Regulation of cyclin D1 expression and cell cycle progression by mitogen-activated protein kinase cascade

Regulation of cyclin D1 expression and cell cycle progression by mitogen-activated protein kinase cascade. Mitogen-activated protein kinases (MAPKs) have been shown to play an important role in transducing extracellular signals into cellular responses. The classic MAPK pathway is commonly activated by growth factors and has been shown to play a crucial role in cell proliferation. Transforming growth factor-β (TGF-β)–activating kinase-1 (TAK1) is a novel MAPK kinase kinase that is reported to stimulate the MKK6-p38K pathway. To elucidate the functional roles of the TAK1 pathway, we transfected its constitutive active form (TAKdN) and negative form (TAKK63W) to LLC-PK1 cells. TAKdN stimulated MKK6 phosphorylation and p38K activity and inhibited the percentages of the S and G2/M phases. TAKK63W, the constitutive negative form, reduced TGF-β–stimulated MKK6 phosphorylation and p38K activity and increased the percentages of the S and G2/M phases. The cyclin D1 protein level is reduced by the TAK1 pathway. We also examined the effects of the TAK1 pathway on cyclin D1 promoter-luciferase assay. The overexpression of TAKdN or p38K inhibited cyclin D1 promoter activity. In contrast, overexpression of the active form of MKK1, the classic MAPK-activator, MKK1 increased cyclin D1 promoter activity and protein level, as well as the percentages of S and G2/M phases

TGF-βbgr-activating kinase-1 inhibits cell cycle and expression of cyclin D1 and A in LLC-PK1 cells

TGF-βbgr-activating kinase-1 inhibits cell cycle and expression of cyclin D1 and A in LLC-PK1 cells.BackgroundTransforming growth factor-βbgr (TGF-βbgr) is known to play an important role in the pathophysiology of renal tubular disease. Researchers have recently identified a novel mitogen-activated protein kinase kinase kinase (MAPKKK), TAK (TGF-βbgr activated kinase)1, which stimulates the MKK3/6-p38K pathway. The purpose of our study was to investigate the functional role of the TAK1-MKK3/6-p38K pathway and classical MAPK cascades in the progression of the cell cycle in renal tubular cells.MethodsThe constitutive active form and negative form of TAK1 (TAK1dN and TAK1K63W, respectively), and active and negative forms of the p42/44 MAPK-activator, MKK1 (S222E and S222A, respectively) were transfected to LLC-PK1 cells. Western blot analyses and promoter-luciferase assay of cyclins D1, D2, D3, E, and A were performed, and cell cycle progression was analyzed by FACS scan.ResultsTAK1dN stimulated MKK6 and p38K activity and inhibited the percentage of the S and G2/M phases. TAK1K63 W inhibited TGF-βbgr-stimulated MKK6 and p38K activity. Cyclin D1 and cyclin A protein levels and promoter activities were negatively regulated by TAK1dN. In contrast, overexpression of the active form of p42/44 MAPK-activator, MKK1, increased cyclin D1 and A promoter activity and protein levels.ConclusionThe growth-inhibitory effects of TGF-βbgr are at least partially mediated by the TAK1-MKK6-p38K pathway. Cyclin D1 and A promoter activity and cell cycle progression in renal tubular cells are negatively regulated by the TAK1-MKK6-p38K pathway and positively regulated by the MKK1-p42/44MAPK pathway

Does weather affect highway capacity

ABSTRACT Various studies on negative effects of rainfall on travel demand and accidents are well documented. However, there are fewer studies on the effect of weather on capacity. As capacity can only be measured on a short section with high traffic flow and it demands more localised weather information which are not easy to collect. The aim of this paper is to determine the effects of rain on capacity and speed and the effects of daylight on capacity. Traffic data from the Tokyo Metropolitan Expressway (MEX) and weather data from the Tokyo Sewerage Bureau's radar rain gauge system (AMESH) are used. From the analysis of 5 highly congested sections of MEX, the effects of rain on capacity and speed are demonstrated. Further analysis of the capacity during the morning peak of the winter and summer months show a reduction in capacity due to effects of daylight. INTRODUCTION Researches into the effects of weather and travel demand were carried out as early as the 50s b

Activated STAT1 suppresses proliferation of cultured rat mesangial cells

Activated STAT1 suppresses proliferation of cultured rat mesangial cells.BackgroundJAK-STAT signaling has been shown to promote development and proliferation in lymphopoietic and hematopoietic lineages. We investigated the effect of activated STAT1 on mesangial cell proliferation.MethodsRat mesangial cells of primary culture (rMCs) were used in the following experiments: (1) Whole cell lysates were immunoblotted against JAK1 and JAK2. (2) Whole cell lysates and nuclear proteins were extracted from rMCs with or without treatment with interferon-γ, and immunoblotting was performed against both STAT1 and tyrosine (701)-phosphorylated STAT1. (3) rMCs and rMCs electroporated with either wild-type STAT1, mutated STAT1, or antibody against STAT1 were incubated with interferon-γ for 20 hours, followed by a further incubation with [3H]-thymidine for four hours.ResultsJAK1, JAK2, and STAT1 were detected in whole cell lysates, suggesting that JAK-STAT signaling could be activated by interferon-γ (INF-γ). Using an antibody specific for tyrosine-phosphorylated STAT1, we detected signal in the INF-γ–treated nuclear extracts, which showed translocation of phosphorylated STAT1 to the nucleus. [3H]-thymidine incorporation in the presence of INF-γ was significantly lower than that of control in a dose-dependent manner. The introduction of wild-type STAT1 enhanced the effect of interferon-γ and decreased [3H]-thymidine incorporation, whereas tyrosine-mutated (Y701F) STAT1 and SH2 domain (R602T)-mutated STAT1 reversed INF-γ–induced suppression of [3H]-thymidine incorporation. Electroinjected antibody against STAT1 increased [3H]-thymidine incorporation upon stimulation with INF-γ.ConclusionSTAT1 activated by interferon-γ suppresses mesangial cell proliferation

Assisted reproductive technology in Japan : A summary report for 2016 by the Ethics Committee of the Japan Society of Obstetrics and Gynecology

Purpose: The Japan Society of Obstetrics and Gynecology started an online cycle-based assisted reproductive technology (ART) registry system in 2007. This report presents the characteristics and treatment outcomes of ART registered for the cycles practiced during 2016. Methods: Cycle‐specific information for all ART cycles implemented in participating ART facilities were collected. A descriptive analysis was conducted for the registry database of 2016. Results: In total, 447 790 treatment cycles and 54 110 neonates (one in 18.1 neonates born in Japan) were reported in 2016. The mean patients’ age was 38.1 years (SD = 4.5). Among the egg retrieval cycles, 104 575 of 251 399 (41.6%) were freeze-all cycles without fresh embryo transfers (ET), while fresh ET was performed in 64 497 cycles (58.4%). A total of 187 132 frozen‐thawed ET cycles were reported, resulting in 62 432 pregnancies and 44 484 neonates born. Single ET was selected for 81.0% of fresh transfers and 82.7% of frozen cycles, resulting in singleton pregnancy/live birth rates of 97.0%/96.4% and 96.7%/96.4%, respectively. Conclusion: The total ART cycles and subsequent live births continued to increase in 2016. Single ET was performed more than 80%, and ET has shifted from using fresh embryos to frozen ones

Assisted reproductive technology in Japan : a summary report of 1992–2014 by the Ethics Committee, Japan Society of Obstetrics and Gynecology

Aim: The Japan Society of Obstetrics and Gynecology implemented a registry report system for the clinical practice of assisted reproductive technology in 1986. The aggregated results from 1992 to 2014 are reported herein. Methods and Results: The total number of registered treatments was 393 745 cycles, of which 66 550 were pregnancy cycles and 46 008 were cycles with a live birth. Compared to the number of registered treatments in 2008, when the cycle‐based registry was newly introduced, there was a 2.07‐fold increase in the total number of treatments and a 2.25‐fold increase in the number of cycles with a live birth. As the average age of patients who receive assisted reproductive technology has become markedly higher year by year, the most common age of those patients who received assisted reproductive technology in 2014 was 40 years. Conclusion: The total numbers of both assisted reproductive technology treatments and assisted reproductive technology live births are likely to be higher in the future. In addition, the trend toward aging patients seems to be continuing into the future

Assisted reproductive technology in Japan : a summary report for 2015 by The Ethics Committee of The Japan Society of Obstetrics and Gynecology

Purpose: The Japan Society of Obstetrics and Gynecology (JSOG) implemented an assisted reproductive technology (ART) registry system in 1986. Here are reported the characteristics and treatment outcomes of ART cycles that were registered in 2015. Methods: JSOG has requested all participating ART facilities to register cycle-specific information for all ART cycles since 2007. A descriptive analysis was performed by using the registry database for 2015. Results: In total, 424 151 cycles and 51 001 neonates (1 in 19.7 neonates born in Japan) were registered in 2015. The patients’ mean age was 38.2 years (standard deviation = 4.5). Among the fresh cycles, 94 158 of 244 718 (38.5%) egg retrieval cycles were cycles with freeze-all embryos or oocytes, while fresh embryo transfer (ET) was performed in 70 254 cycles, signaling a decrease from 2014. There were 169 898 frozen-thawed ET cycles, resulting in 56 355 pregnancies and 40 599 neonates. Single ET was performed at a rate of 79.7% for fresh and 81.8% for frozen cycles and the singleton pregnancy/live birth rates were 96.9%/96.5% and 96.8%/96.4% for the respective cycles. Conclusion: The total ART cycles and live births resulting from ART has been increasing in Japan. Single ET was performed at a rate of almost 80% and ET cycles have shifted from fresh to frozen cycles

Complete paternal uniparental isodisomy for chromosome 1 revealed by mutation analyses of the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with congenital insensitivity to pain with anhidrosis

Uniparental disomy (UPD) is defined as the presence of a chromosome pair that derives from only one parent in a diploid individual. The human TRKA gene on chromosome 1q21-q22 encodes a receptor tyrosine kinase for nerve growth factor and is responsible for an autosomal recessive genetic disorder: congenital insensitivity to pain with anhidrosis (CIPA). We report here the second case of paternal UPD for chromosome 1 in a male patient with CIPA who developed normally at term and did not show overt dysmorphisms or malformations. He had only the usual features of CIPA with a homozygous mutation at the TRKA locus and a normal karyotype with no visible deletions or evidence of monosomy 1. Haplotype analysis of the TRKA locus and allelotype analyses of whole chromosome 1 revealed that the chromosome pair was exclusively derived from his father. Non-maternity was excluded by analyses of autosomes other than chromosome 1. Thus, we have identified a complete paternal isodisomy for chromosome 1 as the cause of reduction to homozygosity of the TRKA gene mutation, leading to CIPA. Our findings further support the idea that there are no paternally imprinted genes on chromosome 1 with a major effect on phenotype. UPD must be considered as a rare but possible cause of autosomal recessive disorders when conducting genetic testing

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection