel RNA-binding protein, αCP-1, interacted with STAT3C. αCP-1 is a K-homology domain-containing RNA-binding protein with specificity for C-rich pyrimidine tracts. Such proteins play pivotal roles in a broad-spectrum of transcriptional and translational events. The over-expression of αCP-1 augmented the suppressive effect of STAT3C on NF-κB activation in HEK293/TLR4 cells. Furthermore, the forced expression of αCP-1 enhanced the antagonistic effect of IL-10 on IL-6 production in RAW264.7 cells, while small interfering RNA against αCP-1 reduced it. These data suggest that αCP-1 is involved in the STAT3-mediated suppression of NF-κB activity. © The Japanese Society for Immunology. 2007. All rights reserved.

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Adaptor protein SH2-B linking receptor-tyrosine kinase and Akt promotes adipocyte differentiation by regulating peroxisome proliferator-activated receptor γ messenger ribonucleic acid levels

Yoshiga Daigo, Sato Naoichi, Torisu Takehiro, Mori Hiroyuki, Yoshida Ryoko, Nakamura Seiji, Takaesu Giichi, Kobayashi Takashi, Yoshimura Akihiko

Molecular Endocrinology 21 ( 5 ) 1120 - 1131 2007.05

ISSN 0888-8809

Adipocyte differentiation is regulated by insulin and IGF-I, which transmit signals by activating their receptor tyrosine kinase. SH2-B is an adaptor protein containing pleckstrin homology and Src homology 2 (SH2) domains that have been implicated in insulin and IGF-I receptor signaling. In this study, we found a strong link between SH2-B levels and adipogenesis. The fat mass and expression of adipogenic genes including peroxisome proliferator-activated receptor γ (PPARγ) were reduced in white adipose tissue of SH2-B^-/- mice. Reduced adipocyte differentiation of SH2-B-deficient mouse embryonic fibroblasts (MEFs) was observed in response to insulin and dexamethasone, whereas retroviral SH2-B overexpression enhanced differentiation of 3T3-L1 preadipocytes to adipocytes. SH2-B overexpression enhanced mRNA level of PPARγ in 3T3-L1 cells, whereas PPARγ levels were reduced in SH2-B-deficient MEFs in response to insulin. SH2-B-mediated up-regulation of PPARγ mRNA was blocked by a phosphatidylinositol 3-kinase inhibitor, but not by a MAPK kinase inhibitor. Insulin-induced Akt activation and the phosphorylation of forkhead transcription factor (FKHR/Foxo1), a negative regulator of PPARγ transcription, were up-regulated by SH2-B overexpression, but reduced in SH2-B-deficeint MEFs. These data indicate that SH2-B is a key regulator of adipogenesis both in vivo and in vitro by regulating the insulin/IGF-I receptor-Akt-Foxo1-PPARγ pathway. Copyright © 2007 by The Endocrine Society.

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Reciprocal regulation of SOCS1 and SOCS3 enhances resistance to ionizing radiation in glioblastoma multiforme

Zhou Hong, Miki Rika, Eeva Mervi, Fike Francesca M., Seligson David, Yang Lu, Yoshimura Akihiko, Teitell Michael A., Jamieson Christina A M, Cacalano Nicholas A.

