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• Human SMG-1, a novel phosphatidylinositol 3-kinase-related protein kinase, associates with components of the mRNA surveillance complex and is involved in the regulation of nonsense-mediated mRNA decay

  2001.09

  DOI

Published Papers 【 display / non-display 】

Published Papers 【 display / non-display 】

• Maintenance of R-loop structures by phosphorylated hTERT preserves genome integrity.

  Mitsuhiro Machitani, Akira Nomura, Taro Yamashita, Mami Yasukawa, Saori Ueki, Ken-Ichi Fujita, Toshihide Ueno, Akio Yamashita, Yoshikazu Tanzawa, Masahiko Watanabe, Toshiyasu Taniguchi, Noriko Saitoh, Shuichi Kaneko, Yukinari Kato, Hiroyuki Mano, Kenkichi Masutomi

  Nature cell biology   26 ( 6 ) 932 - 945   2024.06 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  As aberrant accumulation of RNA-DNA hybrids (R-loops) causes DNA damage and genome instability, cells express regulators of R-loop structures. Here we report that RNA-dependent RNA polymerase (RdRP) activity of human telomerase reverse transcriptase (hTERT) regulates R-loop formation. We found that the phosphorylated form of hTERT (p-hTERT) exhibits RdRP activity in nuclear speckles both in telomerase-positive cells and telomerase-negative cells with alternative lengthening of telomeres (ALT) activity. The p-hTERT did not associate with telomerase RNA component in nuclear speckles but, instead, with TERRA RNAs to resolve R-loops. Targeting of the TERT gene in ALT cells ablated RdRP activity and impaired tumour growth. Using a genome-scale CRISPR loss-of-function screen, we identified Fanconi anaemia/BRCA genes as synthetic lethal partners of hTERT RdRP. Inactivation of RdRP and Fanconi anaemia/BRCA genes caused accumulation of R-loop structures and DNA damage. These findings indicate that RdRP activity of p-hTERT guards against genome instability by removing R-loop structures.

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• Angiotensin II type 1 receptor-associated protein deletion combined with angiotensin II stimulation accelerates the development of diabetic kidney disease in mice on a C57BL/6 strain

  Taguchi, S; Azushima, K; Yamaji, T; Suzuki, T; Abe, E; Tanaka, S; Hirota, K; Tsukamoto, S; Morita, R; Kobayashi, R; Kinguchi, S; Yamashita, A; Wakui, H; Tamura, K

  HYPERTENSION RESEARCH ( Hypertension Research )  47 ( 1 ) 55 - 66   2024.01 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  The progress in the research field of diabetic kidney disease (DKD) has been disturbed by the lack of reliable animal models. Angiotensin II (Ang II) type 1 receptor (AT1R)-associated protein (ATRAP) promotes internalization of AT1R and selectively inhibits pathological AT1R signaling. In this study, we investigated whether overactivation of the renin-angiotensin system (RAS) through a combination of ATRAP deletion with Ang II stimulation developed a progressive DKD model in C57BL/6 mice, which are resistant to the development of kidney injury. Eight-week-old male systemic ATRAP-knockout mice on the C57BL/6 strain (KO) and their littermate wild-type mice (Ctrl) were divided into five groups: 1) Ctrl, 2) Ctrl-streptozotocin (STZ), 3) KO-STZ, 4) Ctrl-STZ-Ang II, and 5) KO-STZ-Ang II. Ang II was administered for 6 weeks from 4 weeks after STZ administration. At 10 weeks after STZ administration, mice were euthanized to evaluate kidney injuries. Neither ATRAP deletion alone nor Ang II stimulation alone developed a progressive DKD model in STZ-induced diabetic C57BL/6 mice. However, a combination of ATRAP deletion with Ang II stimulation accelerated the development of DKD as manifested by overt albuminuria, glomerular hypertrophy, podocyte loss, mesangial expansion, kidney interstitial fibrosis and functional insufficiency, concomitant with increased angiotensinogen and AT1R expression in the kidneys. In STZ-induced diabetic C57BL/6 mice that are resistant to the development of kidney injury, the combination of ATRAP deletion and Ang II stimulation accelerates the development of DKD, which may be associated with intrarenal RAS overactivation.

