1,569 research outputs found
Emerging role of Hpo signaling and YAP in hepatocellular carcinoma
No full textVicente Valero III,1 Timothy M Pawlik,1 Robert A Anders21Department of Surgery, Division of Surgical Oncology, 2Department of Pathology, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USAAbstract: Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related mortality worldwide. Due to the poor prognosis and limited therapeutic options, there is great interest in further understanding better the molecular underpinnings and potential molecular targets associated with HCC. The Hippo (Hpo) signaling pathway and YAP, its principal downstream effector, represent an innovative area of research in HCC. Pioneered in Drosophila melanogaster, the Hpo cascade controls tissue homeostasis including organ size, cell proliferation, apoptosis, as well as cell-cycle regulation and differentiation. This conserved kinase cascade in mammals depends on central control by the tumor suppressor mammalian sterile 20-like kinase 1/2 (Mst1/2). The Mst1/2 commences the downstream kinase cascade, ultimately activating the oncoprotein YAP and allowing its physical association with downstream targets to enhance the gene expression signatures that are involved in proliferation and survival. Alterations in YAP expression and defective regulation of other key Hpo pathway members, such as Mst1/2, Salvador, neurofibromatosis and Mer (Nf2/mer), large tumor suppressor homolog 1/2 (Lats1/2), and Mps one binder kinase activator-like 1A and 1B (Mob1) drive carcinogenesis in animal models. The dysregulation of the Hpo pathway – resulting in an unchecked activation of YAP – culminates in the development of a broad range of human tumor types, including HCC. The abrogation of Mst1/2-mediated YAP phosphorylation permits YAP entry into the nucleus in murine models and functions similarly in human HCCs. Chemoresistance mechanisms displayed by HCC tumors occur in a YAP-dependent manner. The HCC specimens exhibit YAP overexpression, and YAP serves as an independent prognostic marker for disease-free survival and overall survival in patients with HCC. Recently, the small molecule inhibitor, verteporfin has been shown to attenuate YAP activity in murine models, perhaps offering a novel therapeutic approach for patients with advanced HCC.Keywords: hepatocellular carcinoma, yes-associated-protein, Hippo signaling, liver cancer, hepatic malignanc
Experiments on pattern-based relation learning
No full text© 2009 Willy Yap & Timothy BaldwinRelation extraction is a sub-task of Information Extraction (IE) that is concerned with extracting semantic relations---such as antonymy, synonymy or hypernymy---between word pairs from corpus data. Past work in relation extraction has concentrated on creating a small set of patterns that are good indicators of whether a word pair contains a semantic relation. In recent years, there has been work on using machine learning to automatically learn these patterns from text. We build on this research in running a series of experiments to investigate the impact of corpus type, corpus size and different parameter settings on learning a range of lexical relations
The role of Yes-associated protein (YAP) in vertebrate development
No full textYes-associated protein 65 (YAP) contains multiple protein-protein interaction domains and functions as both a transcriptional co-activator and as a scaffolding protein within the cytoplasm or nucleus. Given that YAP binds to so many proteins that are critical for proper embryonic development and that this factor functions as a transcriptional co-activator, YAP likely plays an important role during early embryonic development. Given that YAP knockout mice struggled to progress normally through early development, in part because of nutritional deficiencies, we sought to better characterize a role for YAP during this time period by using embryos that develop externally: Xenopus laevis and Danio rerio. YAP morpholino (MO)-mediated loss-of-function resulted in a delay of mesoderm induction and severely impaired A-P axis elongation, phenotypes that were similar to YAP-/- mice. YAP gain-of-function experiments in Xenopus laevis expanded the progenitor populations in the neural plate and neural plate border zone, while concomitantly inhibiting differentiation markers for the neural crest, preplacodal ectoderm, hatching gland, epidermis, and somitic muscle. Regulation of gene expression is critically important in development and improper regulation of gene expression can lead to a variety of developmental defects, such as loss of conceptus, birth defects, and cancer. I found that yap expression is controlled by a TATA-less promoter, which includes a GC box where Sp1 binds and regulates yap transcription. I also found that adrenomedullin, a multifunctional peptide hormone known to act as a vasodilator, angiogenic factor, regulator of placental development, and tumor growth promoter, is a newly identified, putative target of YAP. These studies demonstrate that YAP is involved in the process of cell differentiation and the lack or overabundance of YAP protein disrupts the developmental time line of vertebrates with grievous consequences. Understanding the mechanistic details of these effects involve delineating the transcriptional control of YAP and its target genes. In the future, elucidating the linkage between YAP, the nuclear architecture, and transcriptional regulation will bolster our understanding of cell differentiation
CDK4/6 Inhibitors: Promising Opportunities beyond Breast Cancer.
