A5090303297- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- Stress Responses and Cortisol
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Pituitary Gland Disorders and Treatments
- Hormonal Regulation and Hypertension
- Genomics and Chromatin Dynamics
- Sodium Intake and Health
- RNA modifications and cancer
- Neuroendocrine regulation and behavior
- RNA regulation and disease
- Nutritional Studies and Diet
- Neurogenesis and neuroplasticity mechanisms
- Adrenal and Paraganglionic Tumors
- Estrogen and related hormone effects
- Cancer Immunotherapy and Biomarkers
- Cancer, Hypoxia, and Metabolism
- X-ray Diffraction in Crystallography
- Adrenal Hormones and Disorders
- Tryptophan and brain disorders
- Crystallization and Solubility Studies
- Blood Pressure and Hypertension Studies
- Diabetes Treatment and Management
- Animal Genetics and Reproduction
- Pancreatic function and diabetes
Fukuoka University
2016-2024
Kumamoto Medical Center
2024
Nagoya University
2013-2023
Weatherford College
2022
Obayashi (Japan)
2022
Kyoto University
2015-2017
Japan Advanced Institute of Science and Technology
2013
Fujita Health University
2007-2011
Kyushu University
1995-2010
Inserm
2000-2009
Significance Familial dysautonomia (FD) is caused by missplicing of the IκB kinase complex-associated protein (IKAP) gene, which results in skipping exon 20, especially neurons. FD would be treatable if 20 inclusion were increased correctly to reestablish correct splicing. Here, we have established a dual-color splicing reporter that recapitulates FD-type By using this reporter, identified small chemical compound, named rectifier aberrant (RECTAS), rectifies FD. RECTAS promotes both and...
The DAX-1 (NR0B1) gene encodes an unusual member of the nuclear hormone receptor superfamily which acts as a transcriptional repressor. Mutations in human cause X-linked adrenal hypoplasia congenita (AHC) associated with hypogonadotropic hypogonadism (HHG). We have studied intracellular localization protein cortex and mouse Leydig tumor cells found it to be both cytoplasmic. A significant proportion is polyribosomes complexed polyadenylated RNA. directly binds RNA, two domains within being...
The mammalian testis determining factor SRY and its related Sox factors are critical developmental regulators. They share significant similarity in their high mobility group (HMG) domain display discrete patterns of tissue-specific expression. Here we show that the protein SOX6 colocalize with splicing nucleus dynamically redistributed following blockage living cells. Anti-SOX6 antibodies supershift spliceosomal complex from assembled reactions inhibit vitro multiple pre-mRNA substrates....
Acetylcholinesterase (AChE), encoded by the ACHE gene, hydrolyzes neurotransmitter acetylcholine to terminate synaptic transmission. Alternative splicing close 3΄ end generates three distinct isoforms of AChET, AChEH and AChER. We found that hnRNP H binds two specific G-runs in exon 5a human activates distal alternative splice site (ss) between exons 5b generate AChET. Specific effect was corroborated siRNA-mediated knockdown artificial tethering H. Furthermore, competes for binding CstF64...
Abstract Duchenne muscular dystrophy (DMD) is a fatal progressive muscle-wasting disease. Various attempts are underway to convert severe DMD milder phenotype by modulating the splicing of dystrophin gene and restoring its expression. In our previous study, we reported TG003, an inhibitor CDC2-like kinase 1 (CLK1), as splice-modifying compound for exon-skipping therapy; however, metabolically unstable feature hinders clinical application. Here, show orally available CLK1, named TG693, which...
Abstract Steroidogenic factor 1/adrenal 4 binding protein (SF-1/Ad4BP) is an essential nuclear receptor for steroidogenesis as well adrenal and gonadal gland development. Mesenchymal bone marrow cells (BMCs) contain pluripotent progenitor cells, which differentiate into multiple lineages. In a previous study, we reported that adenovirus-mediated forced expression of SF-1 could transform mouse primary long-term cultured BMCs steroidogenic cells. For future clinical application, trials using...
Abstract CHRNA1 gene, encoding the muscle nicotinic acetylcholine receptor alpha subunit, harbors an inframe exon P3A. Inclusion of P3A disables assembly subunits. A single nucleotide mutation in identified congenital myasthenic syndrome causes exclusive inclusion The gains a de novo binding affinity for splicing enhancing RNA-binding protein, hnRNP LL and displaces suppressing L. L binds to another repressor PTB through proline-rich region promotes polypyrimidine tract upstream P3A, whereas...
