Articles de revues : « YAE1 »

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Merlin, Christophe, Gregory Gardiner, Sylvain Durand et Millicent Masters. « The Escherichia coli metD Locus Encodes an ABC Transporter Which Includes Abc (MetN), YaeE (MetI), and YaeC (MetQ) ». Journal of Bacteriology 184, n^o 19 (1 octobre 2002) : 5513–17. http://dx.doi.org/10.1128/jb.184.19.5513-5517.2002.

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ABSTRACT We report that the genes abc, yaeC, and yaeE comprise metD, an Escherichia coli locus encoding a dl-methionine uptake system. MetD is an ABC transporter with Abc the ATPase, YaeE the permease, and YaeC the likely substrate binding protein. Expression of these genes is regulated by l-methionine and MetJ, a common repressor of the methionine regulon. We propose to rename abc, yaeE, and yaeC as metN, metI, and metQ, respectively.

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Prusty, Nihar Ranjan, Francesca Camponeschi, Simone Ciofi-Baffoni et Lucia Banci. « The human YAE1-ORAOV1 complex of the cytosolic iron-sulfur protein assembly machinery binds a [4Fe-4S] cluster ». Inorganica Chimica Acta 518 (avril 2021) : 120252. http://dx.doi.org/10.1016/j.ica.2021.120252.

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Wiatrowski, Heather A., et Marian Carlson. « Yap1 Accumulates in the Nucleus in Response to Carbon Stress in Saccharomyces cerevisiae ». Eukaryotic Cell 2, n^o 1 (février 2003) : 19–26. http://dx.doi.org/10.1128/ec.2.1.19-26.2003.

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ABSTRACT Yap1 is a transcription factor of the AP-1 family that is required for the adaptive response to oxidative stress in Saccharomyces cerevisiae. We recovered Yap1 in a two-hybrid screen for proteins that interact with the Sip2 subunit of the Snf1 protein kinase, which is required for the adaptation of cells to glucose limitation. Yap1 becomes enriched in the nucleus when cells are subjected to oxidative stress. We show that the localization of Yap1 is similarly sensitive to carbon stress. When glucose-grown cells were shifted to medium containing glycerol or no added carbon source, green fluorescent protein (GFP)-Yap1 accumulated in the nucleus. After adaptation to growth in glycerol, GFP-Yap1 was again primarily cytoplasmic. Nuclear accumulation was independent of respiration and of the Snf1, PKA, TOR, and Yak1 pathways, and the mechanism is distinct from that involved in the response to hydrogen peroxide. Addition of glutathione to the medium inhibited nuclear accumulation of GFP-Yap1 in response to carbon stress but did not affect the relocalization of Gal83 or Mig1. Other stresses such as increased temperature, acidic pH, and ionic stress did not cause nuclear enrichment of GFP-Yap1. These findings suggest a role for Yap1 in the response to carbon stress.

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Ben, Chi, Xiaojing Wu, Atsushi Takahashi-Kanemitsu, Christopher Takaya Knight, Takeru Hayashi et Masanori Hatakeyama. « Alternative splicing reverses the cell-intrinsic and cell-extrinsic pro-oncogenic potentials of YAP1 ». Journal of Biological Chemistry 295, n^o 41 (6 août 2020) : 13965–80. http://dx.doi.org/10.1074/jbc.ra120.013820.

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In addition to acting as a transcriptional co-activator, YAP1 directly mediates translocalization of the pro-oncogenic phosphatase SHP2 from the cytoplasm to nucleus. In the cytoplasm, SHP2 potentiates RAS–ERK signaling, which promotes cell proliferation and cell motility, whereas in the nucleus, it mediates gene regulation. As a result, elucidating the details of SHP2 trafficking is important for understanding its biological roles, including in cancer. YAP1 comprises multiple splicing isoforms defined in part by the presence (as in YAP1-2γ) or absence (as in YAP1-2α) of a γ-segment encoded by exon 6 that disrupts a critical leucine zipper. Although the disruptive segment is known to reduce co-activator function, it is unclear how this element impacts the physical and functional relationships between YAP1 and SHP2. To explore this question, we first demonstrated that YAP1-2γ cannot bind SHP2. Nevertheless, YAP1-2γ exhibits stronger mitogenic and motogenic activities than does YAP1-2α because the YAP1-2α–mediated delivery of SHP2 to the nucleus weakens cytoplasmic RAS–ERK signaling. However, YAP1-2γ confers less in vivo tumorigenicity than does YA1-2α by recruiting tumor-inhibitory macrophages. Mechanistically, YAP1-2γ transactivates and the YAP1-2α–SHP2 complex transrepresses the monocyte/macrophage chemoattractant CCL2. Thus, cell-intrinsic and cell-extrinsic pro-oncogenic YAP1 activities are inversely regulated by alternative splicing of exon 6. Notably, oncogenic KRAS down-regulates the SRSF3 splicing factor that prevents exon 6 skipping, thereby creating a YAP1-2α–dominant situation that supports a “cold” immune microenvironment.

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Gál, József, Attila Szvetnik, Róbert Schnell et Miklós Kálmán. « The metDd-Methionine Transporter Locus of Escherichia coli Is an ABC Transporter Gene Cluster ». Journal of Bacteriology 184, n^o 17 (1 septembre 2002) : 4930–32. http://dx.doi.org/10.1128/jb.184.17.4930-4932.2002.

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ABSTRACT The metD d-methionine transporter locus of Escherichia coli was identified as the abc-yaeE-yaeC cluster (now renamed metNIQ genes). The abc open reading frame is preceded by tandem MET boxes bracketed by the −10 and −35 boxes of a promoter. The expression driven by this promoter is controlled by the MetJ repressor and the level of methionine.

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Kawauchi, Daisuke, Kristian Pajtler, Yiju Wei, Konstantin Okonechnikov, Patricia Silva, David Jones, Mikio Hoshino, Stefan Pfister, Marcel Kool et Wei Li. « TB-06 MOLECULAR MECHANISM OF BRAIN TUMOUR FORMATION DRIVEN BY SUPRATENTORIAL EPENDYMOMA-SPECIFIC YAP1 FUSION GENES ». Neuro-Oncology Advances 1, Supplement_2 (décembre 2019) : ii11. http://dx.doi.org/10.1093/noajnl/vdz039.048.

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Abstract YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions but not YAP1 wildtype are sufficient to drive malignant transformation of neural progenitors in the developing cerebral cortex in mice, and the resulting tumours share histo-molecular characteristics of human ependymomas. Nuclear localization of YAP1-MAMLD1 protein is associated with its oncogenicity and is mediated by the nuclear localization signal of MAMLD1 in a YAP1-Ser127 phosphorylation-independent manner. Chromatin immunoprecipitation-sequencing analyses of human YAP1-MAMLD1-positive ependymoma reveal enrichment of NFI and TEAD transcription factor binding site motifs in YAP1-bound regulatory elements, hypothesizing the important role of these transcription factors in YAP1-MAMLD1-driven tumourigenesis. Indeed, co-immunoprecipitation assays revealed physical interactions of TEADs and NFIA/B with the YAP1 and MAMLD1 domains of the fusion protein, respectively. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumour induction in mice. Together, these results demonstrate that the YAP1-MAMLD1 fusion functions as an oncogenic driver of ependymoma through recruitment of TEADs and NFIs, indicating a rationale for preclinical studies to block the interaction between YAP1 fusions and NFI and TEAD transcription factors.

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Kim, Yong Sook, Mira Kim, Dong Im Cho, Soo Yeon Lim, Ju Hee Jun, Mi Ra Kim, Bo Gyeong Kang et al. « PSME4 Degrades Acetylated YAP1 in the Nucleus of Mesenchymal Stem Cells ». Pharmaceutics 14, n^o 8 (9 août 2022) : 1659. http://dx.doi.org/10.3390/pharmaceutics14081659.

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Intensive research has focused on minimizing the infarct area and stimulating endogenous regeneration after myocardial infarction. Our group previously elucidated that apicidin, a histone deacetylase (HDAC) inhibitor, robustly accelerates the cardiac commitment of naïve mesenchymal stem cells (MSCs) through acute loss of YAP1. Here, we propose the novel regulation of YAP1 in MSCs. We found that acute loss of YAP1 after apicidin treatment resulted in the mixed effects of transcriptional arrest and proteasomal degradation. Subcellular fractionation revealed that YAP1 was primarily localized in the cytoplasm. YAP1 was acutely relocalized into the nucleus and underwent proteasomal degradation. Interestingly, phosphor-S127 YAP1 was shuttled into the nucleus, suggesting that a mechanism other than phosphorylation governed the subcellular localization of YAP1. Apicidin successfully induced acetylation and subsequent dissociation of YAP1 from 14-3-3, an essential molecule for cytoplasmic restriction. HDAC6 regulated both acetylation and subcellular localization of YAP1. An acetylation-dead mutant of YAP1 retarded nuclear redistribution upon apicidin treatment. We failed to acquire convincing evidence for polyubiquitination-dependent degradation of YAP1, suggesting that a polyubiquitination-independent regulator determined YAP1 fate. Nuclear PSME4, a subunit of the 26 S proteasome, recognized and degraded acetyl YAP1 in the nucleus. MSCs from PSME4-null mice were injected into infarcted heart, and aberrant sudden death was observed. Injection of immortalized human MSCs after knocking down PSME4 failed to improve either cardiac function or the fibrotic scar area. Our data suggest that acetylation-dependent proteasome subunit PSME4 clears acetyl-YAP1 in response to apicidin treatment in the nucleus of MSCs.

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Hartley, A. D., M. P. Ward et S. Garrett. « The Yak1 protein kinase of Saccharomyces cerevisiae moderates thermotolerance and inhibits growth by an Sch9 protein kinase-independent mechanism. » Genetics 136, n^o 2 (1 février 1994) : 465–74. http://dx.doi.org/10.1093/genetics/136.2.465.

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Abstract The growth defect associated with the loss of yeast A kinase activity can be alleviated by the overexpression or deletion of two other kinases, Sch9 and Yak1, respectively. Using tests of epistasis, we have shown that Sch9 and Yak1 define separate signaling pathways and must, therefore, suppress the A kinase defect by different mechanisms. Nevertheless, the Yak1 kinase appears to regulate cellular processes that are under A kinase control. For example, acquisition of heat resistance is correlated with Yak1 kinase activity, such that YAK1-overexpressing cells are over 200-fold more resistant than isogenic yak1 strains. These results, for the first time, associate a phenotype, other than suppression of the A kinase growth defect, with the loss of Yak1 activity and argue a broader role for the Yak1 kinase in cell growth.

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Zeng, Cheng, Pei-Li Wu, Zhao-Tong Dong, Xin Li, Ying-Fang Zhou et Qing Xue. « YAP1 inhibits ovarian endometriosis stromal cell invasion through ESR2 ». Reproduction 160, n^o 3 (septembre 2020) : 481–90. http://dx.doi.org/10.1530/rep-19-0565.

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Endometriosis is an estrogen-dependent disease, and estrogen receptor 2 (ESR2) plays a critical role in the pathogenesis of ovarian endometriosis by promoting cell invasion. Yes-associated protein 1 (YAP1) plays suppressive roles in several types of tumors. However, the relationship between YAP1 and ESR2 is not fully understood. The aim of this study was to investigate the regulatory mechanism of YAP1 in terms of ESR2 and YAP1 regulation of endometriotic stromal cell (ECSC) invasion in ovarian endometriosis. Our results demonstrated that YAP1 mRNA and protein levels in eutopic endometrium (EU) tissues were higher than those in paired ectopic endometrium (EC) tissues. ECSCs transfected with siYAP1 exhibited a significant increase in both ESR2 mRNA levels and protein expression. Simultaneously, YAP1 overexpression in ECSCs yielded the opposite results. Co-IP assays demonstrated YAP1-NuRD complex formation by YAP1, CHD4 and MTA1 in ECSCs. YAP1 bound to two sites, (-539, -533) and (-158, -152), upstream of the ESR2 transcription initiation site. YAP1 binding to the two sites of the ESR2 promoter in ECSCs was significantly lower than that in eutopic endometrial stromal cells (EUSCs) from EU tissues. ECSCs transfected with siYAP1 exhibited increased invasion activity, while ECSCs transfected with siESR2 showed inhibition of invasion. However, transfection with siYAP1 and siESR2 together decreased the number of invading cells compared with transfection with siYAP1 alone. Therefore, we conclude that decreased levels of YAP1 in ovarian endometriomas enhance ESR2 expression via formation of a YAP1-NuRD complex, which further binds to the ESR2 promoters. Furthermore, YAP1 inhibits ECSCs invasion.

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Szulzewsky, Frank, Pia Hoellerbauer, Hua-Jun Wu, P. J. Cimino, Franziska Michor, Patrick Paddison, Valeri Vasioukhin et Eric Holland. « GENE-04. THE ONCOGENIC FUNCTIONS OF YAP1-GENE FUSIONS CAN BE INHIBITED BY DISRUPTION OF YAP1-TEAD INTERACTION ». Neuro-Oncology 21, Supplement_6 (novembre 2019) : vi98. http://dx.doi.org/10.1093/neuonc/noz175.406.

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Abstract Supratentorial ependymoma can be sub-stratified into clinically relevant subtypes characterized by distinct molecular features. The subtype defined by high YAP1 activity harbored two distinct YAP1 gene fusions, YAP1-MAMLD1 and YAP1-FAM118B. In addition, YAP1 gene fusions have been detected in several other cancer types, including Epithelioid Hemangioendothelioma and Endocervical Adenocarcinoma. YAP1 is a key transcriptional co-activator and proto-oncogene that is negatively regulated by the Hippo pathway. Here, we show that both YAP1-MAMLD1 and YAP1-FAM118B, as well as additional YAP1 fusion genes found in other cancer types, are potent oncogenic drivers that cause tumor formation in the brain and the hindlimb in mice upon overexpression by somatic cell gene transfer. Using different in vitro assays, including Luciferase, RNA-, and ChIP Seq, we show that both the N-terminal YAP1 part and the C-terminal fusion partners exert activity. We can show that the YAP1 activity still relies on the binding to TEAD transcription factors, whereas the C terminal activity does not. Furthermore, the different fusion proteins have become independent from negative Hippo pathway signaling by constitutive nuclear localization and protection from degradation. In addition, by introducing point mutations and truncations to block the YAP1 and the MAMLD1 function we can show that the activity of both halves contributes to the oncogenic function of YAP1-MAMLD1. Using in vitro and in vivo assays we can show that pharmacological and genetic ablation of YAP-TEAD interaction diminishes the oncogenic potential of the fusions, indicating that this might be a potential therapeutic approach for these tumors in the future.

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Qadir, Javeria, Syeda Kiran Riaz, Kiran Taj, Natasha Sattar, Namood-e. Sahar, Jahangir Sarwar Khan, Mahmood Akhtar Kayani, Farhan Haq et Muhammad Faraz Arshad Malik. « Increased YAP1 expression is significantly associated with breast cancer progression, metastasis and poor survival ». Future Oncology 17, n^o 21 (juillet 2021) : 2725–34. http://dx.doi.org/10.2217/fon-2020-1080.

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YAP1 plays a key role as a transcriptional coactivator in the Hippo pathway. Based on conflicting reports regarding YAP1 function in cancer, this study discerned its role in breast carcinogenesis. First, a systematic review of salient breast cancer studies targeting YAP1 dysregulation was performed. Additionally, freshly excised tumor specimens of approximately 200 breast cancer patients were processed for quantification of YAP1 expression at mRNA and protein levels using quantitative PCR and immunohistochemistry, respectively. YAP1 expression was nine folds higher in tumors versus controls and significantly associated with metastasis (p < 0.05) and poor survival in Pakistani breast cancer patients. These findings establish the role of YAP1 overexpression in tumorigenesis and metastasis. Hence, YAP1 inhibition may be considered a possible therapeutic strategy.

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Tang, Hao, Ping Gong, Ling Tao et Yurong Hua. « miR-194 Inhibits Ovarian Cancer Cell Proliferation and Reduces Cisplatin Resistance by Targeting Yes-Associated Protein ». Journal of Biomaterials and Tissue Engineering 10, n^o 8 (1 août 2020) : 1170–75. http://dx.doi.org/10.1166/jbt.2020.2379.

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Elevated expression of Yes-associated protein (YAP1) is associated with ovarian cancer. Bioinformatics analysis showed a relationship between miR-194 and YAP1. Our study intends to assess whether miR-194 regulates YAP1 expression and affects the proliferation of ovarian cancer cells and CDDP resistance. CDDP-resistant cell line A2780/CDDP was established and the expression of miR-194 and YAP1 in parental A2780 cells and normal ovarian epithelial IOSE80 cells were compared. A2780/CDDP cells were separated into miR-NC group and miR-194 mimic group followed by analysis of miR-194 and YAP1 expression, and cell apoptosis and proliferation by flow cytometry. There was a targeted relationship between miR-194 and YAP1 mRNA. A2780/CDDP cells had the lowest miR-194 expression followed by A2780 cells and IOSE80 cells. In addition, YAP1 level was highest in A2780/CDDP cells followed by A2780 cells and IOSE80 cells. Compared with miR-NC group, miR-194 expression was significantly increased in miR-194 mimic transfection group and YAP1 protein expression was significantly decreased, with increased cell apoptosis and reduced cell proliferation ability. Decreased miR-194 expression and increased YAP1 expression are related to ovarian cancer CDDP resistance. Increased miR-194 can down-regulate YAP1, inhibit ovarian cancer cell proliferation, promote cell apoptosis, and reduce CDDP resistance.

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Szulzewsky, Frank, Sonali Arora, Aleena Arakaki, Philipp Sievers, Damian Almiron Bonnin, Patrick Paddison, Felix Sahm, Patrick Cimino, Taranjit Gujral et Eric Holland. « MODL-36. EXPRESSION OF YAP1-MAML2 AND CONSTITUTIVELY ACTIVE YAP1 DRIVE THE FORMATION OF MENINGIOMA-LIKE TUMORS IN MICE THAT RESEMBLE NF2-MUTANT MENINGIOMAS ». Neuro-Oncology 24, Supplement_7 (1 novembre 2022) : vii298—vii299. http://dx.doi.org/10.1093/neuonc/noac209.1163.

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Abstract YAP1 is a transcriptional co-activator and oncogene under the control of the Hippo Signaling Pathway. Functional inactivation of Hippo Pathway tumor suppressors, including NF2, are frequent events in human cancers. Meningiomas are the most common primary brain tumors, and a large percentage exhibit heterozygous loss of chromosome 22 (harboring the NF2 gene) and functional inactivation of the remaining NF2 gene copy, implicating oncogenic YAP activity in the pathobiology of almost half of these tumors. An alternate type of activating YAP1 mutation are YAP1 gene fusions that have been identified in several cancer subtypes. Recently, fusions between YAP1 and MAML2 have been identified in a subset of pediatric NF2-wild type meningiomas. Here, we show that the expression profile of human YAP1-MAML2-positive pediatric meningiomas resembles that of the common NF2-mutant meningiomas based on global and YAP-related gene expression signatures. We then use the RCAS/tv-a system for postnatal gene transfer and show that the intracranial expression of YAP1-MAML2 in neonatal mice results in the formation of meningioma-like tumors that exert a similar gene expression pattern as seen in human YAP1 fusion-positive and NF2-mutant meningiomas and regulate classical YAP1 target genes. We demonstrate that YAP1-MAML2 exerts oncogenic YAP activity that is resistant to inhibitory Hippo pathway signaling and relies on the interaction with TEAD transcription factors. Pharmacological disruption of this interaction is sufficient to inhibit the viability of YAP1-MAML2-expressing mouse tumors ex vivo. Finally, we show that constitutively active YAP1 (S127/397A-YAP1) is also sufficient to cause the formation of similar meningioma-like tumors suggesting that the YAP component of the gene fusion is the critical driver of these tumors. In summary, our results implicate YAP1-MAML2 as a sufficient oncogenic driver in YAP1-MAML2 fusion-positive meningiomas, which mimic NF2-mutant meningiomas, and highlight TEAD-dependent YAP activity as a potential therapeutic target in these tumors.

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Garrett, S., M. M. Menold et J. R. Broach. « The Saccharomyces cerevisiae YAK1 gene encodes a protein kinase that is induced by arrest early in the cell cycle ». Molecular and Cellular Biology 11, n^o 8 (août 1991) : 4045–52. http://dx.doi.org/10.1128/mcb.11.8.4045-4052.1991.

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Null mutations in the gene YAK1, which encodes a protein with sequence homology to known protein kinases, suppress the cell cycle arrest phenotype of mutants lacking the cyclic AMP-dependent protein kinase (A kinase). That is, loss of the YAK1 protein specifically compensates for loss of the A kinase. Here, we show that the protein encoded by YAK1 has protein kinase activity. Yak1 kinase activity is low during exponential growth but is induced at least 50-fold by arrest of cells prior to the completion of S phase. Induction is not observed by arrest at stages later in the cell cycle. Depending on the arrest regimen, induction can occur either by an increase in Yak1 protein levels or by an increase in Yak1 specific activity. Finally, an increase in Yak1 protein levels causes growth arrest of cells with attenuated A kinase activity. These results suggest that Yak1 acts in a pathway parallel to that of the A kinase to negatively regulate cell proliferation.

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Garrett, S., M. M. Menold et J. R. Broach. « The Saccharomyces cerevisiae YAK1 gene encodes a protein kinase that is induced by arrest early in the cell cycle. » Molecular and Cellular Biology 11, n^o 8 (août 1991) : 4045–52. http://dx.doi.org/10.1128/mcb.11.8.4045.

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Null mutations in the gene YAK1, which encodes a protein with sequence homology to known protein kinases, suppress the cell cycle arrest phenotype of mutants lacking the cyclic AMP-dependent protein kinase (A kinase). That is, loss of the YAK1 protein specifically compensates for loss of the A kinase. Here, we show that the protein encoded by YAK1 has protein kinase activity. Yak1 kinase activity is low during exponential growth but is induced at least 50-fold by arrest of cells prior to the completion of S phase. Induction is not observed by arrest at stages later in the cell cycle. Depending on the arrest regimen, induction can occur either by an increase in Yak1 protein levels or by an increase in Yak1 specific activity. Finally, an increase in Yak1 protein levels causes growth arrest of cells with attenuated A kinase activity. These results suggest that Yak1 acts in a pathway parallel to that of the A kinase to negatively regulate cell proliferation.

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Yang, Zhenghui, Hao Xiong, Shanshan Wei, Qingxiu Liu, Yan Gao, Lishi Liu, Zhili Hu et al. « Yes-Associated Protein Promotes the Development of Condyloma Acuminatum through EGFR Pathway Activation ». Dermatology 236, n^o 5 (13 septembre 2019) : 454–66. http://dx.doi.org/10.1159/000500216.

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Objective: Investigate the role of Yes-associated protein (YAP1) in the development of condyloma acuminatum (CA). Methods: We enrolled 30 male patients with CA and 20 healthy individuals as a control group, to compare the YAP1 expression in their tissue samples. Following this, we overexpressed and downregulated YAP1 expression in HaCaT cells to examine the migratory, proliferative, and apoptotic potential of HaCaT cells expressing different levels of YAP1. Results: In the CA patient tissue samples, an increase in YAP1 expression can be observed. In vitro,the overexpression of YAP1 was shown to promote the growth and migration of HaCaT cells and to activate epidermal growth factor receptor (EGFR) pathway-associated proteins, while the downregulation of YAP1 inhibited cell growth and migration of these cells. Conclusions: YAP1 promotes the growth of keratinocytes in CA through the activation of the EGFR pathway, and it may mediate the development of human papilloma virus-associated diseases.

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Lee, Yangkyu, Soong June Bae, Na Lae Eun, Sung Gwe Ahn, Joon Jeong et Yoon Jin Cha. « Correlation of Yes-Associated Protein 1 with Stroma Type and Tumor Stiffness in Hormone-Receptor Positive Breast Cancer ». Cancers 14, n^o 20 (11 octobre 2022) : 4971. http://dx.doi.org/10.3390/cancers14204971.

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(1) Background: Yes-associated protein 1 (YAP1) is an oncogene activated under the dysregulated Hippo pathway. YAP1 is also a mechanotransducer that is activated by matrix stiffness. So far, there are no in vivo studies on YAP1 expression related to stiffness. We aimed to investigate the association between YAP1 activation and tumor stiffness in human breast cancer samples, using immunohistochemistry and shear-wave elastography (SWE). (2) Methods: We included 488 patients with treatment-naïve breast cancer. Tumor stiffness was measured and the mean, maximal, and minimal elasticity values and elasticity ratios were recorded. Nuclear YAP1 expression was evaluated by immunohistochemistry and tumor-infiltrating lymphocytes (TILs); tumor-stroma ratio (TSR) and stroma type of tumors were also evaluated. (3) Results: Tumor stiffness was higher in tumors with YAP1 positivity, low TILs, and high TSR and was correlated with nuclear YAP1 expression; this correlation was observed in hormone receptor positive (HR+) tumors, as well as in tumors with non-collagen-type stroma. (4) Conclusions: We confirmed the correlation between nuclear YAP1 expression and tumor stiffness, and nuclear YAP1 expression was deemed a prognostic candidate in HR+ tumors combined with SWE-measured tumor stiffness.

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Jin, Zhong, et Bing Chen. « LncRNA ZEB1-AS1 regulates colorectal cancer cells by miR-205/YAP1 axis ». Open Medicine 15, n^o 1 (8 mars 2020) : 175–84. http://dx.doi.org/10.1515/med-2020-0026.

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AbstractBackgroundRecent studies demonstrated that long non-coding RNAs (lncRNAs) were involved in many biological processes. Dysregulated lncRNAs are related to many cancers, including colorectal cancer (CRC). However, the molecular mechanism of lncRNA ZEB1-AS1 in CRC is not clear.MethodsLncRNA ZEB1-AS1, miR-205, and YAP1 expression were measured by quantitative reverse transcriptase PCR (QRT-PCR). YAP1 protein expression was measured by western blotting. Cell viability was measured by MTT assay. Cell apoptosis was detected by flow cytometry. Luciferase reporter assay was used to confirm the relationship between ZEB1-AS1, miR-205, and YAP1.ResultsLncRNA ZEB1-AS1 and YAP1 was upregulated in CRC tissues. The expression of YAP1 was positively correlated with ZEB1-AS1. Knockdown of ZEB1-AS1 inhibited cell viability and induced apoptosis in CRC cell line SW480 and HCT116 which could be reversed by overexpression of YAP1. ZEB1-AS1 targeted and regulated miR-205 which could directly bind to YAP1. Meanwhile, ZEB1-AS1 regulated the expression of YAP1 via modulating miR-205.ConclusionLong non-coding RNA ZEB1-AS1 silencing could inhibit cell proliferation and induce apoptosis of colorectal cancer via regulating miR-205 and YAP1.

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Sahebjam, Solmaz, et Mark R. Gilbert. « Modeling YAP fusions : a paradigm for investigating rare cancers ? » Genes & ; Development 36, n^o 15-16 (1 août 2022) : 874–75. http://dx.doi.org/10.1101/gad.350069.122.

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Loss of the NF2 tumor suppressor gene is a common finding in meningiomas, and more recently YAP1 fusions have been found in a subset of pediatric NF2 wild-type meningiomas. In the previous issue of Genes & Development, Szulzewsky and colleagues (pp. 857–870) showed that TEAD-dependent YAP1 activity by either the loss of the NF2 gene or YAP1-MAML2 fusion is an oncogenic process promoting meningioma tumorigenesis. Furthermore, pharmacological inhibition of YAP1-TEAD resulted in antitumor activity in both YAP1 fusion-positive and NF2 mutant meningiomas. Together, these data indicate that disruption of the YAP1-TEAD interaction raises a potential therapeutic option for these tumors that requires future investigation.

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Tavanti, Giulia Stefania, Chiara Verdelli, Annamaria Morotti, Paola Maroni, Vito Guarnieri, Alfredo Scillitani, Rosamaria Silipigni et al. « Yes-Associated Protein 1 Is a Novel Calcium Sensing Receptor Target in Human Parathyroid Tumors ». International Journal of Molecular Sciences 22, n^o 4 (18 février 2021) : 2016. http://dx.doi.org/10.3390/ijms22042016.

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The Hippo pathway is involved in human tumorigenesis and tissue repair. Here, we investigated the Hippo coactivator Yes-associated protein 1 (YAP1) and the kinase large tumor suppressor 1/2 (LATS1/2) in tumors of the parathyroid glands, which are almost invariably associated with primary hyperparathyroidism. Compared with normal parathyroid glands, parathyroid adenomas (PAds) and carcinomas show variably but reduced nuclear YAP1 expression. The kinase LATS1/2, which phosphorylates YAP1 thus promoting its degradation, was also variably reduced in PAds. Further, YAP1 silencing reduces the expression of the key parathyroid oncosuppressor multiple endocrine neoplasia type 1(MEN1), while MEN1 silencing increases YAP1 expression. Treatment of patient-derived PAds-primary cell cultures and Human embryonic kidney 293A (HEK293A) cells expressing the calcium-sensing receptor (CASR) with the CASR agonist R568 induces YAP1 nuclear accumulation. This effect was prevented by the incubation of the cells with RhoA/Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitors Y27632 and H1152. Lastly, CASR activation increased the expression of the YAP1 gene targets CYR61, CTGF, and WNT5A, and this effect was blunted by YAP1 silencing. Concluding, here we provide preliminary evidence of the involvement of the Hippo pathway in human tumor parathyroid cells and of the existence of a CASR-ROCK-YAP1 axis. We propose a tumor suppressor role for YAP1 and LATS1/2 in parathyroid tumors.

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Vuong, Phu, Drew Bennion, Jeremy Mantei, Danielle Frost et Rajeev Misra. « Analysis of YfgL and YaeT Interactions through Bioinformatics, Mutagenesis, and Biochemistry ». Journal of Bacteriology 190, n^o 5 (28 décembre 2007) : 1507–17. http://dx.doi.org/10.1128/jb.01477-07.

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ABSTRACT In Escherichia coli, YaeT, together with four lipoproteins, YfgL, YfiO, NlpB, and SmpA, forms a complex that is essential for β-barrel outer membrane protein biogenesis. Data suggest that YfgL and YfiO make direct but independent physical contacts with YaeT. Whereas the YaeT-YfiO interaction needs NlpB and SmpA for complex stabilization, the YaeT-YfgL interaction does not. Using bioinformatics, genetics, and biochemical approaches, we have identified three residues, L173, L175, and R176, in the mature YfgL protein that are critical for both function and interactions with YaeT. A single substitution at any of these sites produces no phenotypic defect, but two or three simultaneous alterations produce mild or yfgL-null phenotypes, respectively. Interestingly, biochemical data show that all YfgL variants, including those with single substitutions, have weakened in vivo YaeT-YfgL interaction. These defects are not due to mislocalization or low steady-state levels of YfgL. Cysteine-directed cross-linking data show that the region encompassing L173, L175, and R176 makes direct contact with YaeT. Using the same genetic and biochemical strategies, it was found that altering residues D227 and D229 in another region of YfgL from E221 to D229 resulted in defective YaeT bindings. In contrast, mutational analysis of conserved residues V319 to H328 of YfgL shows that they are important for YfgL biogenesis but not YfgL-YaeT interactions. The five YfgL mutants defective in YaeT associations and the yfgL background were used to show that SurA binds to YaeT (or another complex member) without going through YfgL.

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Ajani, Jaffer A., Yan Xu, Longfei Huo, Ruiping Wang, Yuan Li, Ying Wang, Melissa Pool Pizzi et al. « YAP1 mediates gastric adenocarcinoma peritoneal metastases that are attenuated by YAP1 inhibition ». Gut 70, n^o 1 (27 avril 2020) : 55–66. http://dx.doi.org/10.1136/gutjnl-2019-319748.

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ObjectivePeritoneal carcinomatosis (PC; malignant ascites or implants) occurs in approximately 45% of advanced gastric adenocarcinoma (GAC) patients and associated with a poor survival. The molecular events leading to PC are unknown. The yes-associated protein 1 (YAP1) oncogene has emerged in many tumour types, but its clinical significance in PC is unclear. Here, we investigated the role of YAP1 in PC and its potential as a therapeutic target.MethodsPatient-derived PC cells, patient-derived xenograft (PDX) and patient-derived orthotopic (PDO) models were used to study the function of YAP1 in vitro and in vivo. Immunofluorescence and immunohistochemical staining, RNA sequencing (RNA-Seq) and single-cell RNA-Seq (sc-RNA-Seq) were used to elucidate the expression of YAP1 and PC cell heterogeneity. LentiCRISPR/Cas9 knockout of YAP1 and a YAP1 inhibitor were used to dissect its role in PC metastases.ResultsYAP1 was highly upregulated in PC tumour cells, conferred cancer stem cell (CSC) properties and appeared to be a metastatic driver. Dual staining of YAP1/EpCAM and sc-RNA-Seq revealed that PC tumour cells were highly heterogeneous, YAP1high PC cells had CSC-like properties and easily formed PDX/PDO tumours but also formed PC in mice, while genetic knockout YAP1 significantly slowed tumour growth and eliminated PC in PDO model. Additionally, pharmacologic inhibition of YAP1 specifically reduced CSC-like properties and suppressed tumour growth in YAP1high PC cells especially in combination with cytotoxics in vivo PDX model.ConclusionsYAP1 is essential for PC that is attenuated by YAP1 inhibition. Our data provide a strong rationale to target YAP1 in clinic for GAC patients with PC.

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Althoff, Mark J., Ramesh C. Nayak, Shailaja Hegde, Ashley M. Wellendorf, Breanna Bohan, Marie-Dominique Filippi, Mei Xin et al. « Yap1-Scribble polarization is required for hematopoietic stem cell division and fate ». Blood 136, n^o 16 (15 octobre 2020) : 1824–36. http://dx.doi.org/10.1182/blood.2019004113.

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Abstract Yap1 and its paralogue Taz largely control epithelial tissue growth. We have identified that hematopoietic stem cell (HSC) fitness response to stress depends on Yap1 and Taz. Deletion of Yap1 and Taz induces a loss of HSC quiescence, symmetric self-renewal ability, and renders HSC more vulnerable to serial myeloablative 5-fluorouracil treatment. This effect depends on the predominant cytosolic polarization of Yap1 through a PDZ domain-mediated interaction with the scaffold Scribble. Scribble and Yap1 coordinate to control cytoplasmic Cdc42 activity and HSC fate determination in vivo. Deletion of Scribble disrupts Yap1 copolarization with Cdc42 and decreases Cdc42 activity, resulting in increased self-renewing HSC with competitive reconstitution advantages. These data suggest that Scribble/Yap1 copolarization is indispensable for Cdc42-dependent activity on HSC asymmetric division and fate. The combined loss of Scribble, Yap1, and Taz results in transcriptional upregulation of Rac-specific guanine nucleotide exchange factors, Rac activation, and HSC fitness restoration. Scribble links Cdc42 and the cytosolic functions of the Hippo signaling cascade in HSC fate determination.

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Zhu, Shunfu, Neng Jiang et Jianjun Zhu. « miR-375 Regulates the Proliferation, Apoptosis and Colony Formation of Thyroid Cancer Cells via Targeting YAP1 ». Journal of Biomaterials and Tissue Engineering 12, n^o 5 (1 mai 2022) : 1053–58. http://dx.doi.org/10.1166/jbt.2022.2978.

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Objective: Yes-associated protein 1 (YAP1) regulates cell proliferation and apoptosis. Abnormal miR-375 level was related to thyroid cancer. Software predicted a relationship between miR-375 and YAP1. Our study investigated whether miR-375 regulates YAP1 expression and affects thyroid cancer cells. Methods: The tumor tissues and adjacent tissues of thyroid cancer patients were collected to measure miR-375 and YAP1 expression. The dual luciferase reporter experiment verified the regulation between miR-375 and YAP1. Thyroid cancer cell line B-CPAP and TPC-1 cells were divided into miR-NC group and miR-375 mimic group followed by analysis of cell proliferation by flow cytometry, caspase-3 activity, and cell clone formation ability by plate cloning assay. Results: Compared with adjacent cancer tissues, miR-375 in thyroid cancer tissues was decreased and YAP1 was increased. miR-375 targets YAP1. Compared with Nthy-ori 3-1 cells, miR-375 in B-CPAP and TPC-1 cells was significantly reduced and YAP1 was increased. Transfection with miR-375 mimic significantly inhibited cell proliferation, increase caspase-3 activity, and reduced the ability of cells to form clones. Conclusion: miR-375 can inhibit YAP1 expression, decrease the proliferation of thyroid cancer cells, induce cell apoptosis, and reduce clone formation.

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Godlewski, J., J. Kiezun, B. E. Krazinski, Z. Kozielec, P. M. Wierzbicki et Z. Kmiec. « The Immunoexpression of YAP1 and LATS1 Proteins in Clear Cell Renal Cell Carcinoma : Impact on Patients’ Survival ». BioMed Research International 2018 (2018) : 1–9. http://dx.doi.org/10.1155/2018/2653623.

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The aim of the study was to determine by immunohistochemistry cellular localization and immunoreactivity levels of YAP1 and LATS1 proteins in paired sections of tumor and unchanged renal tissues of 54 clear cell renal cell carcinoma (ccRCC) patients. Associations between clinical-pathological and overall survival (OS; median follow-up was 40.6 months) data of patients and YAP1 and LATS1 immunoreactivity were analyzed by uni- and multivariate Cox regression model and log-rank test. YAP1 immunoreactivity was found in the nuclei of tumor cells in 64.8% of ccRCC patients, whereas only 24.1% of tumors revealed cytoplasmic YAP1 expression. LATS1 immunoexpression was observed only in the cytoplasm of tumor cells in 59.3% of patients. LATS1 immunoreactivity in cancer cells negatively correlated with the size of primary tumor. The overall YAP1 immunoreactivity did not correlate with clinical-pathological data of patients. However, the subgroup of ccRCC patients who presented with cytoplasmic YAP1 immunoexpression had significantly shorter OS (median = 26.8 months) than patients without cytoplasmic YAP1 expression (median undefined). Multivariate Cox analysis revealed that increased cytoplasmic YAP1 (HR = 4.53) and decreased LATS1 immunoreactivity levels (HR = 0.90) were associated with worse prognosis, being independent prognostic factors. These results suggest that YAP1 and LATS1 can be considered as new prognostic factors in ccRCC.

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Dong, Tianqi, Yuncang Yuan, Xudong Xiang, Shuping Sang, Hao Shen, Lei Wang, Chunyan Yang, Fangfang Li, Hongliang Li et Shangyong Zheng. « High cytoplasmic YAP1 expression predicts a poor prognosis in patients with colorectal cancer ». PeerJ 8 (19 novembre 2020) : e10397. http://dx.doi.org/10.7717/peerj.10397.

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Purpose Yes associated protein 1 (YAP1), which is a standout amongst the most essential effectors of the Hippo pathway, assumes a vital part in a few kinds of cancer. However, whether YAP1 is an oncogene in CRC (colorectal cancer) remains controversial, and the association between the subcellular localization of YAP1 and clinical implications in CRC remains unknown. Patients and methods In this study, we investigated the subcellular localization of YAP1 in CRC cells by immunohistochemistry and then associate these findings with clinical information in a large CRC cohort with 919 CRC patients. Results The results show that CRC tissues has a significant higher expression of cytoplasmic YAP1 compared to adjacent normal tissues (all P < 0.001). Cytoplasmic YAP1 expression was significantly associated with the number of lymph nodes removed and differentiation grade (all P < 0.001). Furthermore, after correcting confounding variables, for example, TNM stage and differentiation grade, the multivariate Cox analysis confirmed cytoplasmic YAP1-high subgroup had a significant shorter DFS (HR = 3.255; 95% CI [2.290–4.627]; P < 0.001) and DSS (HR = 4.049; 95% CI [2.400–6.830]; P < 0.001) than cytoplasmic YAP1-low subgroup. High cytoplasmic YAP1 expression is associated with a worse survival in stage III CRC patients who received chemotherapy. Conclusion Cytoplasmic YAP1 could be could be utilized as a prognosis factor in CRC patients, and may be an indicator of whether certain patients population could benefit from postoperative chemotherapy.

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Cinar, Bekir, Marwah M. Al-Mathkour, Shafiq A. Khan et Carlos S. Moreno. « Androgen attenuates the inactivating phospho–Ser-127 modification of yes-associated protein 1 (YAP1) and promotes YAP1 nuclear abundance and activity ». Journal of Biological Chemistry 295, n^o 25 (6 mai 2020) : 8550–59. http://dx.doi.org/10.1074/jbc.ra120.013794.

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The transcriptional coactivator YAP1 (yes-associated protein 1) regulates cell proliferation, cell–cell interactions, organ size, and tumorigenesis. Post-transcriptional modifications and nuclear translocation of YAP1 are crucial for its nuclear activity. The objective of this study was to elucidate the mechanism by which the steroid hormone androgen regulates YAP1 nuclear entry and functions in several human prostate cancer cell lines. We demonstrate that androgen exposure suppresses the inactivating post-translational modification phospho–Ser-127 in YAP1, coinciding with increased YAP1 nuclear accumulation and activity. Pharmacological and genetic experiments revealed that intact androgen receptor signaling is necessary for androgen's inactivating effect on phospho–Ser-127 levels and increased YAP1 nuclear entry. We also found that androgen exposure antagonizes Ser/Thr kinase 4 (STK4/MST1) signaling, stimulates the activity of protein phosphatase 2A, and thereby attenuates the phospho–Ser-127 modification and promotes YAP1 nuclear localization. Results from quantitative RT-PCR and CRISPR/Cas9–aided gene knockout experiments indicated that androgen differentially regulates YAP1-dependent gene expression. Furthermore, an unbiased computational analysis of the prostate cancer data from The Cancer Genome Atlas revealed that YAP1 and androgen receptor transcript levels correlate with each other in prostate cancer tissues. These findings indicate that androgen regulates YAP1 nuclear localization and its transcriptional activity through the androgen receptor–STK4/MST1–protein phosphatase 2A axis, which may have important implications for human diseases such as prostate cancer.

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Smith, Jordan L., Haiwei Mou, Xiao-Ou Zhang, Deniz Ozata et Wen Xue. « Modeling and identifying therapeutic targets in Hepatoblastoma. » Journal of Clinical Oncology 37, n^o 15_suppl (20 mai 2019) : e21518-e21518. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e21518.

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e21518 Background: Hepatoblastoma, an aggressive pediatric liver tumor, most often affects young children under five years of age. Surgical resection and chemotherapy have saved many children’s lives; yet, the overall five-year survival rate is 70%, and worse for children who present with unresectable tumors. Addressing the clinical need for HB-targeted therapies requires a better understanding of how HB tumors maintain their tumorigenic potential. Recent studies suggest that YAP1, the transcriptional co-regulator, and the Wnt/β-catenin pathway cooperate for HB tumor initiation. Further YAP1 is hyperactivated in nearly 80% of children’s HB tumors; however, will YAP1 inhibition result in therapeutic benefit for pediatric patients? Methods: To assess the role of YAP1 signaling in HB tumor maintenance, we generated a conditional mouse model of HB driven by doxycycline-inducible YAP1S127A and constitutively active β-Catenin. Delivery of doxycycline induces YAP1S127A expression and mice develop HB tumors within six weeks. After tumor formation, doxycycline is withdrawn, turning off YAP1 expression, and tumor progression is monitored using in vivo bioluminescent imaging. Results: Here we show in our conditional mouse model of HB that YAP1 is essential for tumor maintenance. In vivo YAP1 withdrawal leads to > 90% tumor regression within 10 weeks. Transcriptional analyses reveal that YAP1 withdraw in regressing tumors potently induces hepatocyte differentiation and metabolism genes, including HNF4a and FoxA2 target genes. Conclusions: Establishment of a luminescent conditional model of HB provides a new platform to critically address and explore therapeutic vulnerabilities in HB. Specifically, our data suggest HB tumor maintenance requires YAP1. Finally, in vivo tumor regression following YAP1 withdraw serves as preclinical evidence for the therapeutic potential of YAP1 inhibitory therapies in children with HB.

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Yoo, Lee, Jun, Noh, Lee, Jung, Jung et al. « The YAP1–NMU Axis Is Associated with Pancreatic Cancer Progression and Poor Outcome : Identification of a Novel Diagnostic Biomarker and Therapeutic Target ». Cancers 11, n^o 10 (30 septembre 2019) : 1477. http://dx.doi.org/10.3390/cancers11101477.

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Yes-associated protein (YAP)-1 is highly upregulated in pancreatic cancer and associated with tumor progression. However, little is known about the role of YAP1 and related genes in pancreatic cancer. Here, we identified target genes regulated by YAP1 and explored their role in pancreatic cancer progression and the related clinical implications. Analysis of different pancreatic cancer databases showed that Neuromedin U (NMU) expression was positively correlated with YAP1 expression in the tumor group. The Cancer Genome Atlas data indicated that high YAP1 and NMU expression levels were associated with poor mean and overall survival. YAP1 overexpression induced NMU expression and transcription and promoted cell motility in vitro and tumor metastasis in vivo via upregulation of epithelial–mesenchymal transition (EMT), whereas specific inhibition of NMU in cells stably expressing YAP1 had the opposite effect in vitro and in vivo. To define this functional association, we identified a transcriptional enhanced associate domain (TEAD) binding site in the NMU promoter and demonstrated that YAP1–TEAD binding upstream of the NMU gene regulated its transcription. These results indicate that the identified positive correlation between YAP1 and NMU is a potential novel drug target and biomarker in metastatic pancreatic cancer.

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García, Patricia, Lorena Rosa, Sergio Vargas, Helga Weber, Jaime A. Espinoza, Felipe Suárez, Isabel Romero-Calvo et al. « Hippo-YAP1 Is a Prognosis Marker and Potentially Targetable Pathway in Advanced Gallbladder Cancer ». Cancers 12, n^o 4 (25 mars 2020) : 778. http://dx.doi.org/10.3390/cancers12040778.

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Gallbladder cancer is an aggressive disease with late diagnosis and no efficacious treatment. The Hippo-Yes-associated protein 1 (YAP1) signaling pathway has emerged as a target for the development of new therapeutic interventions in cancers. However, the role of the Hippo-targeted therapy has not been addressed in advanced gallbladder cancer (GBC). This study aimed to evaluate the expression of the major Hippo pathway components mammalian Ste20-like protein kinase 1 (MST1), YAP1 and transcriptional coactivator with PDZ-binding motif (TAZ) and examined the effects of Verteporfin (VP), a small molecular inhibitor of YAP1-TEA domain transcription factor (TEAD) protein interaction, in metastatic GBC cell lines and patient-derived organoids (PDOs). Immunohistochemical analysis revealed that advanced GBC patients had high nuclear expression of YAP1. High nuclear expression of YAP1 was associated with poor survival in GBC patients with subserosal invasion (pT2). Additionally, advanced GBC cases showed reduced expression of MST1 compared to chronic cholecystitis. Both VP treatment and YAP1 siRNA inhibited the migration ability in GBC cell lines. Interestingly, gemcitabine resistant PDOs with high nuclear expression of YAP1 were sensitive to VP treatment. Taken together, our results suggest that key components of the Hippo-YAP1 signaling pathway are dysregulated in advanced gallbladder cancer and reveal that the inhibition YAP1 may be a candidate for targeted therapy.

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Zhai, Yangyang, Wei Sang, Liping Su, Yusheng Shen, Yanran Hu et Wei Zhang. « Analysis of the expression and prognostic value of MT1-MMP, β1-integrin and YAP1 in glioma ». Open Medicine 17, n^o 1 (1 janvier 2022) : 492–507. http://dx.doi.org/10.1515/med-2022-0449.

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Abstract Increased expression of membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14) is associated with the development of many cancers. MT1-MMP may promote the entry of yes-associated protein1 (YAP1) into the nucleus by regulating the regulation of β1-integrin. The purpose of this study was to investigate the effects of MT1-MMP, β1-integrin and YAP1 on the prognosis of gliomas. The expression of proteins was detected by bioinformatics and immunohistochemistry. The relationship between three proteins and clinicopathological parameters was analyzed by the χ 2 test. Survival analysis was used to investigate the effects of three proteins on prognosis. The results showed that high expressions of MT1-MMP, β1-integrin and YAP1 were found in glioblastoma (GBM) compared with lower-grade glioma (LGG). There was a significantly positive correlation between MT1-MMP and β1-integrin (r = 0.387), MT1-MMP and YAP1 (r = 0.443), β1-integrin and YAP1 (r = 0.348). Survival analysis showed that patients with overexpression of MT1-MMP, β1-integrin and YAP1 had a worse prognosis. YAP1 expression was the independent prognostic factor for progression-free survival (PFS). There was a statistical correlation between the expression of MT1-MMP and YAP1 and isocitrate dehydrogenase 1 (IDHl) mutation. Thus, this study suggested that MT1-MMP, β1-integrin and YAP1, as tumor suppressors, are expected to be promising prognostic biomarkers and therapeutic targets for glioma patients.

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Zhang, Luo, Xing Song, Xiaodong Li, Changping Wu et Jingting Jiang. « Yes-Associated Protein 1 as a Novel Prognostic Biomarker for Gastrointestinal Cancer : A Meta-Analysis ». BioMed Research International 2018 (14 novembre 2018) : 1–10. http://dx.doi.org/10.1155/2018/4039173.

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Background. Yes-associated protein 1 (YAP1) is an effector of Hippo pathway, which plays a significant role in cell proliferation and tumor progression. The relationship between YAP1 and gastrointestinal cancer has been explored in many previous studies. We conducted a meta-analysis to explore the prognostic effect of YAP1 in patients with gastrointestinal cancer.Methods. A systematic search was performed through the PubMed, Web of Science, Embase, and Cochrane library databases to collect eligible studies. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were used to evaluate the relationship between YAP1 expression and gastrointestinal cancer clinical outcomes.Results. A total of 2941 patients from 18 studies were enrolled. The results showed that elevated YAP1 expression predicted a poor prognosis in gastrointestinal cancer (HR = 1.56; 95% CI: 1.29-1.89;P< 0.001). Subgroup analyses indicated significant association between YAP1 overexpression and shorter OS of patients with esophageal squamous cell carcinoma (HR = 1.85; 95% CI: 1.25-2.73;P= 0.002), gastric cancer (HR = 1.41,95% CI: 1.02-1.95;P= 0.037), and colorectal cancer (pooled HR = 1.75; 95% CI: 1.42-2.15;P< 0.001). However, YAP1 expression did not affect DFS of patients with gastrointestinal cancer (pooled HR = 1.33; 95% CI: 0.95-1.88;P= 0.101).Conclusion. Elevated YAP1 expression in patients with gastrointestinal cancer might be related to shorter OS. YAP1 protein could serve as a potential predictor of poor prognosis in gastrointestinal cancer.

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Larsen, Davidsen, Dahlgaard, Pedersen et Troelsen. « HNF4α and CDX2 Regulate Intestinal YAP1 Promoter Activity ». International Journal of Molecular Sciences 20, n^o 12 (18 juin 2019) : 2981. http://dx.doi.org/10.3390/ijms20122981.

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The Hippo pathway is important for tissue homeostasis, regulation of organ size andgrowth in most tissues. The co‐transcription factor yes‐associated protein 1 (YAP1) serves as a maindownstream effector of the Hippo pathway and its dysregulation increases cancer development andblocks colonic tissue repair. Nevertheless, little is known about the transcriptional regulation ofYAP1 in intestinal cells. The aim of this study to identify gene control regions in the YAP1 gene andtranscription factors important for intestinal expression. Bioinformatic analysis of caudal typehomeobox 2 (CDX2) and hepatocyte nuclear factor 4 alpha (HNF4α) chromatin immunoprecipitatedDNA from differentiated Caco‐2 cells revealed potential intragenic enhancers in the YAP1 gene.Transfection of luciferase‐expressing YAP1 promoter‐reporter constructs containing the potentialenhancer regions validated one potent enhancer of the YAP1 promoter activity in Caco‐2 and T84cells. Two potential CDX2 and one HNF4α binding sites were identified in the enhancer by in silicotranscription factor binding site analysis and protein‐DNA binding was confirmed in vitro usingelectrophoretic mobility shift assay. It was found by chromatin immunoprecipitation experimentsthat CDX2 and HNF4α bind to the YAP1 enhancer in Caco‐2 cells. These results reveal a previouslyunknown enhancer of the YAP1 promoter activity in the YAP1 gene, with importance for highexpression levels in intestinal epithelial cells. Additionally, CDX2 and HNF4α binding areimportant for the YAP1 enhancer activity in intestinal epithelial cells.

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Kraemer, Susan M., David A. Goldstrohm, