4,730 research outputs found
Expanding the Hippo pathway : hMOB3 modulates apoptotic MST1 signaling and supports tumor growth in glioblastoma
No full textProtein kinases are critical players of signal transduction pathways involved in development, physiological and pathological processes. Deregulation of protein kinase signaling is found to be causal or related to varieties of human diseases, such as cancer, cardiovascular disease and diabetes. The human genome encodes 518 protein kinases. Approximately 60 out of them belong to the AGC group of Serine/Threonine protein kinases, including the ste20 like MST kinase family and NDR kinase family. Members of these families are highly conserved from yeast to men and regulate essential processes such as growth, proliferation and apoptosis. The Hippo pathway is a recently identified tumor suppressive network, where the MST-NDR family kinases form a kinase cascade regulating the downstream signaling through the effector YAP/TAZ.
In addition to signaling through the NDR family kinases, the Hippo/MST kinases also control cell apoptosis bypass these classical effectors YAP/TAZ. Despite the fact that JNK, FOXO3, H2B are well characterized downstream targets of apoptotic MST kinases, the regulatory mechanisms of apoptotic MST signaling are still largely unknown.
The human MOB family consists of six members encoded by six different genes (hMOB1A, -1B, -2, -3A, -3B and -3C). While as an activator for hMOB1A/B in MST-LATS/NDR kinase cascade, hMOB2 is a specific negative regulator of NDR kinase by competing the binding of hMOB1 to NDR kinase. Although hMOB3 family members share higher amino acid identity with hMOB1 than hMOB2, hMOB3 proteins do not interact or (de)activate NDR family kinases. Hence, the functions of hMOB3A/B/C are completely undefined.
A previous microarray study performed in the lab indicated that hMOB3 family members were deregulated in glioblastoma. In the present study, we first investigated the pathological roles of human MOB3 proteins and found that hMOB3 is highly upregulated in glioblastoma. Moreover, mRNA expression levels of hMOB3 members correlate with survival, suggesting hMOB3 members as potential prognostic markers. We extended the biochemical analysis by looking for the interaction partners of hMOB3 and demonstrated that hMOB3 binds to MST1 and inhibits the apoptotic cleavage of MST1 kinase. We further verified that hMOB3 promotes tumorigenesis of gliobalstoma cells in vivo by a U87MG derived flank model. Taken together, our results suggest that manipulate hMOB3 might represent a therapeutic strategy in malignant gliomas
YAP regulates an SGK1/mTORC1/SREBP-dependent lipogenic program to support proliferation and tissue growth
No full textThe coordinated regulation of growth control and metabolic pathways is required to meet the energetic and biosynthetic demands associated with proliferation. Emerging evidence suggests that the Hippo pathway effector Yes-associated protein 1 (YAP) reprograms cellular metabolism to meet the anabolic demands of growth, although the mechanisms involved are poorly understood. Here, we demonstrate that YAP co-opts the sterol regulatory element-binding protein (SREBP)-dependent lipogenic program to facilitate proliferation and tissue growth. Mechanistically, YAP stimulates de novo lipogenesis via mechanistic target of rapamcyin (mTOR) complex 1 (mTORC1) signaling and subsequent activation of SREBP. Importantly, YAP-dependent regulation of serum- and glucocorticoid-regulated kinase 1 (SGK1) is required to activate mTORC1/SREBP and stimulate de novo lipogenesis. We also find that the SREBP target genes fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD) are conditionally required to support YAP-dependent proliferation and tissue growth. These studies reveal that de novo lipogenesis is a metabolic vulnerability that can be targeted to disrupt YAP-dependent proliferation and tissue growth
Nd: YAP Laser in the Elimination of Endodontic Nickel-Titanium Files Fractured in Rooted Canals (Part 1: Teeth With Minimal Root Curvature)
No full textpeer reviewedBackground
Fracture of nickel-titanium (Ni-Ti) instruments in root canals is commonly associated with compromised outcomes in endodontic treatment. There is no single, universally accepted approach for managing this complication. The objective of this study is to evaluate the effectiveness of an Nd: YAP laser-assisted protocol in removing fractured Ni-Ti files in teeth with minimal root curvature (less than 15 degrees).
Methods
A total of 66 notched Ni-Ti files located at the apical third of the extracted teeth with minimal root curvature (less than 15 degrees) were included. The Nd: YAP laser was used with parameters set to a power of 3W, delivering 300 mJ per pulse. The fiber had a diameter of 200 µm, and the laser operated in pulsed mode at a frequency of 10 Hz, a pulse duration of 150 s, and an energy density of 955.41 J/cm2 per second. The safety of the irradiation parameters was proven in a previous study. The edge of the laser fiber was inserted in the canal until close contact with the fractured file was achieved during all the irradiation procedures. Total elimination and bypass of the instrument were considered a success while partial bypass, non-bypass, or lateral perforation were considered a failure. In addition, the average time required to bypass or eliminate the broken Ni-Ti files was recorded. Scanning electron microscopy (SEM) was used to evaluate physical modifications after irradiation, and X-ray emission spectroscopy was employed to calculate the percentage of nickel and titanium incorporated into the dentinal walls of the canals.
Results
Six samples were excluded from the study. From the 60 included, the success rate was 100%, with 71.66% (n=43) bypass and 28.33% total elimination (n=17) of the fractured instrument. The mean and standard deviation of the measured time for bypassing or completely removing the broken files was 7.463 ± 3.679 seconds. Chemical analysis revealed that Ni and Ti residues were predominantly present in the irradiated canal area with a mass percentage of 5.548 ± 4.621 and 7.371% ± 5.393 for Ni and Ti, respectively, at the impact area and decreased toward the apical region.
Conclusion
This study proposes a promising protocol using Nd: YAP laser for removing fractured Ni-Ti files in teeth with minimal root curvature that is less than 15 degrees
YAP/TAZ direct commitment and maturation of lymph node fibroblastic reticular cells
No full textFibroblastic reticular cells (FRCs) are immunologically specialized myofibroblasts of lymphoid organ, and FRC maturation is essential for structural and functional properties of lymph nodes (LNs). Here we show that YAP and TAZ (YAP/TAZ), the final effectors of Hippo signaling, regulate FRC commitment and maturation. Selective depletion of YAP/TAZ in FRCs impairs FRC growth and differentiation and compromises the structural organization of LNs, whereas hyperactivation of YAP/TAZ enhances myofibroblastic characteristics of FRCs and aggravates LN fibrosis. Mechanistically, the interaction between YAP/TAZ and p52 promotes chemokine expression that is required for commitment of FRC lineage prior to lymphotoxin-beta receptor (LTbetaR) engagement, whereas LTbetaR activation suppresses YAP/TAZ activity for FRC maturation. Our findings thus present YAP/TAZ as critical regulators of commitment and maturation of FRCs, and hold promise for better understanding of FRC-mediated pathophysiologic processes
Self-compression of 4.9 µm pulses to sub-40 fs with 2 mJ energy in Zinc Sulfide
No full textNonlinear self-compression of few-cycle multi-mJ pulses at 4.9 µm in ZnS is presented. 80 fs input pulses are compressed to 37 fs with 2.1 mJ energy at a 1 kHz repetition rate. © 2024 The Author(s
Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease
No full textObesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease
Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease
No full textObesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease
Correction to: Chamoun et al., Bacterial pathogenesis and interleukin-17: interconnecting mechanisms of immune regulation, host genetics, and microbial virulence that influence severity of infection
No full textChamoun MN, Blumenthal A, Sullivan MJ, Schembri MA, Ulett GC. 2018. Bacterial pathogenesis and interleukin-17: interconnecting mechanisms of immune regulation, host genetics, and microbial virulence that influence severity of infection. Critical Reviews in Microbiology. https://doi.org/10.1080/1040841X.2018.1426556.
When the above article was first published online, the below three corrections were missed.
The author ‘Antje Blumenthal’ was wrongly affiliated to the affiliation “cSchool of Chemistry and Molecular Biosciences, and Australian Infectious Disease Research Centre, The University of Queensland, Brisbane, Australia”. Now this affiliation has been removed for this author.
The affiliation ‘bTranslational Research Institute, The University of Queensland Diamantina Institute, Woolloongabba, Australia’ of the author ‘Antje Blumenthal’ should read ‘bThe University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia’.
In Table 3, the sentence ‘Benefit of manipulating IL-17 levels to improve immunization strategies M. tuberculosis’ should read “Benefit of manipulating IL-17 levels to improve immunization strategies against M. tuberculosis”.No Full Tex
Generation of 22-mJ, 2.0-ps Pulses from a 1-kHz Ho:YLF Regenerative Chirped Pulse Amplifier
No full textWe report a CW-pumped Ho:YLF regenerative amplifier (RA) delivering pulses with 22.5-mJ energy and 2.0-ps duration at 1 kHz. The RA emitting at 2051 nm is broadband-seeded and implemented in a chirped pulse amplification system. © 2024 The Author(s
Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap
No full textActivation of the Hippo pathway effector Yap underlies many liver cancers, however no germline or somatic mutations have been identified. Autophagy maintains essential metabolic functions of the liver, and autophagy-deficient murine models develop benign adenomas and hepatomegaly, which have been attributed to activation of the p62/Sqstm1-Nrf2 axis. Here, we show that Yap is an autophagy substrate and mediator of tissue remodeling and hepatocarcinogenesis independent of the p62/Sqstm1-Nrf2 axis. Hepatocyte-specific deletion of Atg7 promotes liver size, fibrosis, progenitor cell expansion, and hepatocarcinogenesis, which is rescued by concurrent deletion of Yap. Our results shed new light on mechanisms of Yap degradation and the sequence of events that follow disruption of autophagy, which is impaired in chronic liver disease
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