PubMed Health⌕ Search

Biomedical subjects

Kenichi Yoshida

Publications and source records attributed to Kenichi Yoshida.

At least 19 recordsLinked to original sources
PubMed2026

BCL11B enhancer hijacking by t(14;16)(q32;q24) translocation defines a novel high-risk subtype of T-ALL.

The molecular classification of T-cell acute lymphoblastic leukemia (T-ALL) remains incomplete, limiting risk stratification and the development of targeted therapies. Enhancer hijacking is a critical oncogenic mechanism that deregulates proto-oncogenes by repositioning cisregulatory regions via structural variants. Here, we performed an integrated analysis of pediatric and adult T-ALL and mixed-phenotype acute leukemias (MPALs), using whole-genome and whole-transcriptome sequencing. This analysis identified a group of 14 patients with predominantly T-lineage neoplasms driven by a t(14;16)(q32;q24) translocation, harboring universal GATA3 mutations and CDKN2A/B deletions. Mechanistically, this translocation repositions the ThymoD locus downstream of BCL11B, causing monoallelic, ectopic overexpression of FENDRR and mesenchymal transcription factor genes FOXF1 and FOXC2 and activating epithelial-mesenchymal transition transcription signatures. Immunophenotypic and single-cell RNA sequencing analyses revealed marked lineage ambiguity with myeloid and B-cell differentiation potentials specific to this subtype. Furthermore, functional analyses in CD34+ cord blood cells demonstrated that FOXF1 overexpression promotes myeloid differentiation while suppressing T-cell differentiation, serving as a key factor for lineage specification. Clinically, this subtype was detected in 0.15% to 4.0% of T-ALL/MPAL cases depending on the cohort, showing a median age of 15 years and enrichment in adolescents and young adults. Importantly, patients with t(14;16)(q32;q24) have an extremely poor prognosis, showing a trend toward worse outcomes than high-risk groups such as KMT2A-rearranged early T-cell progenitor-like, SPI1-rearranged, and LMO2 γδ-like T-ALLs. The unique molecular landscape and poor prognosis of patients with the t(14;16)(q32;q24) translocation underscore the need for the development of novel subtype-specific therapeutic approaches.

Humans↗
PubMed2007

Identification of FAZF as a novel BMP2-induced transcription factor during osteoblastic differentiation.

Bone morphogenetic protein 2 (BMP2) is a key factor in the regulation of osteoblastic differentiation; however, its downstream mediators are not fully understood. Previously, we identified and characterized transcription factor promyelocytic leukemia zinc finger protein (PLZF), composed of an N-terminal BTB/POZ and C-terminal zinc finger motifs, as an upstream factor of CBFA1 (Runx2/core-binding factor 1). PLZF was induced in an osteoblastic differentiation medium, but was not induced by BMP2. Here, we report the identification of transcription factor fanconi anemia zinc finger protein (FAZF), which is closely related to PLZF. FAZF was induced by BMP2 in human mesenchymal stem cells (hMSCs). In addition to the full-length FAZF, we also identified alternatively spliced mRNAs in which the C-terminal zinc finger motifs were deleted (designated BTB/POZ-only FAZF). Both the full-length and BTB/POZ-only FAZF mRNAs were equally expressed in BMP2-treated hMSCs. The full-length FAZF was exclusively detected in the nucleus, whereas the BTB/POZ-only FAZF protein was localized in the cytoplasm of the transfected cells. The full-length FAZF, but not the BTB/POZ-only FAZF, increased the expression of osteoblastic differentiation markers, including CBFA1, collagen 1A1, osteocalcin, and alkaline phosphatase in C2C12 cells. In conclusion, both FAZF and PLZF differentially participate in the regulation of osteoblastic differentiation via the BMP2 and CBFA1 signaling pathways, respectively.

Alkaline Phosphatase↗
PubMed2006

CDCA4 is an E2F transcription factor family-induced nuclear factor that regulates E2F-dependent transcriptional activation and cell proliferation.

