Transcriptional Co-repressor Function of the Hippo Pathway Transducers YAP and TAZ

SummaryYAP (yes-associated protein) and TAZ are oncogenic transcriptional co-activators downstream of the Hippo tumor-suppressor pathway. However, whether YAP and/or TAZ (YAP/TAZ) engage in transcriptional co-repression remains relatively unexplored. Here, we directly demonstrated that YAP/TAZ represses numerous target genes, including tumor-suppressor genes such as DDIT4 (DNA-damage-inducible transcript 4) and Trail (TNF-related apoptosis-inducing ligand). Mechanistically, the repressor function of YAP/TAZ requires TEAD (TEA domain) transcription factors. A YAP/TAZ-TEAD complex recruits the NuRD complex to deacetylate histones and alters nucleosome occupancy at target genes. Functionally, repression of DDIT4 and Trail by YAP/TAZ is required for mTORC1 (mechanistic target of rapamycin complex 1) activation and cell survival, respectively. Our demonstration of the transcriptional co-repressor activity of YAP/TAZ opens a new avenue for understanding the Hippo signaling pathway

Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway.

YAP (Yes-associated protein) is a transcription co-activator in the Hippo tumour suppressor pathway and controls cell growth, tissue homeostasis and organ size. YAP is inhibited by the kinase Lats, which phosphorylates YAP to induce its cytoplasmic localization and proteasomal degradation. YAP induces gene expression by binding to the TEAD family transcription factors. Dysregulation of the Hippo-YAP pathway is frequently observed in human cancers. Here we show that cellular energy stress induces YAP phosphorylation, in part due to AMPK-dependent Lats activation, thereby inhibiting YAP activity. Moreover, AMPK directly phosphorylates YAP Ser 94, a residue essential for the interaction with TEAD, thus disrupting the YAP-TEAD interaction. AMPK-induced YAP inhibition can suppress oncogenic transformation of Lats-null cells with high YAP activity. Our study establishes a molecular mechanism and functional significance of AMPK in linking cellular energy status to the Hippo-YAP pathway

Mst1-FoxO Signaling Protects Naïve T Lymphocytes from Cellular Oxidative Stress in Mice

Background: The Ste-20 family kinase Hippo restricts cell proliferation and promotes apoptosis for proper organ development in Drosophila. InC. elegans, Hippo homolog also regulates longevity. The mammalian Ste20-like protein kinase, Mst1, plays a role in apoptosis induced by various types of apoptotic stress. Mst1 also regulates peripheral naïve T cell trafficking and proliferation in mice. However, its functions in mammals are not fully understood. Methodology/Principal Findings: Here, we report that the Mst1-FoxO signaling pathway plays a crucial role in survival, but not apoptosis, of naïve T cells. In Mst1 2/2 mice, peripheral T cells showed impaired FoxO1/3 activation and decreased FoxO protein levels. Consistently, the FoxO targets, Sod2 and catalase, were significantly down-regulated in Mst1 2/2 T cells, thereby resulting in elevated levels of intracellular reactive oxygen species (ROS) and induction of apoptosis. Expression of constitutively active FoxO3a restored Mst1 2/2 T cell survival. Crossing Mst1 transgenic mice (Mst1 Tg) with Mst1 2/2 mice reduced ROS levels and restored normal numbers of peripheral naïve T cells in Mst1 Tg;Mst1 2/2 progeny. Interestingly, peripheral T cells from Mst1 2/2 mice were hypersensitive to c-irradiation and paraquat-induced oxidative stresses, whereas those from Mst1 Tg mice were resistant. Conclusions/Significance: These data support the hypothesis that tolerance to increased levels of intracellular RO

Effects of 92% oxygen administration on cognitive performance and physiological changes of intellectually and developmentally disabled people

