Papers by Akira Shimamoto
Nature Genetics, Aug 1, 1997
Gene, Apr 21, 1997
A novel human gene referred to as the WS-3 gene, in the short arm of human chromosome 8, was clon... more A novel human gene referred to as the WS-3 gene, in the short arm of human chromosome 8, was cloned by a combination of exon trapping, thermal asymmetric interlaced-PCR (TAIL-PCR) and the Marathon-Ready cDNA amplification method. The gene consists of 7 exons separated by 6 introns, and is at the telomere side of the STS marker, D8S1055. The full-length WS-3 gene contains 1052 nucleotides and codes for a protein of 190 amino acids with a calculated mol. wt. of 20,747. Southern blot experiments showed that the WS-3 gene exists as a single copy in the human genome. A protein encoded by the WS-3 gene has an R-G-D (Arg-Gly-Asp) motif in the N-terminal region, which seems to confer adhesive properties to macromolecular proteins like fibronectin. Although WS-3 is a small gene with unknown biological function, its ubiquitous expression in various tissues and organs suggests that the encoded protein is one of the essential components of all organs and tissues.
Nippon Rinsho Japanese Journal of Clinical Medicine, Aug 1, 2005
The discovery that small double stranded RNAs mediate RNA interference in mammalian cells opened ... more The discovery that small double stranded RNAs mediate RNA interference in mammalian cells opened the way to the therapeutic use of siRNA. siRNA has the properties well suitable for medicine, which of high selectivity, high efficacy with low dose and natural components of cells. While siRNAs are expected to be epoch-making new drugs, such as a biotech-based medicine, there are several problems concerning side effects and bioavailability to be solved, such as interferon response, off-target activity and short half-life in blood circulation. Here, I will discuss with problems that face therapeutic application of RNA interference.
EBioMedicine, 2015
Background: The telomeric 3′-overhang (G-tail) length is essential for the biological effects of ... more Background: The telomeric 3′-overhang (G-tail) length is essential for the biological effects of telomere dysfunction in vitro, but the association of length with aging and cardiovascular risk is unclear in humans. We investigated the association between the telomere G-tail length of leukocytes and cardiovascular risk, agerelated white matter changes (ARWMCs), and endothelial function. Methods: Patients with a history of cerebrovascular disease and comorbidity were enrolled (n = 102; 69 males and 33 females, 70.1 ± 9.2 years). Total telomere and telomere G-tail lengths were measured using a hybridization protection assay. Endothelial function was evaluated by ultrasound assessment of brachial flow-mediated dilation (FMD). Findings: Shortened telomere G-tail length was associated with age and Framingham risk score (P = 0.018 and P = 0.012). In addition, telomere G-tail length was positively correlated with FMD values (P = 0.031) and negatively with the severity of ARWMCs (P = 0.002). On multivariate regression analysis, telomere G-tail length was independently associated with FMD values (P = 0.022) and the severity of ARWMCs (P = 0.033), whereas total telomere length was not associated with these indicators. Interpretation: Telomere G-tail length is associated with age and vascular risk factors, and might be superior to total telomere length as a marker of endothelial dysfunction and ARWMC severity.
American journal of human genetics, Jan 4, 2015
Fanconi anemia (FA) is a rare genetic disorder characterized by genome instability, increased can... more Fanconi anemia (FA) is a rare genetic disorder characterized by genome instability, increased cancer susceptibility, progressive bone marrow failure (BMF), and various developmental abnormalities resulting from the defective FA pathway. FA is caused by mutations in genes that mediate repair processes of interstrand crosslinks and/or DNA adducts generated by endogenous aldehydes. The UBE2T E2 ubiquitin conjugating enzyme acts in FANCD2/FANCI monoubiquitination, a critical event in the pathway. Here we identified two unrelated FA-affected individuals, each harboring biallelic mutations in UBE2T. They both produced a defective UBE2T protein with the same missense alteration (p.Gln2Glu) that abolished FANCD2 monoubiquitination and interaction with FANCL. We suggest this FA complementation group be named FA-T.