The TRIP-Br1/p34(SEI-1) family proteins participate in cell cycle progression by coactivating E2F1- or p53-dependent transcriptional activation. Here, we report the identification of human CDCA4 (also know as SEI-3/Hepp) as a novel target gene of transcription factor E2F and as a repressor of E2F-dependent transcriptional activation. Analysis of CDCA4 promoter constructs showed that an E2F-responsive sequence in the vicinity of the transcription initiation site is necessary for the E2F1-4-induced activation of CDCA4 gene transcription. Chromatin immunoprecipitation analysis demonstrated that E2F1 and E2F4 bound to an E2F-responsive sequence of the human CDCA4 gene. Like TRIP-Br1/p34(SEI-1) and TRIP-Br2 (SEI-2), the transactivation domain of CDCA4 was mapped within C-terminal acidic region 175-241. The transactivation function of the CDCA4 protein was inhibited by E2F1-4 and DP2, but not by E2F5-8. Inhibition of CDCA4 transactivation activity by E2F1 partially interfered with retinoblastoma protein overexpression. Conversely, CDCA4 suppressed E2F1-3-induced reporter activity. CDCA4 (but not acidic region-deleted CDCA4) suppressed E2F1-regulated gene promoter activity. These findings suggest that the CDCA4 protein functions as a suppressor at the E2F-responsive promoter. Small interfering RNA-mediated knockdown of CDCA4 expression in cancer cells resulted in up-regulation of cell growth rates and DNA synthesis. The CDCA4 protein was detected in several human cells and was induced as cells entered the G1/S phase of the cell cycle. Taken together, our results suggest that CDCA4 participates in the regulation of cell proliferation, mainly through the E2F/retinoblastoma protein pathway.

Amino Acid Sequence↗
PubMed2006

Tumour necrosis factor alpha-stimulated gene-6 inhibits osteoblastic differentiation of human mesenchymal stem cells induced by osteogenic differentiation medium and BMP-2.

To better understand the molecular pathogenesis of OPLL (ossification of the posterior longitudinal ligament) of the spine, an ectopic bone formation disease, we performed cDNA microarray analysis on cultured ligament cells from OPLL patients. We found that TSG-6 (tumour necrosis factor alpha-stimulated gene-6) is down-regulated during osteoblastic differentiation. Adenovirus vector-mediated overexpression of TSG-6 inhibited osteoblastic differentiation of human mesenchymal stem cells induced by BMP (bone morphogenetic protein)-2 or OS (osteogenic differentiation medium). TSG-6 suppressed phosphorylation and nuclear accumulation of Smad 1/5 induced by BMP-2, probably by inhibiting binding of the ligand to the receptor, since interaction between TSG-6 and BMP-2 was observed in vitro. TSG-6 has two functional domains, a Link domain (a hyaluronan binding domain) and a CUB domain implicated in protein interaction. The inhibitory effect on osteoblastic differentiation was completely lost with exogenously added Link domain-truncated TSG-6, while partial inhibition was retained by the CUB domain-truncated protein. In addition, the inhibitory action of TSG-6 and the in vitro interaction of TSG-6 with BMP-2 were abolished by the addition of hyaluronan. Thus, TSG-6, identified as a down-regulated gene during osteoblastic differentiation, suppresses osteoblastic differentiation induced by both BMP-2 and OS and is a plausible target for therapeutic intervention in OPLL.

Alkaline Phosphatase↗
PubMed2006

Propagation phenomena of wideband guided waves in a bended pipe.

Ultrasonic guided waves in pipes have been anticipated as a rapid screening technique for pipe inspection because of their long-range propagation due to low energy leakage. In this paper, the propagation phenomena of guided waves in a bended pipe were investigated using a wideband laser ultrasonic system. The laser ultrasonic system, together with wavelet transformation, is a powerful tool for observing the dispersive phenomena intrinsic to guided waves. Bended stainless steel (SUS304) pipes with 6-mm outer diameter and 1-mm wall thickness were used in the experiments. The bending angles of the pipes were set to 0 degrees (straight pipe), 10 degrees, 30 degrees, 60 degrees and 90 degrees. The radius of the bend was 12.5 mm in all the pipes. A Q-switched Nd:YAG laser was employed to generate the guided waves. The generated guided waves were detected with a heterodyne interferometer. The obtained time-domain signals and their wavelet coefficients indicated the following two conclusions: (1) The amplitude of the F(1,1) mode converted from the L(0,1) mode increased with the increase of the bending angle. (2) Mode conversions from the L(0,1) to F(1,1) modes and vice versa were clearly observed in the low-frequency range up to around 200 kHz.

Journal Article↗
PubMed2006

JPO1/CDCA7, a novel transcription factor E2F1-induced protein, possesses intrinsic transcriptional regulator activity.

JPO1/CDCA7 was originally identified as a c-Myc-responsive gene that participates in neoplastic transformation. Here, we report the identification of JPO1/CDCA7 as a direct transcriptional target of transcription factor E2F1. We demonstrated that overexpression of E2F1 by adenoviral-mediated gene transfer upregulated JPO1/CDCA7 mRNA expression in human cells. Analysis of human and mouse JPO1/CDCA7 promoter constructs showed that an E2F-responsive sequence was necessary for E2F1-induced activation of the JPO1/CDCA7 gene transcription. Among the members of the E2F family, E2F1 to E2F4, but not E2F5 or E2F6, activated the JPO1/CDCA7 reporter construct. Chromatin immunoprecipitation analysis demonstrated that E2F1, E2F2, and E2F4 specifically bound to an E2F-responsive sequence of the human JPO1/CDCA7 gene. Like JPO2/R1, which has a homologous transcriptional regulator domain, the C-terminal cysteine-rich region of JPO1/CDCA7 protein induced transcriptional activity in a mammalian one-hybrid assay. Taken together, our results suggest that JPO1/CDCA7 is a unique transcription regulator whose expression is activated by E2F1 as well as c-Myc.

Animals↗
PubMed2006

Designed fabrication of ordered porous au/ag nanostructured films for surface-enhanced Raman scattering substrates.

This article reports the designed preparation of two different kinds of novel porous metal nanostructured films, namely, an ordered macroporous Au/Ag nanostructured film and an ordered hollow Au/Ag nanostructured film. Different from previous reports, the presently proposed method can be conveniently used to control film structures by simply varying the experimental conditions. The morphology of these films has been characterized by scanning electron microscopy (SEM), and their performance as surface-enhanced Raman scattering (SERS) substrates has been evaluated by using rhodamine 6G (R6G) as a probe molecule. We show that such porous nanostructured films consisting of larger interconnected aggregates are highly desirable as SERS substrates in terms of high Raman intensity enhancement, excellent stability, and reproducibility. The interconnected nanostructured aggregate, long-range ordering porosity, and nanoscale roughness are important factors responsible for this large SERS enhancement ability.

Journal Article↗
PubMed2006

Acute loss of transcription factor E2F1 induces mitochondrial biogenesis in HeLa cells.

Here, we sought to clarify the comprehensive cellular response to transcription factor E2F1 expression using short interfering RNA (siRNA)-mediated gene silencing to examine the roles of E2F1. For this purpose, we analyzed global gene expression changes in E2F1 knockdown HeLa cells, where no changes in cell growth or apoptosis were observed. Among the identified genes, the mRNA levels of mitochondria-encoded genes were highly elevated in E2F1 siRNA-treated cells, but not in E2F6 siRNA-treated cells, relative to control siRNA-treated cells. These changes were accompanied by a significant increase in the transcription and replication of mitochondria DNA as well as the induction of nuclear-encoded mitochondrial topoisomerase I (TOP1MT) mRNA in E2F1 knockdown cells, but not in E2F6 knockdown cells, whereas the levels of nuclear-encoded mitochondrial transcription factor A (TFAM) mRNA and protein were unchanged, relative to the levels in control siRNA-treated cells. Time-course experiments demonstrated that the induction of TOP1MT coincided with the timing of E2F1 loss. In addition, E2F1 knockdown cells, but not E2F6 knockdown cells, displayed increased ATP levels along with an accumulation of cytochrome b protein. Finally, RNA interference (RNAi)-mediated reduction in E2F1 knockdown HeLa cells, but not in E2F6 knockdown HeLa cells, resulted in increased anticancer drug sensitivity. Taken together, these data demonstrate a novel physiological aspect of E2F1 in human cancer cells, where activated mitochondrial biogenesis occurs as a consequence of the acute loss of E2F1.

Adenosine Triphosphate↗
PubMed2006

A combined computational and experimental study on the structure-regulation relationships of putative mammalian DNA replication initiator GINS.

GINS, a heterotetramer of SLD5, PSF1, PSF2, and PSF3 proteins, is an emerging chromatin factor recognized to be involved in the initiation and elongation step of DNA replication. Although the yeast and Xenopus GINS genes are well documented, their orthologous genes in higher eukaryotes are not fully characterized. In this study, we report the genomic structure and transcriptional regulation of mammalian GINS genes. Serum stimulation increased the GINS mRNA levels in human cells. Reporter gene assay using putative GINS promoter sequences revealed that the expression of mammalian GINS is regulated by 17beta-Estradiol-stimulated estrogen receptor alpha, and human PSF3 acts as a gene responsive to transcription factor E2F1. The goal of this study is to present the current data so as to encourage further work in the field of GINS gene regulation and functions in mammalian cells.