Clinical Cancer Research 13 ( 8 ) 2344 - 2353 2007.04

ISSN 1078-0432

Purpose: The expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3 genes is dysregulated in several solid tumors, causing aberrant activation of cell growth and survival signaling pathways. In this study, we analyzed SOCS1 and SOCS3 gene expression in glioblastoma multiforme (GBM) and studied the role of each protein in GBM cell signaling and radiation resistance. Experimental Design: SOCS1 and SOCS3 gene expression was analyzed in 10 GBM cell lines by reverse transcription-PCR and Western blotting. SOCS3 expression was also studied in 12 primary GBM tissues by immunohistochemistry. The methylation status of the SOCS1 and SOCS3 loci was determined by methylation-specific PCR. Extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) activation in GBM cell lines overexpressing SOCS1 or lacking SOCS3 was determined by phosphorylated-specific Western blotting. Radiation responses in SOCS1-positive and SOCS3-deficient GBM cell lines and fibroblasts from wild-type and SOCS1 or SOCS3 knockout mice were studied in a clonogenic survival assay. Results: All GBM cell lines tested lacked SOCS1 expression, whereas GBM cell lines and primary GBM tumor samples constitutively expressed SOCS3. SOCS1 gene repression was linked to hypermethylation of the SOCS1 genetic locus in GBM cells. Reintroduction of SOCS1 or blocking SOCS3 expression sensitized cells to radiation and decreased the levels of activated ERK MAPKs in GBM cells. Conclusions: SOCS1 and SOCS3 are aberrantly expressed in GBM cell lines and primary tissues. Altered SOCS gene expression leads to increased cell signaling through the ERK-MAPK pathway and may play a role in disease pathogenesis by enhancing GBM radioresistance. © 2007 American Association for Cancer Research.

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SOCS3 is required to temporally fine-tune photoreceptor cell differentiation

Ozawa Yoko, Nakao Keiko, Shimazaki Takuya, Shimmura Shigeto, Kurihara Toshihide, Ishida Susumu, Yoshimura Akihiko, Tsubota Kazuo, Okano Hideyuki

Developmental Biology 303 ( 2 ) 591 - 600 2007.03

ISSN 0012-1606

Suppressor of cytokine signaling 3 (SOCS3) is an intracellular, ligand-induced negative feedback modulator of STAT3 activation that acts during inflammation. Here, we demonstrate that SOCS3 expression is important for normal retinal development in the perinatal period. STAT3 is highly activated in the late-embryonic retina, then downregulated at postnatal day 0 (P0), presumably by the depletion of upstream ligands. We found that SOCS3 was required after P0 to shut down the residual STAT3 activation; this loss of activated STAT3 leads to Rhodopsin expression and rod photoreceptor cell differentiation. SOCS3 deficiency failed to terminate STAT3 activation, thereby delaying expression of Rhodopsin and its upstream transcription factor, crx. Development subsequently continued, but its course was temporally erratic, probably because of faulty compensation. Interestingly, SOCS3 protein expression was first detected postnatally, after STAT3 activation was mostly downregulated. It initially appeared in some of the presumptive photoreceptor cells and gradually spread. SOCS3 mRNA level was constant from the late-embryonic to early-postnatal period. Post-transcriptional inhibition of SOCS3 protein expression maintains a high STAT3 activation during late embryogenesis, and after P0, releasing from the inhibition promptly terminates STAT3 activation. Thus, SOCS3 can act as a temporal fine-tuner of STAT3 activation during photoreceptor cell differentiation. © 2006 Elsevier Inc. All rights reserved.

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Socs 3 modulates the activity of the transcription factor Stat3 in mammary tissue and controls alveolar homeostasis

Robinson Gertraud W., Pacher-Zavisin Margit, Zhu Bing Mei, Yoshimura Akihiko, Hennighausen Lothar

Developmental Dynamics 236 ( 3 ) 654 - 661 2007.03

ISSN 1058-8388

Signal transducer and activator of transcription 5 and 3 (Stat5 and Stat3) control pregnancy-mediated mammary development and involution-dependent remodeling, respectively. Suppressor of cytokine signaling 3 (Socs3) has been implicated in the modulation of both Stat3 and Stat5 activity. To explore the biology of Socs3 in mammary tissue, the gene was deleted using Cre-mediated recombination. Deletion of the Socs3 gene from mammary stem or early progenitor cells did not grossly alter pregnancy-mediated mammary development but resulted in impaired lactation due to attenuated proliferation. Loss of Socs3 from differentiated luminal cells did not interfere with glandular function during lactation, but resulted in accelerated tissue remodeling upon weaning. Loss of Socs3 led to enhanced and precocious Stat3 activation. Thus, Socs3 serves as a modulator of Stat3 activity to ensure controlled proliferation and apoptosis in pregnancy and involution, respectively.

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