Muscle specific receptor tyrosine kinase (MuSK) is an essential postsynaptic transmembrane molecule that mediates clustering of acetylcholine receptors (AChR). MUSK exon 10 alternatively skipped in human, but not mouse. Skipping this disrupts a cysteine-rich region (Fz-CRD), which for Wnt-mediated AChR clustering. To investigate the underlying mechanisms alternative splicing, we exploited block-scanning mutagenesis with human minigene and identified 20-nucleotide block contained exonic...
The pathogenesis of retinal complications, such as hemorrhage and cotton-wool spots formation, during interferon (IFN) therapy is unclear. We studied the relationship between presence complications levels plasma-activated complement 5 (C5a), a known potent intravascular aggregator granulocytes, IFN-alpha therapy.Forty-five patients with chronic hepatitis C but without diabetes mellitus hypertension were studied. was used 10 MU per day for 2 wk 3 times weekly an additional 22 wk. In 25 IFN...
The mechanisms by which huge human introns are spliced out precisely poorly understood. We analyzed large intron 7 (110 199 nucleotides) generated from the dystrophin (DMD) pre‐mRNA RT‐PCR. identified branching between authentic 5′ splice site and branch point; however, sequences far were not detectable. This RT‐PCR product was resistant to exoribonuclease (RNase R) digestion, suggesting that detected lariat has a closed loop structure but contains gaps in its sequence. Transient concomitant...
Nivolumab, an anti–PD-1 antibody, is now considered important therapeutic agent in several advanced malignancies. However, immune-related adverse events such as endocrinopathies have been reported with its use. Thyroid disorder and isolated adrenocorticotropic hormone deficiency frequently nivolumab-induced events. Another endocrinopathy type 1 diabetes mellitus (T1DM), described rapid onset complete insulin insufficiency, at times leading to fulminant T1DM. We report the case of a...
Abstract Aims Chronic stress and glucocorticoid exposure are risk factors for depression. Oxytocin (OT) has been shown to have antistress antidepressant‐like effects in male rodents. However, depression is twice as common women than men, it remains unclear whether OT exerts with Therefore, this study, we investigated the therapeutic effect of chronic administration a female mouse model dexamethasone (DEX)‐induced Methods Female C57BL/6J mice were administered saline (vehicle, s.c.), DEX...
Congenital adrenal hypoplasia, an X-linked disorder, is characterized by primary insufficiency and frequent association with hypogonadotropic hypogonadism. The X-chromosome gene DAX-1 has been most recently identified shown to be responsible for this disorder. We analyzed the genes of two unrelated Japanese patients congenital hypoplasia hypogonadism using PCR amplification genomic DNA its complete exonic sequencing. In a family containing several affected individuals, proband male patient...
Aberrant exon 5 skipping of presenilin‐2 (PS2) pre‐mRNA produces a deleterious protein isoform PS2V, which is almost exclusively observed in the brains sporadic Alzheimer's disease patients. PS2V over‐expression vivo enhances susceptibility to various endoplasmic reticulum (ER) stresses and increases production amyloid‐β peptides. We previously purified identified high mobility group A 1a (HMGA1a) as trans ‐acting factor responsible for aberrant skipping. Using heterologous pre‐mRNAs, here...
Overexpression of high-mobility group A protein 1a (HMGA1a) causes aberrant exon 5 skipping the Presenilin-2 (PS2) pre-mRNA, which is almost exclusively detected in patients with sporadic Alzheimer's disease. An electrophoretic mobility shift assay confirmed U1 small nuclear ribonucleoprotein particle (snRNP)-HMGA1a complex formation (via U1-70K component), RNA containing a specific HMGA1a-binding site and an adjacent 5' splice site. Psoralen cross-linking analysis demonstrated that binding...
Glutamine:fructose-6-phosphate transaminase 1 (GFPT1) is the rate-limiting enzyme of hexosamine biosynthetic pathway (HBP). A 54-bp exon 9 GFPT1 specifically included in skeletal and cardiac muscles to generate a long isoform (GFPT1-L). We showed that SRSF1 Rbfox1/2 cooperatively enhance, hnRNP H/F suppresses, inclusion human by modulating recruitment U1 snRNP. Knockout (KO) GFPT1-L muscle markedly increased amounts UDP-HexNAc, which subsequently suppressed glycolytic pathway. Aged KO mice...
Abstract DAX‐1 (DSS‐AHC Critical Region on the X Chromosome‐1) is a member of nuclear hormone receptor superfamily that has an important role in steroidogenesis and gonadogenesis. To investigate testis, yeast two‐hybrid screen was performed SOX6, Sry box (SOX) protein family, cloned as candidate. The interaction confirmed biochemically expression SOX6 overlapped with developing gonad, well Sertoli cells adult testis. We show here able to inhibit splicing vivo vitro assays, this inhibition...