PloS one, 2014
Werner syndrome (WS) is a premature aging disorder characterized by chromosomal instability and c... more Werner syndrome (WS) is a premature aging disorder characterized by chromosomal instability and cancer predisposition. Mutations in WRN are responsible for the disease and cause telomere dysfunction, resulting in accelerated aging. Recent studies have revealed that cells from WS patients can be successfully reprogrammed into induced pluripotent stem cells (iPSCs). In the present study, we describe the effects of long-term culture on WS iPSCs, which acquired and maintained infinite proliferative potential for self-renewal over 2 years. After long-term cultures, WS iPSCs exhibited stable undifferentiated states and differentiation capacity, and premature upregulation of senescence-associated genes in WS cells was completely suppressed in WS iPSCs despite WRN deficiency. WS iPSCs also showed recapitulation of the phenotypes during differentiation. Furthermore, karyotype analysis indicated that WS iPSCs were stable, and half of the descendant clones had chromosomal profiles that were si...
Nihon rinsho. Japanese journal of clinical medicine, 2005
The discovery that small double stranded RNAs mediate RNA interference in mammalian cells opened ... more The discovery that small double stranded RNAs mediate RNA interference in mammalian cells opened the way to the therapeutic use of siRNA. siRNA has the properties well suitable for medicine, which of high selectivity, high efficacy with low dose and natural components of cells. While siRNAs are expected to be epoch-making new drugs, such as a biotech-based medicine, there are several problems concerning side effects and bioavailability to be solved, such as interferon response, off-target activity and short half-life in blood circulation. Here, I will discuss with problems that face therapeutic application of RNA interference.
Oncogene, Jan 8, 2001
Bloom syndrome (BS) is a recessive human genetic disorder characterized by short stature, immunod... more Bloom syndrome (BS) is a recessive human genetic disorder characterized by short stature, immunodeficiency and an elevated risk of malignancy. The gene mutated in BS, BLM, encodes a RecQ-type DNA helicase. BS cells have mutator phenotypes such as hyper-recombination, chromosome instability and an increased frequency of sister chromatid exchange (SCE). To define the primary role of BLM, we generated BLM(-/-) mutants of the chicken B-cell line DT40. In addition to characteristics of BLM(-/-) cells reported previously by the other group, they are hypersensitive to genotoxic agents such as etoposide, bleomycin and 4-nitroquinoline-1-oxide and irradiation with the short wave length of UV (UVC) light, whereas they exhibit normal sensitivity to X-ray irradiation and hydroxyurea. UVC irradiation to BLM(-/-) cells during G(1) to early S phase caused chromosomal instability such as chromatid breaks and chromosomal quadriradials, leading to eventual cell death. These results suggest that BLM i...
Molecular and cellular biology, 1998
The regulation of Werner's syndrome gene (WRN) expression was studied by characterizing the c... more The regulation of Werner's syndrome gene (WRN) expression was studied by characterizing the cis-regulatory elements in the promoter region and the trans-activating factors that bind to them. First, we defined the transcription initiation sites and the sequence of the 5' upstream region (2.8 kb) of WRN that contains a number of cis-regulatory elements, including 7 Sp1, 9 retinoblastoma control element (RCE), and 14 AP2 motifs. A region consisting of nucleotides -67 to +160 was identified as the principal promoter of WRN by reporter gene assays in HeLa cells, using a series of WRN promoter-luciferase reporter (WRN-Luc) plasmids that contained the 5'-truncated or mutated WRN upstream regions. In particular, two Sp1 elements proximal to the transcription initiation site are indispensable for WRN promoter activity and bind specifically to Sp1 proteins. The RCE enhances WRN promoter activity. Coexpression of the WRN-Luc plasmids with various dosages of plasmids expressing Rb o...
Telomeres and Telomerase in Cancer, 2009
Abstract All eukaryotic chromosome DNA ends have telomere DNA consisting of double-stranded telom... more Abstract All eukaryotic chromosome DNA ends have telomere DNA consisting of double-stranded telomere DNA repeats, which terminate in single-stranded 3 ... Keywords: Telomere length, G-tail, G-tail telomere HPA, Telomere single-stranded 3 0 -overhang, Shelterin, Telomere-...
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Papers by Akira Shimamoto