No full textPatnaik and colleagues report on the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of abemaciclib for the treatment of advanced solid cancers, demonstrating antitumor activity in advanced breast cancers as well as glioblastoma, melanoma, non-small cell lung cancer, colorectal cancer, and ovarian cancer. The development of abemaciclib and other CDK4/6 inhibitors should now be fully optimized through the use of novel predictive biomarkers of response and rational combinations. Cancer Discov; 6(7); 697-9. ©2016 AACRSee related article by Patnaik et al., p. 740
MAPK-Mediated YAP Activation Controls Mechanical-Tension-Induced Pulmonary Alveolar Regeneration
No full textSummaryThe pulmonary alveolar epithelium undergoes extensive regeneration in response to lung injuries, including lung resection. In recent years, our understanding of cell lineage relationships in the pulmonary alveolar epithelium has improved significantly. However, the molecular and cellular mechanisms that regulate pneumonectomy (PNX)-induced alveolar regeneration remain largely unknown. In this study, we demonstrate that mechanical-tension-induced YAP activation in alveolar stem cells plays a major role in promoting post-PNX alveolar regeneration. Our results indicate that JNK and p38 MAPK signaling is critical for mediating actin-cytoskeleton-remodeling-induced nuclear YAP expression in alveolar stem cells. Moreover, we show that Cdc42-controlled actin remodeling is required for the activation of JNK, p38, and YAP in post-PNX lungs. Our findings together establish that the Cdc42/F-actin/MAPK/YAP signaling cascade is essential for promoting alveolar regeneration in response to mechanical tension in the lung
Abstract 3339: Muscarinic acetylcholine receptor subtype 3 regulates gastric stem cell expansion and gastric cancer progression by controlling YAP activation
No full textAbstract
Within the gastrointestine, nerves help to regulate both normal and neoplastic stem cell dynamics. Several previous studies suggested that cholinergic nerve signaling plays an important role in gastrointestinal cancer development, but the exact underlying mechanism has not been clarified. In this study, we examined the role of muscarinic acetylcholine receptor subtype 3 (M3R) in gastric homeostasis and cancer development by using mouse models and human cancer cell lines. In situ hybridization revealed M3R expression in gastric stem cell zone, and its expression was markedly upregulated in gastric cancer cells. We knocked out M3R in Lgr5+ gastric stem cells in Lgr5-CreERT; M3Rflox/flox mice, and found that deletion of M3R inhibited clonal expansion of Lgr5+ cells in regenerative states. In a gastric tumor model of Mist1-CreERT; Apcflox/flox mice, knockout of M3R dramatically suppressed tumor growth. RNA sequencing analysis of these tumors revealed that several important pathways were significantly inhibited in M3R knockout samples, including YAP/TAZ pathway. We established M3R-expressing gastric cancer cell lines, and western blotting, luciferase assay, and RT-PCR analysis confirmed that acetylcholine (ACh) agonist activates YAP pathway through M3R. YAP is upregulated in approximately half of gastric cancer patients, and its expression is significantly associated with disease stage and histological form. This M3R-YAP axis activates the gastric stem cell niche and offers a compelling target for tumor treatment and prevention.
Note: This abstract was not presented at the meeting.
Citation Format: Yoku Hayakawa, Mitsuru Konishi, Kosuke Sakitani, Kazuhiko Koike, Timothy Wang. Muscarinic acetylcholine receptor subtype 3 regulates gastric stem cell expansion and gastric cancer progression by controlling YAP activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3339. doi:10.1158/1538-7445.AM2017-3339</jats:p
Targeting DNA Repair in Cancer: Beyond PARP Inhibitors
No full textGermline aberrations in critical DNA-repair and DNA damage-response (DDR) genes cause cancer predisposition, whereas various tumors harbor somatic mutations causing defective DDR/DNA repair. The concept of synthetic lethality can be exploited in such malignancies, as exemplified by approval of poly(ADP-ribose) polymerase inhibitors for treating BRCA1/2-mutated ovarian cancers. Herein, we detail how cellular DDR processes engage various proteins that sense DNA damage, initiate signaling pathways to promote cell-cycle checkpoint activation, trigger apoptosis, and coordinate DNA repair. We focus on novel therapeutic strategies targeting promising DDR targets and discuss challenges of patient selection and the development of rational drug combinations.
: Various inhibitors of DDR components are in preclinical and clinical development. A thorough understanding of DDR pathway complexities must now be combined with strategies and lessons learned from the successful registration of PARP inhibitors in order to fully exploit the potential of DDR inhibitors and to ensure their long-term clinical success. Cancer Discov; 7(1); 20-37. ©2016 AAC
Towards Precision Medicine in the Clinic: From Biomarker Discovery to Novel Therapeutics.
No full textPrecision medicine continues to be the benchmark to which we strive in cancer research. Seeking out actionable aberrations that can be selectively targeted by drug compounds promises to optimize treatment efficacy and minimize toxicity. Utilizing these different targeted agents in combination or in sequence may further delay resistance to treatments and prolong antitumor responses. Remarkable progress in the field of immunotherapy adds another layer of complexity to the management of cancer patients. Corresponding advances in companion biomarker development, novel methods of serial tumor assessments, and innovative trial designs act synergistically to further precision medicine. Ongoing hurdles such as clonal evolution, intra- and intertumor heterogeneity, and varied mechanisms of drug resistance continue to be challenges to overcome. Large-scale data-sharing and collaborative networks using next-generation sequencing (NGS) platforms promise to take us further into the cancer 'ome' than ever before, with the goal of achieving successful precision medicine
Enigma proteins regulate YAP mechanotransduction
No full textHuman cells can sense mechanical stress acting upon integrin adhesions and respond by sending the YAP (also known as YAP1) and TAZ (also known as WWTR1) transcriptional co-activators to the nucleus to drive TEAD-dependent transcription of target genes. How integrin signaling activates YAP remains unclear. Here, we show that integrin-mediated mechanotransduction requires the Enigma and Enigma-like proteins (PDLIM7 and PDLIM5, respectively; denoted for the family of PDZ and LIM domain-containing proteins). YAP binds to PDLIM5 and PDLIM7 (hereafter PDLIM5/7) via its C-terminal PDZ-binding motif (PBM), which is essential for full nuclear localization and activity of YAP. Accordingly, silencing of PDLIM5/7 expression reduces YAP nuclear localization, tyrosine phosphorylation and transcriptional activity. The PDLIM5/7 proteins are recruited from the cytoplasm to integrin adhesions and F-actin stress fibers in response to force by binding directly to the key stress fiber component α-actinin. Thus, forces acting on integrins recruit Enigma family proteins to trigger YAP activation during mechanotransduction.This article has an associated First Person interview with the first author of the paper
Inhibition of YAP ameliorates renal fibrosis through FGF2 pathway
No full textThe Hippo pathway is an evolutionarily conserved kinase cascade that controls organ size by regulating cell proliferation, differentiation, migration, and apoptosis. Activation of the Hippo pathway leads to the phosphorylation of mammalian Ste20-like kinases 1/2 (MST1/2) and large tumor suppressor 1/2 (LAT1/2), the latter in turn inhibits the core effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) through phosphorylation and thus inhibiting their nuclear localization. On the other hand, inactivation of the Hippo pathway leads to YAP/TAZ activation through promoting YAP/TAZ dephosphorylation and nuclear retention. Once activated, YAP/TAZ interact with TEAD or other transcription factors to induce the expression of a wide range of their downstream genes. Recently, the protein level of YAP was reported to be higher in the kidney of diabetic mice and in renal proximal tubule epithelial cells in response to high glucose, indicating that YAP may play a role in the pathogenesis of diabetic kidney disease.In the present study, we observed that the expression of both YAP and fibroblast growth factor 2 (FGF2) is higher in kidneys of diabetic db/db mice. Oral gavage of atorvastatin (10 mg/kg/daily), a lipid-lowering drug with newly identified YAP inhibitory property, alleviates albuminuria, glomerular hypertrophy, and renal fibrosis in db/db mice, accompanied by reduced renal expression of YAP and FGF2. To investigate whether hyperglycemia in diabetic conditions promotes YAP activation and FGF2 over-expression in kidney cells, we treated human proximal renal tubular epithelial cells (HK2) with 30 mM glucose for 48 hours and found that high glucose increased the mRNA level of YAP target genes (ANKRD1, CTGF, and CYR61) and FGF2. To explore if YAP/TAZ control the FGF2 expression, we transfected HK2 cells with plasmids expressing YAP/TAZ and showed that both expression and secretion of FGF2 were induced by YAP/TAZ over-expression. Oppositely, knockdown of YAP/TAZ decreased the expression of FGF2. The FGF2-promoter reporter gene assay further confirmed that YAP/TAZ promote the FGF2 expression at the transcriptional level. To investigate the effect of YAP activation in renal fibrosis, we constructed the Ksp-Cre transgenic MST1/MST2 double knockout (dKO) mice to achieve kidney-specific YAP activation. The results revealed that the expression of FGF2 is increased in dKO mice accompanied by renal fibrosis development at 8 weeks of age. While tubular-specific MST1/MST2/YAP triple knockout (tKO) mice were partly rescued from renal fibrosis in dKO mice with decreased expression of FGF2. To further clarify if FGF2 mediates YAP/TAZ-induced renal fibrosis, we injected the renal pelvis of dKO mice with the adeno-associated virus carrying CRISPR/Cas9-mediated FGF2 knockdown sequences. As the results showed, one month after virus injection, the FGF2 expression was significantly decreased and the renal fibrosis was ameliorated in the mouse kidneys. Taken together, the present results suggest that YAP activation promotes renal fibrosis through inducing the FGF2 expression and inhibition of YAP ameliorate renal fibrosis partly through decreasing the expression of FGF2.Hippo信號通路是壹條進化上非常保守的信號通路，通過調節細胞增殖，分化，遷移和雕亡來控制器官的大小。 Hippo信號通路的激活導致哺乳動物MST1 / 2激酶和腫瘤抑制因子LAT1 / 2的磷酸化，最終抑制了轉錄共激活因子 YAP 和 TAZ，通過磷酸化作用抑制其入核。另壹方面，Hippo信號通路的失活通過促進YAP / TAZ去磷酸化和入核而導致YAP / TAZ活化。激活後，YAP / TAZ與TEAD或其他轉錄因子相互作用，並誘導其下遊基因的廣泛表達。研究發現，糖尿病小鼠的腎臟和高糖刺激的人近端腎小管上皮細胞中YAP激活，這表明YAP可能參與糖尿病腎病的發病機理。在本研究中，我們發現糖尿病小鼠（db/db）腎臟中的YAP和FGF2表達升高。應用壹種具有YAP抑制特性的降脂藥物阿托伐他汀灌胃（10 mg / kg / 每日），可抑制YAP和FGF2表達，並減輕db/db小鼠的蛋白尿，腎小球肥大和腎纖維化。為了研究糖尿病患者中的高血糖是否促進YAP激活和FGF2的表達，我們用30 mM葡萄糖處理人近端腎小管上皮細胞（HK2）48小時，發現高糖會增加YAP靶基因（ANKRD1，CTGF和CYR61）和FGF2的表達。為了探討YAP / TAZ是否調控FGF2的表達，我們在HK2細胞中過表達YAP / TAZ，發現 YAP / TAZ過表達誘導了FGF2的表達和分泌。相反，YAP / TAZ 敲低降低了FGF2的表達。 FGF2-啟動子報告基因檢測進壹步證實了YAP/TAZ 在轉錄水平調節FGF2表達。為了研究YAP激活在腎纖維化中的作用，我們構建了腎小管特異性MST1 / MST2雙敲除（dKO）小鼠，以實現腎小管特異性YAP激活。實驗結果表明，在8周齡的dKO小鼠中，伴隨著腎纖維化的發展，FGF2的表達增加。腎小管特異性MST1 / MST2 / YAP三重敲除（tKO）小鼠，FGF2的表達下調，腎纖維化有所緩解。為了進壹步闡明FGF2是否參與YAP / TAZ誘導的腎纖維化，我們用帶有CRISPR / Cas9介導的FGF2敲除序列的腺相關病毒對dKO小鼠進行腎盂註射。結果表明，註射後1個月，FGF2表達顯著降低，腎纖維化得到改善。綜上所述，這些結果表明YAP活化通過誘導FGF2表達促進腎纖維化，阿托伐他汀對YAP的抑制可以部分通過降低FGF2的表達改善腎纖維化。Wang, Yu."December 2020."Ph.D. Chinese University of Hong Kong 2021.Includes bibliographical references (leaves 113-121).Abstracts also in Chinese.Title from PDF title page (viewed on September 13, 2022)
- …
