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Research at OU


67  Atsumi, T.*1; Ishihara, K.*2; Kamimura, D.*1; Ikushima, H.*1;
Ohtani, T.; Hirota, S.*1; Kobayashi, H.; Park, S-J.*1; Saeki, Y.*1;
Kitamura, Y.*1; Hirano T.*2
*1(Graduate School of Medicine) *2(Graduate School of Medicine, and Graduate School of Frontier Biosciences)
A Point Mutation of Tyr-759 in Interleukin 6 Family Cytokine Receptor Subunit gp130 Causes Autoimmune Arthritis
Journal of Experimental Medicine, 196, 979-990 (2002)

68 Ban, T.; Hamada, D.; Hasegawa, K.; Naiki, H.; Goto, Y. (Institute for Protein Research)
Direct Observation of Amyloid Fibril Growth Monitored by Thioflavin T Fluorescence
Journal of Biological Chemistry, 278, 16462-16465 (2003)

Amyloid fibril deposition is associated with 20 serious human diseases including Alzheimer's disease and transmissible spongiform encephalopathies. Real-time monitoring of fibril growth is essential to clarify the mechanism of amyloid fibril formation. Here, we show that, by monitoring ThT fluorescence with total internal reflection fluorescence microscopy, the amyloid fibril formation of β2-microgobulin can be visualized without requiring covalent fluorescence labeling. Since ThT binding is common to all amyloid fibrils, the present method will have general applicability for the analysis of amyloid fibrils.

69 Hanayama, R.*1; Tanaka, M.*1; Miwa, K.*1; Shinohara, A.;
Iwamatsu, A.; Nagata, S.*1,2
*1(Graduate School of Medicine) *2(Graduate School of Frontier Biosciences)
Identification of a Factor that Links Apoptotic Cells to Phagocytes
Nature, 417, 182-187 (2002)

70 Hata, K.; Nishimura, R.; Ikeda, F.; Yamashita, K.; Matsubara, M.;
Nokubi, T.; Yoneda, T. (Graduate School of Dentistry)
Differential Roles of Smad1 and p38 Kinase in the Regulation of PPARγ during BMP2-induced Adipogenesis
Molecular Biology of the Cell, 14, 545-555 (2003)

In this study, we investigated the molecular mechanisms by which BMP2 induces adipogenesis of pluripotent mesenchymal cells. We have shown that BMP2 induced the expression of PPARγ along with adipogenesis through Smad1 signaling. In contrast, MKK3/p38 kinase pathway plays a critical role in the functional activation of PPARγ but not in the regulation of PPARγ. Thus, BMP2 controls adipocytic differentiation by utilizing two distinct signaling pathways that play differential roles in adipogenesis of the pluripotent mesenchymal cells.

71 Tanaka, H.; Homma, K.; Iwane, A. H.; Katayama, E.; Ikebe, R.; Saito, J.;
Yanagida, T.; Ikebe, M.; (Graduate School of Frontier Biosciences)
The Motor Domain Determines the Large Step of Myosin-V
Nature, 415, 192-195 (2002)

72 Inoue, T.; Irikura, D.; Okazaki, N.; Kinugasa, S.; Matsumura, H.; Uodome, N.; Yamamoto, M.; Kumasaka, T.; Miyano, M.; Kai, Y.; Urade, Y.
(Graduate School of Engineering)
Mechanism of Metal Activation of Human Hematopoietic Prostaglandin D Synthase
Nature Structural Biology, 10, 291-296 (2003)

We have determined the crystal structures of human hematopoietic prostaglandin (PG) D synthase (H-PGDS) bound to glutathione (GSH) and metal ions. Using GSH as a cofactor, H-PGDS catalyzes the isomerization of PGH2 to PGD2, a mediator for allergy response. H-PGDS is activated by rearrangement of hydrogen bond networks upon binding of metal ions. This effect explains a four-fold reduction in the Km of the enzyme for GSH. The structure provides insights into how a metal ion binding activates human H-PGDS.

73 Iwamoto, R.*1; Yamazaki, S.*1; Asakura, M.*2; Takashima, S.*2;
Hasuwa, H.*1; Miyado, K.*1; Adachi, S.*1; Kitakaze, M.; Hashimoto, K.;
Raab, G.; Nanba, D.; Higashiyama, S.; Hori, M.*2.; Klagsbrun, M.; Mekada, E.*1
*1 (Research Institute for Microbial Diseases) *2 (Graduate School of Medicine)
Heparin-Binding EGF-like Growth Factor and ErbB Signaling Is Essential for Heart Function
Proceedings of the National Academy of Sciences of the United States of America, 100, 3221-3226 (2003)

HB-EGF is a member of the EGF family of growth factors. To examine the role of HB-EGF in vivo, we generated HB-EGF knockout mice (HBdel/del). HBdel/del mice developed severe heart failure with dilated ventricular chambers, similarly to conditional ErbB2 knockout mice. HBdel/del mice developed also enlarged cardiac valves, similarly to EGFR knockout mice. Constitutive tyrosine phosphorylation of both ErbB2 and ErbB4 was significantly reduced in HBdel/del hearts. These indicated that HB-EGF activation of ErbB is essential for normal heart function.

74 Kawasaki, A.; Matsumura, I.; Takigawa, E.; Nakajima, K.; Kanakura, Y.
(Graduate School of Medicine)
Opposing Effects of PML and PML/RARα on STAT3 Activity
Blood, 101, 3668-3673 (2003)

PML acts a tumor suppressor, while PML/RARα causes acute promyelocytic leukemia (APL). Here we found that PML binds to STAT3 and inhibited its activity, which plays a crucial role in G-CSF-dependent growth of myeloid cells. Although PML/RARα did not bind to STAT3, it inhibited the PML/STAT3 association, thereby augmenting STAT3 activity. Furthermore, PML suppressed G-CSF-dependent growth of Ba/F3 cells, while it was enhanced by PML/RARα. These results suggest that dysregulated STAT3 activity may participate in the pathogenesis of APL.

75 Kitajima, K.; Masuhara, M.; Era, T.; Enver, T.; Nakano, T (Research Institute for Microbial Diseases)
GATA-2 and GATA-2/ER Display Opposing Activities in the Development and Differentiation of Blood Progenitors
The EMBO Journal, 21, 3060-3069 (2002)

GATA-2 is a transcription factor essential for the hematopoietic development. We have employed both conditional expression of GATA-2 and a GATA-2/estrogen receptor (ER) chimera to examine the effects of enforced GATA-2 expression in the development and differentiation of hematopoietic progenitors from murine embryonic stem cells. Conditional expression of GATA-2 enhanced the production of hematopoietic progenitors, while GATA-2/ER produced essentially opposite effects. GATA-2 and GATA-2/ER differ in their binding activities and transcriptional interactions from other hematopoietic-associated transcription factors c-Myb and PU.1.

76 Maeda, N.; Shimomura, I.; Kishida, K.; Nishizawa, H.; Matsuda, M.;
Nagaretani, H.; Furuyama, N.; Kondo, H.; Takahashi, M.; Arita, Y.;
Komuro, R.; Ouchi, N.; Kihara, S.; Tochino, Y.; Okutomi, K.; Horie, M.;
Takeda, S.; Aoyama, T.; Funahashi, T.; Matsuzawa, Y. (Department of Internal Medicine and Molecular Science, Graduate School of Medicine)
Diet-induced Insulin Resistance in Mice Lacking Adiponectin/ACRP30
Nature Medicine, 8, 731-737 (2002)

77 Makino, K.*1; Oshima, K.; Kurokawa, K.*2; Yokoyama, K.*1;
Uda, T.*1; Tagomori, K.*1; Iijima, Y.; Najima, M.*2; Nakano, M.*1;
Yamashita, A.; Kubota, Y.*1; Kimura, S.*1; Yasunaga, T.*2;
Honda, T.*1; Shinagawa, H.*1; Hattori, M.; Iida, T.*1
*1(Research Institute for Microbial Diseases) *2(Genome Information Research Center)
Genome Sequence of Vibrio parahaemolyticus: a Pathogenic Mechanism Distinct from That of V. cholerae
Lancet, 361, 743-749 (2003)
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