Publications (15)84.91 Total impact
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Article: Id4, a new candidate gene for senile osteoporosis, acts as a molecular switch promoting osteoblast differentiation.
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ABSTRACT: Excessive accumulation of bone marrow adipocytes observed in senile osteoporosis or age-related osteopenia is caused by the unbalanced differentiation of MSCs into bone marrow adipocytes or osteoblasts. Several transcription factors are known to regulate the balance between adipocyte and osteoblast differentiation. However, the molecular mechanisms that regulate the balance between adipocyte and osteoblast differentiation in the bone marrow have yet to be elucidated. To identify candidate genes associated with senile osteoporosis, we performed genome-wide expression analyses of differentiating osteoblasts and adipocytes. Among transcription factors that were enriched in the early phase of differentiation, Id4 was identified as a key molecule affecting the differentiation of both cell types. Experiments using bone marrow-derived stromal cell line ST2 and Id4-deficient mice showed that lack of Id4 drastically reduces osteoblast differentiation and drives differentiation toward adipocytes. On the other hand knockdown of Id4 in adipogenic-induced ST2 cells increased the expression of Ppargamma2, a master regulator of adipocyte differentiation. Similar results were observed in bone marrow cells of femur and tibia of Id4-deficient mice. However the effect of Id4 on Ppargamma2 and adipocyte differentiation is unlikely to be of direct nature. The mechanism of Id4 promoting osteoblast differentiation is associated with the Id4-mediated release of Hes1 from Hes1-Hey2 complexes. Hes1 increases the stability and transcriptional activity of Runx2, a key molecule of osteoblast differentiation, which results in an enhanced osteoblast-specific gene expression. The new role of Id4 in promoting osteoblast differentiation renders it a target for preventing the onset of senile osteoporosis.PLoS Genetics 07/2010; 6(7):e1001019. · 8.69 Impact Factor -
Article: miR-210 promotes osteoblastic differentiation through inhibition of AcvR1b.
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ABSTRACT: Although microRNAs (miRNAs) are involved in many biological processes, the mechanisms whereby miRNAs regulate osteoblastic differentiation are poorly understood. Here, we found that BMP-4-induced osteoblastic differentiation of bone marrow-derived ST2 stromal cells was promoted and repressed after transfection of sense and antisense miR-210, respectively. A reporter assay demonstrated that the activin A receptor type 1B (AcvR1b) gene was a target for miR-210. Furthermore, inhibition of transforming growth factor-beta (TGF-beta)/activin signaling in ST2 cells with SB431542 promoted osteoblastic differentiation. We conclude that miR-210 acts as a positive regulator of osteoblastic differentiation by inhibiting the TGF-beta/activin signaling pathway through inhibition of AcvR1b.FEBS letters 07/2009; 583(13):2263-8. · 3.54 Impact Factor -
Article: Identification of novel PPARgamma target genes by integrated analysis of ChIP-on-chip and microarray expression data during adipocyte differentiation.
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ABSTRACT: PPARgamma (peroxisome proliferator-activated receptor gamma) acts as a key molecule of adipocyte differentiation, and transactivates multiple target genes involved in lipid metabolic pathways. Identification of PPARgamma target genes will facilitate to predict the extent to which the drugs can affect and also to understand the molecular basis of lipid metabolism. Here, we have identified five target genes regulated directly by PPARgamma during adipocyte differentiation in 3T3-L1 cells using integrated analyses of ChIP-on-chip and expression microarray. We have confirmed the direct PPARgamma regulation of five genes by luciferase reporter assay in NIH-3T3 cells. Of these five genes Hp, Tmem143 and 1100001G20Rik are novel PPARgamma targets. We have also detected PPREs (PPAR response elements) sequences in the promoter region of the five genes computationally. Unexpectedly, most of the PPREs detected proved to be atypical, suggesting the existence of more atypical PPREs than previously thought in the promoter region of PPARgamma regulated genes.Biochemical and Biophysical Research Communications 08/2008; 372(2):362-6. · 2.48 Impact Factor -
Article: miR-125b inhibits osteoblastic differentiation by down-regulation of cell proliferation.
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ABSTRACT: Although various microRNAs regulate cell differentiation and proliferation, no miRNA has been reported so far to play an important role in the regulation of osteoblast differentiation. Here we describe the role of miR-125b in osteoblastic differentiation in mouse mesenchymal stem cells, ST2, by regulating cell proliferation. The expression of miR-125b was time-dependently increased in ST2 cells, and the increase in miR-125b expression was attenuated in osteoblastic-differentiated ST2 cells induced by BMP-4. The transfection of exogenous miR-125b inhibited proliferation of ST2 cells and caused inhibition of osteoblastic differentiation. In contrast, when the endogenous miR-125b was blocked by transfection of its antisense RNA molecule, alkaline phosphatase activity after BMP-4 treatment was elevated. These results strongly suggest that miR-125b is involved in osteoblastic differentiation through the regulation of cell proliferation.Biochemical and Biophysical Research Communications 05/2008; 368(2):267-72. · 2.48 Impact Factor -
Article: Novel homeodomain-interacting protein kinase family member, HIPK4, phosphorylates human p53 at serine 9.
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ABSTRACT: We describe here the cloning and characterization of a novel mouse homeodomain-interacting protein kinase (HIPK)-like gene, Hipk4. Hipk4 is expressed in lung and in white adipose tissue and encodes a 616 amino acid protein that includes a serine/threonine kinase domain. We demonstrate that HIPK4 could phosphorylate human p53 protein at serine 9, both in vitro and in vivo. Among known p53-responsive promoters, activity of the human survivin promoter, which is repressed by p53, was decreased by HIPK4 in p53 functional A549 cells. Human BCL2-associated X protein-promoter activity was not affected. These findings suggest that phosphorylation of p53 at serine 9 is important for p53 mediated transcriptional repression.FEBS Letters 01/2008; 581(29):5649-57. · 3.54 Impact Factor -
Article: Estrogen-related receptor alpha modulates the expression of adipogenesis-related genes during adipocyte differentiation.
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ABSTRACT: Estrogen-related receptor alpha (ERRalpha) is an orphan nuclear receptor that regulates cellular energy metabolism by modulating gene expression involved in fatty acid oxidation and mitochondrial biogenesis in brown adipose tissue. However, the physiological role of ERRalpha in adipogenesis and white adipose tissue development has not been well studied. Here, we show that ERRalpha and ERRalpha-related transcriptional coactivators, peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1alpha (PGC-1alpha) and PGC-1beta, can be up-regulated in 3T3-L1 preadipocytes at mRNA levels under the adipogenic differentiation condition including the inducer of cAMP, glucocorticoid, and insulin. Gene knockdown by ERRalpha-specific siRNA results in mRNA down-regulation of fatty acid binding protein 4, PPARgamma, and PGC-1alpha in 3T3-L1 cells in the adipogenesis medium. ERRalpha and PGC-1beta mRNA expression can be also up-regulated in another preadipocyte lineage DFAT-D1 cells and a pluripotent mesenchymal cell line C3H10T1/2 under the differentiation condition. Furthermore, stable expression of ERRalpha in 3T3-L1 cells up-regulates adipogenic marker genes and promotes triglyceride accumulation during 3T3-L1 differentiation. These results suggest that ERRalpha may play a critical role in adipocyte differentiation by modulating the expression of various adipogenesis-related genes.Biochemical and Biophysical Research Communications 08/2007; 358(3):813-8. · 2.48 Impact Factor -
Article: [Analysis of gene networks during adipogenesis and osteoblastgenesis focusing on the crosstalk and redundant pathways].
Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 01/2005; 49(17 Suppl):2965-9. -
Article: A novel preadipocyte cell line established from mouse adult mature adipocytes.
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ABSTRACT: We have established a novel preadipocyte cell line from mouse adult mature adipocytes. The mature adipocytes were isolated from fat tissues by taking only the floating population of mature fat cells. The isolated mature adipocytes were de-differentiated into fibroblast-like cells. The in vitro studies showed that the cells could re-differentiate into mature adipocytes after over 20 passages. The in vivo transplantation study also demonstrated that the cells had the full potential to differentiate into mature adipocytes, which has not been shown for the 3T3-L1 preadipocyte cell line derived from mouse embryo. We have further analyzed the expression profile of key fat regulatory genes such as the peroxisome proliferator-activated receptorgamma or CCAAT/enhancer-binding protein gene families. We conclude that our cell line could be used as a preferred alternative to 3T3-L1, potentially reflecting the characteristics of mature adipocytes more, since the cell line is actually derived from adult mature adipocytes.Biochemical and Biophysical Research Communications 10/2004; 321(4):967-74. · 2.48 Impact Factor -
Article: Molecular basis of constitutive production of basement membrane components. Gene expression profiles of Engelbreth-Holm-Swarm tumor and F9 embryonal carcinoma cells.
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ABSTRACT: Engelbreth-Holm-Swarm (EHS) tumors produce large amounts of basement membrane (BM) components that are widely used as cell culture substrates mimicking BM functions. To delineate the tissue/organ origin of the tumor and the mechanisms operating in the BM overproduction, a genome-wide expression profile of EHS tumor was analyzed using RIKEN cDNA microarrays containing approximately 40,000 mouse cDNA clones. Expression profiles of F9 embryonal carcinoma cells that produce laminin-1 and other BM components upon differentiation into parietal endoderm-like cells (designated F9-PE) were also analyzed. Hierarchical clustering analysis showed that the gene expression profiles of EHS and F9-PE were the most similar among 49 mouse tissues/organs in the RIKEN Expression Array Database, suggesting that EHS tumor is parietal endoderm-derived. Quantitative PCR analysis confirmed that not only BM components but also the machineries required for efficient production of BM components, such as enzymes involved in post-translational modification and molecular chaperones, were highly expressed in both EHS and F9-PE. Pairs of similar transcription factor isoforms, such as Gata4/Gata6, Sox7/Sox17, and Cited1/Cited2, were also highly expressed in both EHS tumor and F9-PE. Time course analysis of F9 differentiation showed that up-regulation of the transcription factors was associated with those of BM components, suggesting their involvement in parietal endoderm specification and overproduction of the BM components.Journal of Biological Chemistry 01/2004; 278(50):50691-701. · 4.77 Impact Factor -
Article: Continued discovery of transcriptional units expressed in cells of the mouse mononuclear phagocyte lineage.
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ABSTRACT: The current RIKEN transcript set represents a significant proportion of the mouse transcriptome but transcripts expressed in the innate and acquired immune systems are poorly represented. In the present study we have assessed the complexity of the transcriptome expressed in mouse macrophages before and after treatment with lipopolysaccharide, a global regulator of macrophage gene expression, using existing RIKEN 19K arrays. By comparison to array profiles of other cells and tissues, we identify a large set of macrophage-enriched genes, many of which have obvious functions in endocytosis and phagocytosis. In addition, a significant number of LPS-inducible genes were identified. The data suggest that macrophages are a complex source of mRNA for transcriptome studies. To assess complexity and identify additional macrophage expressed genes, cDNA libraries were created from purified populations of macrophage and dendritic cells, a functionally related cell type. Sequence analysis revealed a high incidence of novel mRNAs within these cDNA libraries. These studies provide insights into the depths of transcriptional complexity still untapped amongst products of inducible genes, and identify macrophage and dendritic cell populations as a starting point for sampling the inducible mammalian transcriptome.Genome Research 07/2003; 13(6B):1360-5. · 13.61 Impact Factor -
Article: Systematic expression profiling of the mouse transcriptome using RIKEN cDNA microarrays.
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ABSTRACT: The number of known mRNA transcripts in the mouse has been greatly expanded by the RIKEN Mouse Gene Encyclopedia project. Validation of their reproducible expression in a tissue is an important contribution to the study of functional genomics. In this report, we determine the expression profile of 57,931 clones on 20 mouse tissues using cDNA microarrays. Of these 57,931 clones, 22,928 clones correspond to the FANTOM2 clone set. The set represents 20,234 transcriptional units (TUs) out of 33,409 TUs in the FANTOM2 set. We identified 7206 separate clones that satisfied stringent criteria for tissue-specific expression. Gene Ontology terms were assigned for these 7206 clones, and the proportion of 'molecular function' ontology for each tissue-specific clone was examined. These data will provide insights into the function of each tissue. Tissue-specific gene expression profiles obtained using our cDNA microarrays were also compared with the data extracted from the GNF Expression Atlas based on Affymetrix microarrays. One major outcome of the RIKEN transcriptome analysis is the identification of numerous nonprotein-coding mRNAs. The expression profile was also used to obtain evidence of expression for putative noncoding RNAs. In addition, 1926 clones (70%) of 2768 clones that were categorized as "unknown EST," and 1969 (58%) clones of 3388 clones that were categorized as "unclassifiable" were also shown to be reproducibly expressed.Genome Research 07/2003; 13(6B):1318-23. · 13.61 Impact Factor -
Article: Analysis of the mouse transcriptome for genes involved in the function of the nervous system.
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ABSTRACT: We analyzed the mouse Representative Transcript and Protein Set for molecules involved in brain function. We found full-length cDNAs of many known brain genes and discovered new members of known brain gene families, including Family 3 G-protein coupled receptors, voltage-gated channels, and connexins. We also identified previously unknown candidates for secreted neuroactive molecules. The existence of a large number of unique brain ESTs suggests an additional molecular complexity that remains to be explored.A list of genes containing CAG stretches in the coding region represents a first step in the potential identification of candidates for hereditary neurological disorders.Genome Research 07/2003; 13(6B):1395-401. · 13.61 Impact Factor -
Article: The mouse secretome: functional classification of the proteins secreted into the extracellular environment.
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ABSTRACT: We have developed a computational strategy to identify the set of soluble proteins secreted into the extracellular environment of a cell. Within the protein sequences predominantly derived from the RIKEN representative transcript and protein set, we identified 2033 unique soluble proteins that are potentially secreted from the cell. These proteins contain a signal peptide required for entry into the secretory pathway and lack any transmembrane domains or intracellular localization signals. This class of proteins, which we have termed the mouse secretome, included >500 novel proteins and 92 proteins <100 amino acids in length. Functional analysis of the secretome included identification of human orthologs, functional units based on InterPro and SCOP Superfamily predictions, and expression of the proteins within the RIKEN READ microarray database. To highlight the utility of this information, we discuss the CUB domain-containing protein family.Genome Research 06/2003; 13(6B):1350-9. · 13.61 Impact Factor -
Article: Analysis of the mouse transcriptome for genes involved in the function of the nervous system
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ABSTRACT: We analyzed the mouse Representative Transcript and Protein Set for molecules involved in brain function. We found full-length cDNAs of many known brain genes and discovered new members of known brain gene families, including Family 3 G-protein coupled receptors, voltage-gated channels, and connexins. We also identified previously unknown candidates for secreted neuroactive molecules. The existence of a large number of unique brain ESTs suggests an additional molecular complexity that remains to be explored. A list of genes containing CAG stretches in the coding region represents a first step in the potential identification of candidates for hereditary neurological disorders. -
Article: Estrogen-related receptor α modulates the expression of adipogenesis-related genes during adipocyte differentiation
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ABSTRACT: Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that regulates cellular energy metabolism by modulating gene expression involved in fatty acid oxidation and mitochondrial biogenesis in brown adipose tissue. However, the physiological role of ERRα in adipogenesis and white adipose tissue development has not been well studied. Here, we show that ERRα and ERRα-related transcriptional coactivators, peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) and PGC-1β, can be up-regulated in 3T3-L1 preadipocytes at mRNA levels under the adipogenic differentiation condition including the inducer of cAMP, glucocorticoid, and insulin. Gene knockdown by ERRα-specific siRNA results in mRNA down-regulation of fatty acid binding protein 4, PPARγ, and PGC-1α in 3T3-L1 cells in the adipogenesis medium. ERRα and PGC-1β mRNA expression can be also up-regulated in another preadipocyte lineage DFAT-D1 cells and a pluripotent mesenchymal cell line C3H10T1/2 under the differentiation condition. Furthermore, stable expression of ERRα in 3T3-L1 cells up-regulates adipogenic marker genes and promotes triglyceride accumulation during 3T3-L1 differentiation. These results suggest that ERRα may play a critical role in adipocyte differentiation by modulating the expression of various adipogenesis-related genes.Biochemical and Biophysical Research Communications.
Top co-authors
Top Journals
Institutions
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2004–2010
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Saitama Medical University
- Research Center for Genomic Medicine
Saitama, Saitama-ken, Japan
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2003
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Harvard University
- Department of Neurobiology
Boston, MA, USA
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