Mechanisms of physiological and pathological cardiac hypertrophy

Nature Reviews Cardiology, Journal Year: 2018, Volume and Issue: 15(7), P. 387 - 407

Published: April 19, 2018

Language: Английский

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Mechanobiology of YAP and TAZ in physiology and disease

Nature Reviews Molecular Cell Biology, Journal Year: 2017, Volume and Issue: 18(12), P. 758 - 770

Published: Sept. 27, 2017

Language: Английский

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The Hippo Pathway: Biology and Pathophysiology

Annual Review of Biochemistry, Journal Year: 2018, Volume and Issue: 88(1), P. 577 - 604

Published: Dec. 19, 2018

The Hippo pathway was initially discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth and fate decision, organ size control, regeneration. core the mammals consists kinase cascade, MST1/2 LATS1/2, well downstream effectors, transcriptional coactivators YAP TAZ. These components control programs involved proliferation, survival, mobility, stemness, differentiation. tightly regulated by both intrinsic extrinsic signals, such mechanical force, cell-cell contact, polarity, energy status, stress, many diffusible hormonal factors, majority which act through G protein-coupled receptors. Here, we review current understanding molecular mechanisms signals regulate with emphasis on mechanotransduction effects this basic biology human diseases.

Language: Английский

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Targeting signalling pathways and the immune microenvironment of cancer stem cells — a clinical update

Nature Reviews Clinical Oncology, Journal Year: 2019, Volume and Issue: 17(4), P. 204 - 232

Published: Dec. 2, 2019

Language: Английский

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Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model

Theranostics, Journal Year: 2016, Volume and Issue: 7(1), P. 180 - 195

Published: Dec. 28, 2016

Osteoarthritis (OA) is the most common joint disease throughout world. Exosomes derived from miR-140-5p-overexpressing synovial mesenchymal stem cells (SMSC-140s) may be effective in treating OA. We hypothesized that exosomes SMSC-140 (SMSC-140-Exos) would enhance proliferation and migration abilities of articular chondrocytes (ACs) without harming extracellular matrix (ECM) secretion.SMSCs were transfected with or miR-140-5p. SMSCs SMSC-140s (SMSC-Exos SMSC-140-Exos) isolated identified. Proliferation, ECM secretion measured vitro compared between groups. The mechanism involving alternative Wnt signalling activation Yes-associated protein (YAP) was investigated using lentivirus, oligonucleotides chemical drugs. preventative effect vivo Safranin-O Fast green staining immunohistochemical staining.Wnt5a Wnt5b carried by activated YAP via pathway enhanced side-effect significantly decreasing secretion. Highly-expressed miR-140-5p blocked this RalA. SMSC-140-Exos ACs damaging vitro, while vivo, successfully prevented OA a rat model.These findings highlight promising potential preventing first found source studied their merits shortcomings. Based on our understanding molecular mechanism, we overcame shortcomings modifying exosomes. Such modified hold as future therapeutic strategies.

Language: Английский

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Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow

Nature, Journal Year: 2016, Volume and Issue: 540(7634), P. 579 - 582

Published: Dec. 1, 2016

Language: Английский

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Neural tube closure: cellular, molecular and biomechanical mechanisms

Development, Journal Year: 2017, Volume and Issue: 144(4), P. 552 - 566

Published: Feb. 14, 2017

Neural tube closure has been studied for many decades, across a range of vertebrates, as paradigm embryonic morphogenesis. Neurulation is particular interest in view the severe congenital malformations - 'neural defects' that result when fails. The process neural complex and involves cellular events such convergent extension, apical constriction interkinetic nuclear migration, well precise molecular control via non-canonical Wnt/planar cell polarity pathway, Shh/BMP signalling, transcription factors Grhl2/3, Pax3, Cdx2 Zic2. More recently, biomechanical inputs into morphogenesis have also identified. Here, we review these cellular, mechanisms involved closure, based on studies various vertebrate species, focusing most recent advances field.