Animals↗
PubMed2006

The small heat shock protein alphaB-crystallin inhibits differentiation-induced caspase 3 activation and myogenic differentiation.

Myoblasts respond to growth factor deprivation either by diffentiation into multinucleated myotubes or by undergoing apoptosis. The induction of apoptosis and differentiation in myogenic lineage may use overlapping cellular mechanisms. Here we demonstrate that the expression of the small heat shock protein alphaB-crystallin as well as MyoD and myogenin is induced during myogenic differentiation in C2C12 cells, and these inductions occur at an early stage in the differentiation in vitro. To investigate the effect of alphaB-crystallin on myogenic differentiation and apoptosis, C2C12 cells were infected with adenovirus vector bearing full-length alphaB-crystallin cDNA. Overexpression of alphaB-crystallin in C2C12 cells suppressed differentiation-induced apoptosis and activation of caspase 3, and also decreased the expression of MyoD and myogenin during myogenic differentiation of C2C12 cells induced by the differentiation medium. Our findings suggest that stress such as growth factor deprivation plays an important role in triggering apoptosis associated with myogenic differentiation and alphaB-crystallin suppressed the differentiation, apoptosis and caspase 3 activity.

Animals↗
PubMed2006

Geminin as a molecular target for the development of new anticancer drugs.

The unique biological properties of Geminin, particularly as an inhibitor of DNA replication initiation, have been recognized, and this has prompted a number of investigations into this molecule to explore its potential therapeutic as well as diagnostic usefulness. This review summarizes the possibility of Geminin serving as a new molecular target in the development of new anticancer drugs.

Antineoplastic Agents↗
PubMed2006

Chemical surface modification of high-strength porous Ti compacts by spark plasma sintering.

The biological properties of a titanium (Ti) implant depend on its surface oxide film. The aims of the present study were to increase the specific surface oxide area on Ti using a porous structure and to study the relationship between the amount of apatite coating in simulated body fluid (SBF) and the actual surface area on titanium powders. Ti powders of 110 microm average diameter were sintered by spark plasma sintering. The sintered compacts had a porosity of 28%, a compressive elastic modulus of 7.9 GPa and an ultimate strength of 112 MPa. The compressive strength of the compacts was increased to 588 MPa by subsequent annealing in a vacuum furnace at 1000 degrees C for 24 h. The sintered compacts were treated with aqueous NaOH solution and subsequently heated at 600 degrees C. The pretreated compacts showed apatite crystal precipitation in SBF. The amounts of precipitates through the compacts were compared with those of the Ti plate substrates subjected to the same chemical pretreatment. It was confirmed that the amounts of precipitates through the compacts were more than one hundred times higher than those on the Ti plates. It was concluded that the metal porous compacts developed may be used as functional materials for immobilizing functional proteins and/or drugs, because the precipitated apatite can adsorbed these substances.

Apatites↗
PubMed2005

Comparative genomics on MCM8 orthologous genes reveals the transcriptional regulation by transcription factor E2F.

Minichromosome maintenance protein (MCM) is composed of six structurally related subunits (MCM2-7) and is essential for eukaryotic DNA replication initiation and early stage of elongation process. Recently human and Xenopus MCM8 was identified as a novel member of MCM protein. Here we characterized MCM8 orthologous genes by using bioinformatics. Human MCM8 showed approximately 90%, 90%, 93%, and 79% total-amino acid identity with mouse, rat, dog, and chicken MCM8, respectively. Human, mouse, rat, dog, and chicken MCM8 gene, consisting of 19, 18, 17, 18, and 18 exons, was mapped to 20p12.3-13, 2F3, 3q36, 24, and 3, respectively. We identified transcription factor E2F-binding motifs in the vicinity of the transcription start site among MCM8 orthologous genes. The mammalian but not chicken E2F-binding motif was accompanied by NF-Y binding motif. MCM8 mRNA was upregulated by E2E1 in human culture cells. Chromatin immunoprecipitation (ChIP) demonstrated the direct association of E2F1 and NF-Y with human MCM8 promoter. The promoter activities of human, rat, and chicken MCM8 were demonstrated to be E2F1-dependent. Analysis of human MCM8 promoter constructs showed that an E2F-binding motif in the vicinity of the transcription initiation site is necessary for the transcriptional activation. We also showed that the transcription of human MCM8 is activated by transcription factors E2F1-4, but not by factors E2F5-8.