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• miR-125a-5p/miR-125b-5p contributes to pathological activation of angiotensin II-AT1R in mouse distal convoluted tubule cells by the suppression of Atrap

  Hirota, K; Yamashita, A; Abe, E; Yamaji, T; Azushima, K; Tanaka, S; Taguchi, S; Tsukamoto, S; Wakui, H; Tamura, K

  JOURNAL OF BIOLOGICAL CHEMISTRY ( Journal of Biological Chemistry )  299 ( 12 ) 105478 - 105478   2023.12 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  The renin-angiotensin system (RAS) plays a crucial role in the regulation of blood pressure. Activation of the angiotensin II (Ang II)-Ang II type 1 receptor (AT1R) signaling pathway contributes to the pathogenesis of hypertension and subsequent organ damage. AT1R-associated protein (ATRAP) has been identified as an endogenous inhibitory protein of the AT1R pathological activation. We have shown that mouse Atrap (Atrap) represses various Ang II-AT1R-mediated pathologies, including hypertension in mice. The expression of human ATRAP (ATRAP) /Atrap can be altered in various pathological states in humans and mice, such as Ang II stimulation and serum starvation. However, the regulatory mechanisms of ATRAP/Atrap are not yet fully elucidated. MicroRNAs (miRNAs) are 21-23 nucleotides of small RNAs which post-transcriptionally repress gene expression. Single miRNA can act on hundreds of target mRNAs, and numerous miRNAs have been identified as the Ang II-AT1R signaling-associated disease phenotype modulator, but nothing is known about the regulation of ATRAP/Atrap. In the present study, we identified miR-125a-5p and miR-125b-5p as the evolutionarily conserved miRNAs that potentially act on ATRAP/Atrap mRNA. Further analysis revealed that miR-125a-5p and miR-125b-5p can directly repress both ATRAP and Atrap. In addition, the inhibition of miR-125a-5p/miR-125b-5p resulted in the suppression of the Ang II-AT1R signaling in mouse distal convoluted tubule (mDCT) cells. Taken together, miR-125a-5p/miR-125b-5p activates Ang II-AT1R signaling by the suppression of ATRAP/Atrap. Our results provide new insights into the potential approaches for achieving the organ-protective effects by the repression of the miR-125 family associated with the enhancement of ATRAP/Atrap expression.

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• Combination of sacubitril/valsartan and blockade of the PI3K pathway enhanced kidney protection in a mouse model of cardiorenal syndrome.

  Tsukamoto S, Wakui H, Uehara T, Shiba Y, Azushima K, Abe E, Tanaka S, Taguchi S, Hirota K, Urate S, Suzuki T, Yamada T, Kinguchi S, Yamashita A, Tamura K

  European heart journal open ( European Heart Journal Open )  3 ( 6 ) oead098   2023.11 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  AIMS: Angiotensin receptor-neprilysin inhibitor (ARNI) is an established treatment for heart failure. However, whether ARNI has renoprotective effects beyond renin-angiotensin system inhibitors alone in cardiorenal syndrome (CRS) has not been fully elucidated. Here, we examined the effects of ARNI on the heart and kidneys of CRS model mice with overt albuminuria and identified the mechanisms underlying ARNI-induced kidney protection. METHODS AND RESULTS: C57BL6 mice were subjected to chronic angiotensin II infusion, nephrectomy, and salt loading (ANS); they developed CRS phenotypes and were divided into the vehicle treatment (ANS-vehicle), sacubitril/valsartan treatment (ANS-ARNI), and two different doses of valsartan treatment (ANS-VAL M, ANS-VAL H) groups. Four weeks after treatment, the hearts and kidneys of each group were evaluated. The ANS-vehicle group showed cardiac fibrosis, cardiac dysfunction, overt albuminuria, and kidney fibrosis. The ANS-ARNI group showed a reduction in cardiac fibrosis and cardiac dysfunction compared with the valsartan treatment groups. However, regarding the renoprotective effects characterized by albuminuria and fibrosis, ARNI was less effective than valsartan. Kidney transcriptomic analysis showed that the ANS-ARNI group exhibited a significant enhancement in the phosphoinositide 3-kinase (PI3K)-AKT signalling pathway compared with the ANS-VAL M group. Adding PI3K inhibitor treatment to ARNI ameliorated kidney injury to levels comparable with those of ANS-VAL M while preserving the superior cardioprotective effect of ARNI. CONCLUSION: PI3K pathway activation has been identified as a key mechanism affecting remnant kidney injury under ARNI treatment in CRS pathology, and blockading the PI3K pathway with simultaneous ARNI treatment is a potential therapeutic strategy for treating CRS with overt albuminuria.

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• Simultaneous measurement of nascent transcriptome and translatome using 4-thiouridine metabolic RNA labeling and translating ribosome affinity purification.

  Hirotatsu Imai, Daisuke Utsumi, Hidetsugu Torihara, Kenzo Takahashi, Hidehito Kuroyanagi, Akio Yamashita

  Nucleic acids research   51 ( 14 ) e76   2023.08 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  Regulation of gene expression in response to various biological processes, including extracellular stimulation and environmental adaptation requires nascent RNA synthesis and translation. Analysis of the coordinated regulation of dynamic RNA synthesis and translation is required to determine functional protein production. However, reliable methods for the simultaneous measurement of nascent RNA synthesis and translation at the gene level are limited. Here, we developed a novel method for the simultaneous assessment of nascent RNA synthesis and translation by combining 4-thiouridine (4sU) metabolic RNA labeling and translating ribosome affinity purification (TRAP) using a monoclonal antibody against evolutionarily conserved ribosomal P-stalk proteins. The P-stalk-mediated TRAP (P-TRAP) technique recovered endogenous translating ribosomes, allowing easy translatome analysis of various eukaryotes. We validated this method in mammalian cells by demonstrating that acute unfolded protein response (UPR) in the endoplasmic reticulum (ER) induces dynamic reprogramming of nascent RNA synthesis and translation. Our nascent P-TRAP (nP-TRAP) method may serve as a simple and powerful tool for analyzing the coordinated regulation of transcription and translation of individual genes in various eukaryotes.

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Other Papers 【 display / non-display 】

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• 腎近位尿細管AT1受容体結合因子がアンジオテンシン依存性高血圧に及ぼす影響(Effects of AT1 Receptor-Associated Protein in Renal Proximal Tubules on Angiotensin II-Mediated Hypertension)

  金口 翔, 涌井 広道, 小豆島 健護, 春原 浩太郎, 高口 知之, 大城 光二, 畝田 一司, 白 善雅, 山地 孝拡, 山田 貴之, 小林 竜, 石上 友章, 山下 暁朗, 藤川 哲也, 田村 功一

  日本高血圧学会総会プログラム・抄録集 ( (NPO)日本高血圧学会 )  42回   200 - 200   2019.10

   

• 慢性腎臓病CKDと抗加齢医学 受容体結合性機能制御蛋白と腎性老化

  田村 功一, 涌井 広道, 山地 孝拡, 畝田 一司, 小林 竜, 大城 光二, 金口 翔, 山田 貴之, 浦手 進吾, 山下 暁朗

  Anti-aging Science ( (株)メディカルレビュー社 )  10 ( 1 ) 45 - 45   2018.12

   

• 不死化RPTEC(Renal Proximal Tubule Epithelial Cells)のクローン化による近位尿細管細胞株の樹立及びクローン化細胞におけるATRAPの発現調節の検討

  山地 孝拡, 山下 暁朗, 涌井 広道, 春原 浩太郎, 金口 翔, 山田 貴之, 浦手 進吾, 鈴木 徹, 川井 有紀, 田村 功一

  日本高血圧学会総会プログラム・抄録集 ( (NPO)日本高血圧学会 )  41回   PB05 - 04   2018.09

   

• 糖脂質代謝障害における1型アンジオテンシンII受容体結合蛋白ATRAPの機能的意義

  大城 光二, 涌井 広道, 小豆島 健護, 畝田 一司, 小林 竜, 春原 浩太郎, 岸尾 望, 中島 淳, 山下 暁朗, 田村 功一

  日本内分泌学会雑誌 ( (一社)日本内分泌学会 )  93 ( 4 ) 1383 - 1383   2017.12

   

• 糖脂質代謝障害における1型アンジオテンシンII受容体結合蛋白ATRAPの機能的意義

  大城 光二, 涌井 広道, 小豆島 健護, 畝田 一司, 小林 竜, 春原 浩太郎, 岸尾 望, 中島 淳, 山下 暁朗, 田村 功一

  日本内分泌学会雑誌 ( (一社)日本内分泌学会 )  93 ( 4 ) 1383 - 1383   2017.12

   

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Grant-in-Aid for Scientific Research 【 display / non-display 】

Grant-in-Aid for Scientific Research 【 display / non-display 】

• Challenging research (sprout)

  Project Year: 2021.07  -  2023.03 

  Direct: 5,000,000 (YEN)  Overheads: 6,500,000 (YEN)  Total: 1,500,000 (YEN)

• Grant-in-Aid for Scientific Research(C)

  Project Year: 2020.04  -  2023.03 

  Direct: 3,300,000 (YEN)  Overheads: 4,290,000 (YEN)  Total: 990,000 (YEN)

• A pathophysiological significance of receptor-binding factor in aging-associated cerebral cardiovascular disease

  Grant-in-Aid for Scientific Research(C)

  Project Year: 2020.04  -  2023.03 

  Direct: 3,300,000 (YEN)  Overheads: 4,290,000 (YEN)  Total: 990,000 (YEN)

• Grant-in-Aid for Scientific Research(B)

  Project Year: 2020.04  -  2023.03 

  Direct: 13,600,000 (YEN)  Overheads: 17,680,000 (YEN)  Total: 4,080,000 (YEN)

• Grant-in-Aid for Scientific Research(C)

  Project Year: 2020.04  -  2023.03 

  Direct: 3,300,000 (YEN)  Overheads: 4,290,000 (YEN)  Total: 990,000 (YEN)

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