Language: Английский

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Comprehensive Molecular Characterization of the Hippo Signaling Pathway in Cancer

Cell Reports, Journal Year: 2018, Volume and Issue: 25(5), P. 1304 - 1317.e5

Published: Oct. 1, 2018

Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform comprehensive molecular characterization of 19 core genes in 9,125 samples across 33 cancer types using multidimensional "omic" data from The Cancer Genome Atlas. We identify somatic drivers among and the related microRNA (miRNA) regulators, functional genomic approaches, experimentally characterize YAP TAZ mutation effects miR-590 miR-200a regulation for TAZ. pathway activity is best characterized by YAP/TAZ transcriptional target signature 22 genes, which shows robust prognostic power types. Our elastic-net integrated modeling further reveals cancer-type-specific regulators associated drivers. results highlight importance squamous cell cancers, frequent amplification YAP/TAZ, high expression heterogeneity, significant patterns. This study represents systems-biology approach to characterizing pathways post-genomic era.

Language: Английский

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The Hippo Signaling Network and Its Biological Functions

Annual Review of Genetics, Journal Year: 2018, Volume and Issue: 52(1), P. 65 - 87

Published: Sept. 5, 2018

Hippo signaling is an evolutionarily conserved network that has a central role in regulating cell proliferation and fate to control organ growth regeneration. It promotes activation of the LATS kinases, which gene expression by inhibiting activity transcriptional coactivator proteins YAP TAZ mammals Yorkie Drosophila. Diverse upstream inputs, including both biochemical cues biomechanical cues, regulate enable it have key as sensor cells' physical environment integrator signals. Several components this pathway localize cell-cell junctions contribute regulation polarity, contacts, cytoskeleton. Downregulation uncontrolled proliferation, impairs differentiation, associated with cancer. We review current understanding highlight progress elucidation its regulatory mechanisms biological functions.

Language: Английский

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Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review)

International Journal of Oncology, Journal Year: 2017, Volume and Issue: 51(5), P. 1357 - 1369

Published: Sept. 19, 2017

Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological metabolic reprogramming to adapt tumor microenvironment survive host defense or therapeutic insults. Intra-tumor heterogeneity cancer-cell plasticity give rise resistance recurrence through clonal replacement reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with FGF, Notch, Hedgehog TGFβ/BMP regulate expression functional CSC markers, such as CD44, CD133 (PROM1), EPCAM LGR5 (GPR49). Aberrant canonical non-canonical in human malignancies, including breast, colorectal, gastric, lung, ovary, pancreatic, prostate uterine cancers, leukemia melanoma, are involved survival, bulk-tumor expansion invasion/metastasis. signaling-targeted therapeutics, anti-FZD1/2/5/7/8 monoclonal antibody (mAb) (vantictumab), anti-LGR5 antibody-drug conjugate (ADC) (mAb-mc-vc-PAB-MMAE), anti-PTK7 ADC (PF-06647020), anti-ROR1 mAb (cirmtuzumab), anti-RSPO3 (rosmantuzumab), small-molecule porcupine inhibitors (ETC-159, WNT-C59 WNT974), tankyrase (AZ1366, G007-LK, NVP-TNKS656 XAV939) β-catenin (BC2059, CWP232228, ICG-001 PRI-724), clinical trials preclinical studies treatment patients WNT-driven cancers. therapeutics applicable combination therapy BCR-ABL, EGFR, FLT3, KIT RET treat a subset tyrosine kinase-driven cancers because kinase converge maintenance CSCs. might also be immune checkpoint blockers, atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab pembrolizumab, evasion, although context-dependent effects on immunity should carefully assessed. Omics monitoring, genome sequencing transcriptome tests, immunohistochemical analyses PD-L1 (CD274), PD-1 (PDCD1), ROR1 nuclear organoid-based drug screening, is necessary determine appropriate cancer patients.

Language: Английский

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