Amino Acid Motifs↗
PubMed2005

Identification of a novel cell-cycle-induced MCM family protein MCM9.

The minichromosome maintenance (MCM) proteins are essential for DNA replication initiation and elongation in eukaryotes. In mammalian cells, MCM2-MCM7 complexes are believed to unwind DNA during chromosomal DNA replication. Here we identified a novel MCM family gene, MCM9, by using bioinformatics. Human, mouse, and rat MCM9 showed approximately 90-91% total-amino acid identity. MCM9 showed 24-31% total-amino acid identity with MCM2-MCM8 protein. Phylogenetic analysis on MCM family members revealed that MCM9 was most closely related to MCM8. Human, mouse, and rat MCM9 gene, consisting of 7, 8, and 7 exons, was mapped to 6q22.1-22.33, 10B3, and 20q11, respectively. We identified transcription factor E2F-binding motifs in the vicinity of the transcription start site among human, mouse, and rat MCM9 gene. MCM9 mRNA was upregulated by transcription factor E2E1 and serum stimulation in NIH3T3 cells.

Amino Acid Sequence↗
PubMed2005

Cell-cycle-dependent regulation of the human and mouse Tome-1 promoters.

Tome-1, which refers to a trigger of mitotic entry 1, mediates the destruction of the mitosis-inhibitory kinase, Wee1, via the E3 ligase, SCF. In turn, Tome-1 itself is targeted for degradation by APC in the G1 phase of the cell cycle. In the present study, we analyzed the human and mouse Tome-1 promoter regions. Using synchronized cultures of NIH3T3 cells transfected with Tome-1 promoter/luciferase constructs, we showed that the promoter activity of Tome-1 is activated at the G2/M phase. Using various Tome-1 promoter/luciferase constructs, we showed that the CCAAT box located upstream of the transcription initiation site is important for the basal promoter activity. We identified a repressor element (cell-cycle-dependent element/cell cycle gene homology region) in the vicinity of the transcription start site, and mutations within this element diminished the cell-cycle-dependent transcriptional regulation of Tome-1.

5' Flanking Region↗
PubMed2005

Identification and characterization of human ZNF18 gene in silico.

Zinc finger protein genes are regulatory transcription factors that interact directly with DNA and/or RNA. Here, we identified the ZNF18 gene by using bioinformatics. Human ZNF18 gene, consisting of 9 exons, was located within human genome sequences RP11-1096G20 (AC005410.3). Complete coding sequence of human ZNF18 cDNA was determined by FLJ35337 cDNA (AK092656), which was identified by using partial coding sequence of human ZNF18 cDNA (X52342) as a query. Human, mouse, and rat ZNF18 showed 77-92% total-amino acid identity. N-terminal leucine rich region, krueppel-associated box, and C-terminal three C2H2 type zinc finger motifs were identified within ZNF18 protein. This is the first report on identification and characterization of the ZNF18 gene.

Amino Acid Sequence↗
PubMed2005

Identification and characterization of a novel kelch-like gene KLHL15 in silico.

Kelch-like proteins are implicated in embryogenesis and carcinogenesis through cytoskeleton organization. KLHL (kelch homolog) genes, containing two evolutionary conserved domains--broad-complex, tramtrack, bric-a-brac/poxvirus and zinc finger (BTB/POZ) domains, and kelch motif, are human homologs of Drosophila kelch gene. We identified the KLHL15 gene, a novel human homolog of Drosophila kelch, by using bioinformatics. KLHL15 gene, consisting of 4 exons, was located within human genome sequences RP11-47911 (AC079169.32) and RP11-793H5 (AC079376.26). Complete coding sequence of human KLHL15 cDNA was determined by assembling FLJ32736 cDNA (AK057298) and KIAA1677 cDNA (AB051464). The human, chicken, and zebra fish KLHL15 (604 aa) showed 85-93% total-amino acid identity. N-terminal BTB/POZ domain and C-terminal three KELCH motifs were identified within KLHL15 protein by using the Pfam program. Human KLHL15 mRNA was expressed ubiquitously in various tissues. This is the first report on identification and characterization of the KLHL15 gene.

Amino Acid Sequence↗