Masanobu Morita
Tohoku University
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Publication
Featured researches published by Masanobu Morita.
Genes to Cells | 2003
Junsei Mimura; Keisuke Yamashita; Kenji Nakamura; Masanobu Morita; T. Takagi; Kazuki Nakao; Masatsugu Ema; Kazuhiro Sogawa; Mineo Yasuda; Motoya Katsuki; Yoshiaki Fujii-Kuriyama
The aryl hydrocarbon receptor (AhR or dioxin receptor) is a ligand‐activated transcription factor that is considered to mediate pleiotropic biological responses such as teratogenesis, tumour promotion, epithelial hyperplasia and the induction of drug‐metabolizing enzymes to environmental contaminants usually represented by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD). In contrast to the role of AhR in the regulatory mechanism of xenobiotic‐metabolizing enzymes, there is no direct proof that the AhR is involved in the teratogenic effects of TCDD.
Molecular and Cellular Biology | 1996
K Hirose; Masanobu Morita; Masatsugu Ema; Junsei Mimura; Hiroshi Hamada; Hideta Fujii; Y Saijo; Osamu Gotoh; Kazuhiro Sogawa; Yoshiaki Fujii-Kuriyama
We isolated mouse cDNA clones (Arnt2) that are highly similar to but distinct from the aryl hydrocarbon receptor (AhR) nuclear translocator (Arnt). The composite cDNA covered a 2,443-bp sequence consisting of a putative 2,136-bp open reading frame encoding a polypeptide of 712 amino acids. The predicted Arnt2 polypeptide carries a characteristic basic helix-loop-helix (bHLH)/PAS motif in its N-terminal region with close similarity (81% identity) to that of mouse Arnt and has an overall sequence identity of 57% with Arnt. Biochemical properties and interaction of Arnt2 with other bHLH/PAS proteins were investigated by coimmunoprecipitation assays, gel mobility shift assays, and the yeast two-hybrid system. Arnt2 interacted with AhR and mouse Sim as efficiently as Arnt, and the Arnt2-AhR complex recognized and bound specifically the xenobiotic responsive element (XRE) sequence. Expression of Arnt2 successfully rescued XRE-driven reporter gene activity in the Arnt-defective c4 mutant of Hepa-1 cells. RNA blot analysis revealed that expression of Arnt2 mRNA was restricted to the brains and kidneys of adult mice, while Arnt mRNA was expressed ubiquitously. In addition, whole-mount in situ hybridization of 9.5-day mouse embryos showed that Arnt2 mRNA was expressed in the dorsal neural tube and branchial arch 1, while Arnt transcripts were detected broadly in various tissues of mesodermal and endodermal origins. These results suggest that Arnt2 may play different roles from Arnt both in adult mice and in developing embryos. Finally, sequence comparison of the currently known bHLH/PAS proteins indicates a division into two phylogenetic groups: the Arnt group, containing Arnt, Arnt2, and Per, and the AhR group, consisting of AhR, Sim, and Hif-1alpha.
The EMBO Journal | 2003
Masanobu Morita; Osamu Ohneda; Toshiharu Yamashita; Satoru Takahashi; Norio Suzuki; Osamu Nakajima; Shimako Kawauchi; Masatsugu Ema; Shigeki Shibahara; Tetsuo Udono; Koji Tomita; Makoto Tamai; Kazuhiro Sogawa; Masayuki Yamamoto; Yoshiaki Fujii-Kuriyama
An HLF (HIF‐1α‐like factor)/HIF‐2α‐knockout mouse is embryonic lethal, preventing investigation of HLF function in adult mice. To investigate the role of HLF in adult pathological angiogenesis, we generated HLF‐knockdown (HLFkd/kd) mice by inserting a neomycin gene sandwiched between two loxP sequences into exon 1 of the HLF gene. HLFkd/kd mice expressing 80–20% reduction, depending on the tissue, in wild‐type HLF mRNA were fertile and apparently normal. Hyperoxia–normoxia treatment, used as a murine model of retinopathy of prematurity (ROP), induced neovascularization in wild‐type mice, but not in HLFkd/kd mice, whereas prolonged normoxia following hyperoxic treatment caused degeneration of retinal neural layers in HLFkd/kd mice due to poor vascularization. Cre‐mediated removal of the inserted gene recovered normal HLF expression and retinal neovascularization in HLFkd/kd mice. Expression levels of various angiogenic factors revealed that only erythropoietin (Epo) gene expression was significantly affected, in parallel with HLF expression. Together with the results from intraperitoneal injection of Epo into HLFkd/kd mouse, this suggests that Epo is one of the target genes of HLF responsible for experimental ROP.