Background: The present study addressed how 92% oxygen administration affects cognitive performance, blood oxygen saturation (SpO(2)), and heart rate (HR) of intellectually and developmentally disabled people. Methods: Seven males (28.9 +/- 1.8 years) and seven females (34.4 +/- 8.3 years) with intellectual and developmental disabilities (disabled level 2.1 +/- 0.5) completed an experiment consisting a 0-back task with normal air (21% oxygen) administered in one run and hyperoxic air (92% oxygen) administered in the other run. The experimental sequence in each run consisted of a 1-min adaptation phase, 2-min control phase, and 2-min 0-back task phase, where SpO(2) and HR were gauged for each phase. Results: The administration of 92% oxygen increased 0-back task performance of intellectually and developmentally disabled people, in association with increased SpO(2) and decreased HR. Our results demonstrate that sufficient oxygen supply subserving cognitive functions, even as a short-term effect, could increase cognitive ability for the intellectually and developmentally disabled people. Conclusions: It is concluded that enriched oxygen can positively affect, at least in the short-term, the working memory of those with intellectual and developmental disabilityopen0

Pathogen-induced binding of the soybean zinc finger homeodomain proteins GmZF-HD1 and GmZF-HD2 to two repeats of ATTA homeodomain binding site in the calmodulin isoform 4 (GmCaM4) promoter

Calmodulin (CaM) is involved in defense responses in plants. In soybean (Glycine max), transcription of calmodulin isoform 4 (GmCaM4) is rapidly induced within 30 min after pathogen stimulation, but regulation of the GmCaM4 gene in response to pathogen is poorly understood. Here, we used the yeast one-hybrid system to isolate two cDNA clones encoding proteins that bind to a 30-nt A/T-rich sequence in the GmCaM4 promoter, a region that contains two repeats of a conserved homeodomain binding site, ATTA. The two proteins, GmZF-HD1 and GmZF-HD2, belong to the zinc finger homeodomain (ZF-HD) transcription factor family. Domain deletion analysis showed that a homeodomain motif can bind to the 30-nt GmCaM4 promoter sequence, whereas the two zinc finger domains cannot. Critically, the formation of super-shifted complexes by an anti-GmZF-HD1 antibody incubated with nuclear extracts from pathogen-treated cells suggests that the interaction between GmZF-HD1 and two homeodomain binding site repeats is regulated by pathogen stimulation. Finally, a transient expression assay with Arabidopsis protoplasts confirmed that GmZF-HD1 can activate the expression of GmCaM4 by specifically interacting with the two repeats. These results suggest that the GmZF-HD1 and –2 proteins function as ZF-HD transcription factors to activate GmCaM4 gene expression in response to pathogen

Breath analyzer for personalized monitoring of exercise-induced metabolic fat burning

Dionisio V. Del Orbe recibió su Licenciatura en Ingeniería Aeronáutica de la Universidad de Western Michigan (2012), EE. UU., y una Maestría en Ingeniería de Manufactura Microelectrónica del Instituto de Tecnología de Rochester (2015), EE. UU. Recibió su doctorado en Ingeniería Mecánica KAIST (2022), Corea del Sur, y trabajó como investigador de posgrado en el Departamento de Investigación de TIC Médicas y de Bienestar en ETRI, Corea del Sur. Su investigación se centra en sensores de gases químicos para diversas aplicaciones, especialmente, análisis de aliento y detección de gases tóxicos/inflamables; también tiene intereses en dispositivos portátiles y flexibles. Actualmente, es docente e investigador en UNAPEC, República Dominicana.Obesity increases the risk of chronic diseases, such as type 2 diabetes mellitus, dyslipidemia, and cardiovascular diseases. Simple anthropometric measurements have time limitations in reflecting short-term weight and body fat changes. Thus, for detecting, losing or maintaining weight in short term, it is desirable to develop portable/ compact devices to monitor exercise-induced fat burn in real time. Exhaled breath acetone and blood-borne β-hydroxybutyric acid (BOHB) are both correlated biomarkers of the metabolic fat burning process that takes place in the liver, predominantly post-exercise. Here, we have fabricated a compact breath analyzer for convenient, noninvasive and personalized estimation of fat burning in real time in a highly automated manner. The analyzer collects end-tidal breath in a standardized, user-friendly manner and it is equipped with an array of four low-power MEMS sensors for enhanced accuracy; this device presents a combination of required and desirable design features in modern portable/compact breath analyzers. We analyzed the exhaled breath (with our analyzer) and the blood samples (for BOHB) in 20 participants after exercise; we estimated the values of BOHB, as indication of the fat burn, resulting in Pearson coefficient r between the actual and predicted BOHB of 0.8. The estimation uses the responses from the sensor array in our analyzer and demographic and anthropo- metric information from the participants as inputs to a machine learning algorithm. The system and approach herein may help guide regular exercise for weight loss and its maintenance based on individuals’ own metabolic changes

Isolated Petroclival Craniopharyngioma with Aggressive Skull Base Destruction

We report a rare case of petroclival craniopharyngioma with no connection to the sellar or suprasellar region. MRI and CT images revealed a homogenously enhancing retroclival solid mass with aggressive skull base destruction, mimicking chordoma or aggressive sarcoma. However, there was no calcification or cystic change found in the mass. Here, we report the clinical features and radiographic investigation of this uncommon craniopharyngioma arising primarily in the petroclival region

The Relation between Birth Weight and Insulin Resistance in Korean Adolescents

Low birth weight is associated with insulin resistance and type 2 diabetes in adults. The fetal programming hypothesis has shown that insulin resistance and its associated metabolic disturbances result from a poor gestational environment, for which low birth weight is a surrogate. An at-home questionnaire survey was performed on 660 middle school students (12-15 years) in Seoul, Korea, and 152 cases were randomly selected based on their birth weight. Subjects were divided into three groups according to birth weight. We recorded their birth weight and measured their current anthropometric data, blood pressure, lipid profile, HOMA-IR, and HOMA-β, and compared these parameters among the groups. The relation of birth weight to physiological characteristics in adolescence was examined. Systolic blood pressure, lipid profiles, and fasting plasma glucose, HOMA-β were not significantly different among the groups, but diastolic blood pressure was lower in the third tertile. Insulin, C-peptide, and HOMA-IR were higher in the lower birth weight tertile. After adjustment for confounding factors, birth weight was inversely related to diastolic blood pressure, insulin, C-peptide, and HOMA-IR. We conclude that low birth weight may predict the risk of the insulin resistance and its progression over age, and that adequate gestational nutrition is therefore necessary to prevent low birth weight

Refractory Duodenal Crohn's Disease Successfully Treated with Infliximab

Crohn's disease (CD) may involve any part of the gastrointestinal tract, from the mouth to the anus. Approximately >90% of cases occur in the small bowel and colon. Upper gastrointestinal involvement, especially duodenal manifestation, is relatively rare. Therefore, adequate medical treatment for duodenal CD has not yet been established. We report a case of CD with duodenal involvement. A 46-year-old man with Crohn's ileocolitis presented to our hospital with right upper quadrant pain. An endoscopy showed a deep excavated ulcer with deformity at the duodenal bulb, and he was initially treated with azathioprine (1 mg/kg), Pentasa (3.0 g/day), and a proton pump inhibitor for 1 year. However, the deep ulcer did not heal. Therefore, infliximab infusion therapy was initiated, and the duodenal lesion completely resolved on follow-up esophagogastroduodenoscopy. We report a case of duodenal CD that completely resolved following infliximab infusion, with a review of the literature

LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function

Autophagy perturbation represents an emerging therapeutic strategy in cancer. Although LATS1 and LATS2 kinases, core components of the mammalian Hippo pathway, have been shown to exert tumor suppressive activities, here we report a pro-survival role of LATS1 but not LATS2 in hepatocellular carcinoma (HCC) cells. Specifically, LATS1 restricts lethal autophagy in HCC cells induced by sorafenib, the standard of care for advanced HCC patients. Notably, autophagy regulation by LATS1 is independent of its kinase activity. Instead, LATS1 stabilizes the autophagy core-machinery component Beclin-1 by promoting K27-linked ubiquitination at lysine residues K32 and K263 on Beclin-1. Consequently, ubiquitination of Beclin-1 negatively regulates autophagy by promoting inactive dimer formation of Beclin-1. Our study highlights a functional diversity between LATS1 and LATS2, and uncovers a scaffolding role of LATS1 in mediating a cross-talk between the Hippo signaling pathway and autophagy