Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that modulates a wide variety of cellular responses by regulating target gene expression. It principally transmits signals via receptor-activated transcription factors Smad2 and Smad3, which form trimeric complexes with Smad4 upon activation and regulate gene expression by binding to genomic DNA. Here, we examined the mechanisms by which TGF-β regulates the transcription of target genes in a cell context-dependent manner by screening a double-stranded DNA oligonucleotide library for DNA sequences bound to endogenous activated Smad complexes.
View Article and Find Full Text PDFImportance: There is currently no consensus on clinically effective interventions for polypharmacy among older inpatients.
Objective: To evaluate the effect of multidisciplinary team-based medication optimization on survival, unscheduled hospital visits, and rehospitalization in older inpatients with polypharmacy.
Design, Setting, And Participants: This open-label randomized clinical trial was conducted at 8 internal medicine inpatient wards within a community hospital in Japan.
Transforming growth factor β (TGF-β) is a pleiotropic cytokine that is widely distributed throughout the body. Its receptor proteins, TGF-β type I and type II receptors, are also ubiquitously expressed. Therefore, the regulation of various signaling outputs in a context-dependent manner is a critical issue in this field.
View Article and Find Full Text PDFIn mammalian cells, Smad2 and Smad3, two receptor-regulated Smad proteins, play crucial roles in the signal transmission of transforming growth factor-β (TGF-β) and are involved in various cell regulatory processes, including epithelial-mesenchymal transition-associated cell responses, that is, cell morphological changes, E-cadherin downregulation, stress fiber formation, and cell motility enhancement. Smad2 contains an additional exon encoding 30 amino acid residues compared with Smad3, leading to distinct Smad2 and Smad3 functional properties. Intriguingly, Smad2 also has an alternatively spliced isoform termed Smad2Δexon3 (also known as Smad2β) lacking the additional exon and behaving similarly to Smad3.
View Article and Find Full Text PDFSmad2 and Smad3 are receptor-regulated Smad proteins that transmit signals from cytokines belonging to the transforming growth factor (TGF)-β family, which are vital for adult tissue homeostasis. The overactivation of such proteins often engenders the development of pathological conditions. Smad3 reportedly mediates TGF-β-induced fibrosis.
View Article and Find Full Text PDFThe epithelial-mesenchymal transition (EMT) is a crucial morphological event that occurs during epithelial tumor progression. Snail and ZEB1/2 (ZEB1 and ZEB2), known as EMT transcription factors, are key regulators of this transition. ZEB1/2 are positively correlated with EMT phenotypes and the aggressiveness of cancers.
View Article and Find Full Text PDFThe unfolded protein response (UPR) controls protein homeostasis through transcriptional and translational regulation. However, dysregulated UPR signaling has been associated with the pathogenesis of many human diseases. Therefore, the compounds modulating UPR may provide molecular insights for these pathologies in the context of UPR.
View Article and Find Full Text PDFTransforming growth factor-β (TGF-β) signaling promotes cancer progression. In particular, the epithelial-mesenchymal transition (EMT) induced by TGF-β is considered crucial to the malignant phenotype of cancer cells. Here, we report that the EMT-associated cellular responses induced by TGF-β are mediated by distinct signaling pathways that diverge at Smad3.
View Article and Find Full Text PDFSmad6 and Smad7 are classified as inhibitory Smads (I-Smads). They are crucial in the fine-tuning of signals by cytokines of the transforming growth factor-β (TGF-β) family. They are negative feedback regulators and principally target the activated type I receptors as well as the activated Smad complexes, but with distinct specificities.
View Article and Find Full Text PDFE-cadherin, an epithelial cell-specific cell adhesion molecule, has both promoting and suppressing effects on tumor invasion and metastasis. It is often downregulated during cancer progression through gene deletion/mutation, transcriptional repression, or epigenetic silencing. We describe a novel regulatory switch to induce stimulus-dependent downregulation of mRNA encoding E-cadherin (CDH1 mRNA) in KRAS-mutated cancer cells.
View Article and Find Full Text PDFIntroduction: Whether medication optimisation improves clinical outcomes in elderly individuals remains unclear. The current study aims to evaluate the effect of multidisciplinary team-based medication optimisation on survival, rehospitalisation and unscheduled hospital visits in elderly patients.
Methods And Analysis: We report the protocol of a single-centre, open-label, randomised controlled trial.
Smad proteins are transcriptional regulators activated by TGF-β. They are known to bind to two distinct Smad-responsive motifs, namely the Smad-binding element (SBE) (5'-GTCTAGAC-3') and CAGA motifs (5'-AGCCAGACA-3' or 5'-TGTCTGGCT-3'). However, the mechanisms by which these motifs promote Smad activity are not fully elucidated.
View Article and Find Full Text PDFIn response to cellular stresses, activating transcriptional factor 4 (ATF4) regulates the expression of both stress-relieving genes and apoptosis-inducing genes, eliciting cell fate determination. Since pharmacological activation of ATF4 exerts potent anti-tumor effects, modulators of ATF4 activation may have potential in cancer therapy. We herein attempted to identify small molecules that activate ATF4.
