YAP and the Hippo pathway in pediatric cancer

Ahmed, Atif; Mohamed, Abdalla; Gener, Melissa; Li, Weijie; Taboada, Eugenio

doi:10.1080/23723556.2017.1295127

Cited by 49 publications

(48 citation statements)

References 65 publications

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“…Mst1, a critical regulator of the hippo pathway, is closely related to evolutionarily conserved serine/threonine protein kinases that play a pivotal role in cell proliferation, survival, morphology and motility and organ size [47]. Recent studies in conditional Mst1 ablation and transgenic Mst1/2 double-knockout mice exhibit abrogation of Yap phosphorylation with intense nuclear accumulation, leading to the development of hepatocellular carcinoma, pancreatic cancer, cardiac reperfusion injury and metabolic liver disease [48,49]. However, our data introduced Mst1 into the etiology of endometriosis.…”

Section: Discussionmentioning

confidence: 99%

Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy

Zhao

Yang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Mitochondrial homeostasis is implicated in the development and progression of endometriosis through poorly defined mechanisms. Mst1 is the major growth suppressor related to cancer migration, apoptosis and proliferation. However, whether Mst1 is involved in endometriosis apoptosis and migration via regulating the mitochondrial function remains to be elucidated. Methods: Expression of Mst1 in endometriosis was examined via western blots. Cellular apoptosis was detected via MTT and TUNEL assay. Gain of function assay about Mst1 was conducted via adenovirus over-expression. Mitochondrial functions were evaluated via mitochondrial membrane potential JC-1 staining, ROS flow cytometry analysis, mPTP opening assessment and immunofluorescence of HtrA2/Omi. The mitophagy activity were examined via western blots and immunofluorescence. Results: First, we found that Mst1 was significantly downregulated in the ectopic endometrium of endometriosis compared to the normal endometrium. However, the recovery of Mst1 function was closely associated with the inability of endometrial stromal cells (ESCs) to migrate and survive. A functional study indicated that regaining Mst1 enhanced Drp1 post-transcriptional phosphorylation at Ser616 and repressed Parkin transcription activity via p53, leading to mitochondrial fission activation and mitophagy inhibition. Excessive Drp1-related fission forced the mitochondria to liberate HtrA2/Omi into the cytoplasm. Moreover, Mst1-induced defective mitophagy evoked cellular

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Section: Discussionmentioning

confidence: 99%

Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy

Zhao

Yang

et al. 2018

Cell Physiol Biochem

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“…This pathway mediates cellcell contact inhibition and is activated by the phosphorylation of the large tumor suppressor kinase LATS2. NF2 as well as AMOT and TAOK1 regulate LATS2 activities and in doing so inhibit the pro-proliferation transcription factors YAP and TAZ (Ahmed et al, 2017). The absence of these LATS regulators results in the inhibition of the Hippo pathway, which allows for the nuclear translocation of YAP and TAZ and unmitigated transcription of the target genes that lead to excessive proliferation.…”

Section: Shh and Primary Cilia Govern Snap Proliferationmentioning

confidence: 99%

Genome-wide screens in accelerated human stem cell-derived neural progenitor cells identify Zika virus host factors and drivers of proliferation

Wells

Salick

Piccioni

et al. 2018

Preprint

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Neural progenitor cells (NPCs) are essential to brain development and their dysfunction is linked to several disorders, including autism, Zika Virus Congenital Syndrome, and cancer. Understanding of these conditions has been improved by advancements with stem cellderived NPC models. However, current differentiation methods require many days or weeks to generate NPCs and show variability in efficacy among cell lines. Here, we describe human Stem cell-derived NGN2accelerated Progenitor cells (SNaPs), which are produced in only 48 hours. SNaPs express canonical forebrain NPC protein markers, are proliferative, multipotent, and like other human NPCs, are susceptible to Zika-mediated death. We further demonstrate SNaPs are valuable for large-scale investigations of genetic and environmental influencers of neurodevelopment by deploying them for genome-wide CRISPR-Cas9 screens. Our studies expand knowledge of NPCs by identifying known and novel Zika host factors, as well as new regulators of NPC proliferation validated by reidentification of the autism spectrum gene PTEN.the DOX-inducible overexpression of NGN2 and the linked puromycin resistance gene (Figure 1b). After expansion of the transduced hPSCs, we initiated NGN2 induction by adding DOX and the small molecule inhibitors of the SMAD Figure 1: Rapid induction of stem cell-derived human neural progenitor cells. A, Normalized expression of pluripotency, progenitor, and neuronal transcript markers over the course of NGN2-directed differentiation of induced neurons (from Nehme et al., 2018). B, Schematic describing the SNaP induction and expansion protocol. C, Bright field images of SW.1 induced pluripotent stem cells (left) and SNaPs at 48 hours post-induction (right). Scale bar = 25 µm. D, SNaP immunostaining of forebrain NPC protein markers at 48 hours post-induction. Scale bar = 50 µm. E, SNaPs self-organize into rosette-like structures 2 days after first passage. Scale bar = 50 µm. F, Magnified images of a SOX1-positive rosette structure. Scale bar = 25 µm. G, Quantification of protein marker expression in SNaPs at 48 hours post-induction, 2 days after first passage, and after passage 10 (n = 8-24 wells from 2-3 differentiations). H, Heat map depicting percentage of NPC marker-positive cells in P1-2 SNaPs from 47 different hPSC lines (n = 4 wells). Data are represented as mean ± S.D.

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“…Accumulating evidence has implicated that YAP serves an important and multifaceted role in cancer progression, including gastric cancer, pediatric cancer and breast cancer (7)(8)(9)(10). YAP also been demonstrated to be overexpressed in various types of solid tumors, including gastric cancer, pediatric cancer and breast cancer, and its overexpression is associated with tumor initiation, invasion and metastasis (9,11,12).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of YAP inhibits proliferation, invasion and increases cisplatin sensitivity in human hepatocellular carcinoma cells

Wang¹,

Wu²,

Zhong³

2018

Oncol Lett

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Abstract. Yes-associated protein (YAP) serves an essential role in tumorigenesis. However, the potential role and the molecular mechanism underlying the effect of YAP on hepatocellular carcinoma (HCC) cells have not been elucidated. In the current study, it was revealed that YAP expression was increased significantly in HCC cancer tissues and its overexpression was associated with tumor differentiation. The silencing of YAP by small interferring RNA led to the inhibition of HCC cell growth, which was associated with the promotion of apoptosis. The silencing of YAP also decreased the invasive potential of HCC cells and the activity of the phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling pathway. Furthermore, silencing of YAP increased the chemosensitivity of HCC cells to cisplatin (CDDP) through inactivation of the PI3K/AKT signaling pathway. In vivo studies using PDTX model suggested a promotive role for YAP in the growth of HCC and knockdown of YAP increased the anti-tumor activity of CDDP. Taken together, these results revealed that YAP is overexpressed in HCC, and promotes proliferation, invasion and drug resistance of HCC cells. Inhibition of YAP, alone or in combination with traditional chemotherapy, may effectively combat HCC.

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YAP and the Hippo pathway in pediatric cancer

Cited by 49 publications

References 65 publications

Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy

Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy

Genome-wide screens in accelerated human stem cell-derived neural progenitor cells identify Zika virus host factors and drivers of proliferation

Downregulation of YAP inhibits proliferation, invasion and increases cisplatin sensitivity in human hepatocellular carcinoma cells

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