Journal of Biological Chemistry | 1999
Shimako Kawauchi; Satoru Takahashi; Osamu Nakajima; Hajime Ogino; Masanobu Morita; Makoto Nishizawa; Kunio Yasuda; Masayuki Yamamoto
To elucidate the regulatory mechanisms underlying lens development, we searched for members of the large Maf family, which are expressed in the mouse lens, and found three, c-Maf, MafB, and Nrl. Of these, the earliest factor expressed in the lens was c-Maf. The expression of c-Maf was most prominent in lens fiber cells and persisted throughout lens development. To examine the functional contribution of c-Maf to lens development, we isolated genomic clones encompassing the murine c-maf gene and carried out its targeted disruption. Insertion of the β-galactosidase (lacZ) gene into the c-maf locus allowed visualization of c-Maf accumulation in heterozygous mutant mice by staining for LacZ activity. Homozygous mutant embryos and newborns lacked normal lenses. Histological examination of these mice revealed defective differentiation of lens fiber cells. The expression of crystallin genes was severely impaired in the c-maf-null mutant mouse lens. These results demonstrate that c-Maf is an indispensable regulator of lens differentiation during murine development.
Molecular and Cellular Biology | 1996
Masatsugu Ema; Masanobu Morita; Shuntaro Ikawa; Masahiro Tanaka; Youichi Matsuda; Osamu Gotoh; Yukio Saijoh; Hideta Fujii; Hiroshi Hamada; Yasuo Kikuchi; Yoshiaki Fujii-Kuriyama
From a cDNA library of mouse skeletal muscle, we have isolated mouse Sim1 (mSim1) cDNA encoding a polypeptide of 765 amino acids with striking amino acid identify in basic helix-loop-helix (89% identify) and PAS (89 % identify) domains to previously identified mSim2, although the carboxy-terminal third of the molecule did not show any similarity to mSim2 or Drosophila Sim (dSim). Yeast two-hybrid analysis and coimmunoprecipitation experiments demonstrated that both of the mSim gene products interacted with Arnt even more efficiently than AhR, a natural partner of Arnt, suggesting a functional cooperativity with Arnt. In sharp contrast with dSim having transcriptional-enhancing activity in the carboxy-terminal region, the two mSims possessed a repressive activity toward Arnt in the heterodimer complex. This is the first example of bHLH-PAS proteins with transrepressor activity, although some genetic data suggest that dSim plays a repressive role in gene expression (Z. Chang, D. Price, S. Bockheim, M. J. Boedigheimer, R. Smith, and A. Laughon, Dev. Biol. 160:315-322, 1993; D. M. Mellerick and M. Nirenberg, Dev. Biol. 171:306-316, 1995). Whole-mount in situ hybridization showed restricted and characteristic expression patterns of the two mSim mRNAs in various tissues and organs during embryogenesis, such as those for the somite, the nephrogenic cord, and the mesencephalon (for mSim1) and those for the diencephalon, branchial arches, and limbs (for mSim2). From sequence similarity and chromosomal localization, it is concluded that mSim2 is an ortholog of hSim2, which is proposed to be a candidate gene responsible for Downs syndrome. The sites of mSim2 expression showed an overlap with the affected regions of the syndrome, further strengthening involvement of mSim2 in Downs syndrome.
Cell Stem Cell | 2008
Masatsugu Ema; Daisuke Mori; Hitoshi Niwa; Yoshikazu Hasegawa; Yojiro Yamanaka; Seiji Hitoshi; Junsei Mimura; Yoh ichi Kawabe; Tomohiro Hosoya; Masanobu Morita; Daisuke Shimosato; Kazuhiko Uchida; Norio Suzuki; Jun Yanagisawa; Kazuhiro Sogawa; Janet Rossant; Masayuki Yamamoto; Satoru Takahashi; Yoshiaki Fujii-Kuriyama
The transcription factor Klf4 has demonstrated activity in the reprogramming of somatic cells to a pluripotent state, but the molecular mechanism of this process remains unknown. It is, therefore, of great interest to understand the functional role of Klf4 and related genes in ESC regulation. Here, we show that homozygous disruption of Klf5 results in the failure of ESC derivation from ICM cells and early embryonic lethality due to an implantation defect. Klf5 KO ESCs show increased expression of several differentiation marker genes and frequent, spontaneous differentiation. Conversely, overexpression of Klf5 in ESCs suppressed the expression of differentiation marker genes and maintained pluripotency in the absence of LIF. Our results also suggest that Klf5 regulates ESC proliferation by promoting phosphorylation of Akt1 via induction of Tcl1. These results, therefore, provide new insights into the functional and mechanistic role of Klf5 in regulation of pluripotency.
Genes to Cells | 2001
Tomonori Hosoya; Yoshihito Oda; Satoru Takahashi; Masanobu Morita; Shimako Kawauchi; Masatsugu Ema; Masayuki Yamamoto; Yoshiaki Fujii-Kuriyama
Within the basic region‐helix‐loop‐helix (bHLH)‐PAS family of transcription factors, Arnt and Arnt2 play unique roles; these two factors not only heterodimerize with themselves, but also with other members of this family and they act as transcription regulators which bind to specific DNA elements. Whereas Arnt is broadly expressed in various tissues, the expression of Arnt2 is known to be limited to the neural tissues.
Molecular and Cellular Biology | 2000
Hironori Yamagiwa; Hideto Hoshino; Akihiko Muto; Kazushige Sato; Masanobu Morita; Norio Hayashi; Masayuki Yamamoto; Kazuhiko Igarashi
ABSTRACT Bach2 is a B-cell- and neuron-specific transcription repressor that forms heterodimers with the Maf-related oncoproteins. We show here that Bach2 activates transcription by interacting with its novel partner MAZR. MAZR was isolated by the yeast two-hybrid screen using the BTB/POZ domain of Bach2 as bait. Besides the BTB/POZ domain, MAZR possesses Zn finger motifs that are closely related to those of the Myc-associated Zn finger (MAZ) protein. MAZR mRNA was coexpressed with Bach2 in B cells among hematopoietic cells and in developing mouse limb buds, suggesting a cooperative role for MAZR and Bach2 in these cells. MAZR forms homo- and hetero-oligomers with Bach2 through the BTB domain, which oligomers bind to guanine-rich sequences. Unlike MAZ, MAZR functioned as a strong activator of the c-myc promoter in transfection assays with B cells. However, it does not possess a typical activation domain, suggesting a role for it as an unusual type of transactivator. The fgf4 gene, which regulates morphogenesis of limb buds, contains both guanine-rich sequences and a Bach2 binding site in its regulatory region. In transfection assays using fibroblast cells, the fgf4 gene was upregulated in the presence of both MAZR and Bach2 in a BTB/POZ domain-dependent manner. The results provide a new perspective on the function of BTB/POZ domain factors and indicate that BTB/POZ domain-mediated oligomers of transcription factors may serve as combinatorial codes for gene expression.
Molecular and Cellular Biology | 2003
Masanobu Morita; Toshiharu Yamashita; Tomomasa Shimanuki; Osamu Nakajima; Satoru Takahashi; Shiro Ikegami; Kaoru Inokuchi; Keisuke Yamashita; Masayuki Yamamoto; Yoshiaki Fujii-Kuriyama
ABSTRACT Basic transcription element binding protein (BTEB) is a transcription factor with a characteristic zinc finger motif and is most remarkably enhanced by thyroid hormone T3 treatment (R. J. Denver et al., J. Biol. Chem. 272:8179-8188, 1997). To investigate the function of BTEB per se and to touch on the effects of T3 (3,5,3′-triiodothyronine) on mouse development, we generated BTEB-deficient mice by gene knockout technology. Homologous BTEB−/− mutant mice were bred according to apparently normal Mendelian genetics, matured normally, and were fertile. Mutant mice could survive for at least 2 years without evident pathological defects. From the expression of lacZ, which was inserted into the reading frame of the BTEB gene, BTEB showed a characteristic tissue-specific expression profile during the developmental process of brain and bone. Dramatically increased expression of BTEB was observed in Purkinje cells of the cerebellum and pyramidal cell layers of the hippocampus at P7 when synapses start to form in the brain. Although general behavioral activities such as locomotion, rearing, and speed of movement were not so much affected in the BTEB−/− mutant mice, they showed clearly reduced activity levels in rotorod and contextual fear-conditioning tests; this finding was probably due to defective functions of the cerebellum, hippocampus, and amygdala.
Molecular and Cellular Biology | 2015
Ryota Saito; Takafumi Suzuki; Keiichiro Hiramoto; Soichiro Asami; Eriko Naganuma; Hiromi Suda; Tatsuro Iso; Hirotaka Yamamoto; Masanobu Morita; Liam Baird; Yuki Furusawa; Takaaki Negishi; Masakazu Ichinose; Masayuki Yamamoto
ABSTRACT The Keap1-Nrf2 system plays a central role in cytoprotection against electrophilic/oxidative stresses. Although Cys151, Cys273, and Cys288 of Keap1 are major sensor cysteine residues for detecting these stresses, it has not been technically feasible to evaluate the functionality of Cys273 or Cys288, since Keap1 mutants that harbor substitutions in these residues and maintain the ability to repress Nrf2 accumulation do not exist. To overcome this problem, we systematically introduced amino acid substitutions into Cys273/Cys288 and finally identified Cys273Trp and Cys288Glu mutations that do not affect Keap1s ability to repress Nrf2 accumulation. Utilizing these Keap1 mutants, we generated stable murine embryonic fibroblast (MEF) cell lines and knock-in mouse lines. Our analyses with the MEFs and peritoneal macrophages from the knock-in mice revealed that three major cysteine residues, Cys151, Cys273, and Cys288, individually and/or redundantly act as sensors. Based on the functional necessity of these three cysteine residues, we categorized chemical inducers of Nrf2 into four classes. Class I and II utilizes Cys151 and Cys288, respectively, while class III requires all three residues (Cys151/Cys273/Cys288), while class IV inducers function independently of all three of these cysteine residues. This study thus demonstrates that Keap1 utilizes multiple cysteine residues specifically and/or collaboratively as sensors for the detection of a wide range of environmental stresses.