View Article and Find Full Text PDFTribbles related homolog 1 is the mammalian ortholog of Tribbles, which controls cell division and migration during development in Drosophila. TRB1 is a pseudokinase and functions as a scaffold protein. Recent findings suggest that TRB1 plays important roles in hepatic lipid metabolism and participates in insulin resistance.
View Article and Find Full Text PDFThe p53 tumor suppressor plays critical roles in cell cycle regulation and apoptotic cell death in response to various cellular stresses, thereby preventing cancer development. Therefore, the activation of p53 through small molecules is an attractive therapeutic strategy for the treatment of cancers retaining wild-type p53. We used a library of 700 Myanmar wild plant extracts to identify small molecules that induce p53 transcriptional activity.
View Article and Find Full Text PDFActa Biochim Biophys Sin (Shanghai)
January 2018
Smad3 and STAT3 are intracellular molecules that transmit signals from plasma membrane receptors to the nucleus. Smad3 operates downstream of growth/differentiation factors that utilize activin receptor-like kinase (ALK)-4, 5, or 7, such as transforming growth factor-β (TGF-β), activin, and myostatin. STAT3 principally functions downstream of cytokines that exert their effects via gp130 and Janus family kinases, including interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and oncostatin M.
View Article and Find Full Text PDFActivating transcription factor 4 (ATF4) is well known for its role in the endoplasmic reticulum (ER) stress response. ATF4 also transcriptionally induces multiple effectors that determine cell fate depending on cellular context. In addition, ATF4 can communicate both pro-apoptotic and pro-survival signals.
View Article and Find Full Text PDFTransforming growth factor β (TGF-β) signaling facilitates tumor development during the advanced stages of tumorigenesis, but induces cell-cycle arrest for tumor suppression during the early stages. However, the mechanism of functional switching of TGF-β is still unknown, and it is unclear whether inhibition of TGF-β signaling results amelioration or exacerbation of cancers. Here we show that the tumor suppressor p53 cooperates with Smad proteins, which are TGF-β signal transducers, to selectively activate plasminogen activator inhibitor type-1 (PAI-1) transcription.
View Article and Find Full Text PDFRespir Physiol Neurobiol
August 2016
Unlabelled: The purpose of this study was to elucidate the cardiovascular response during hyperpnoea in endurance-trained runners compared to sedentary controls. Twelve runners and ten sedentary individuals participated in this study. A maximal respiratory endurance test (MRET) was performed as follows: target minute ventilation was initially set at 30% of maximal voluntary ventilation (MVV12) and was increased by 10% MVV12 every 3min.
View Article and Find Full Text PDFCurr Cancer Drug Targets
October 2016
Epithelial-mesenchymal transition (EMT) plays an important role in the development of tumor metastases by facilitating cell migration and invasion. One of the hallmarks of EMT is the diminished expression of E-cadherin and gain of mesenchymal traits, which are regulated by core EMT-inducing transcriptional factors (EMT-TFs), such as Snail/Slug, ZEB1/ZEB2, and Twist1. EMT-TFs are known to be extremely labile proteins, and their protein levels are tightly controlled by the ubiquitin-proteasome system (UPS).
View Article and Find Full Text PDFTribbles-related protein (TRB) family members are the mammalian orthologs of Drosophila tribbles. Tribbles was originally identified as a cell cycle regulator during Drosophila development. Tribbles genes are evolutionary conserved, and three TRB genes (TRB1, TRB2 and TRB3) have been identified in mammals.
View Article and Find Full Text PDFTribbles 1 (TRB1), a member of the Tribbles family, is a pseudokinase that is conserved among species and implicated in various human diseases including leukemia, cardiovascular diseases, and metabolic disorders. However, the role of TRB1 in the immune response is not understood. To evaluate this role, we examined regulation of TRB1 expression and the function of TRB1 in interleukin-2 (IL-2) induction in Jurkat cells, a human acute T cell leukemia cell line.
View Article and Find Full Text PDFThe purpose of the present study was to elucidate the effect of increasing expiratory muscle work on sympathetic vasoconstrictor outflow and arterial blood pressure (BP) during dynamic exercise. We hypothesized that expiratory muscle fatigue would elicit increases in sympathetic vasomotor outflow and BP during submaximal exercise. The subjects performed four submaximal exercise tests; two were maximal expiratory pressure (PE max) tests and two were muscle sympathetic nerve activity (MSNA) tests.
View Article and Find Full Text PDFThe purpose of this study was to elucidate inspiratory accessory muscle deoxygenation and myoelectric activity during isolated volitional hyperpnoea under hypoxic conditions. Subjects performed voluntary isocapnic hyperpnoea (tidal volume=30-40% of forced vital capacity, breathing frequency=60 breaths/min) in normoxia [inspired gas fraction (FIO₂)=0.21] and hypoxia (FIO₂).
View Article and Find Full Text PDFSynthetic cannabinoids developed by chemical modification are believed to bind to cannabinoid receptors and cause neurological effects similar to cannabis; however, their effects on drug metabolizing enzymes are unknown. This study aimed to elucidate the effect of synthetic cannabinoids on cytochrome P450 1A activity. Naphthoylindole, a basic structure of the major synthetic cannabinoids, strongly inhibited CYP1A activity in a competitive manner; the apparent Ki value was 0.
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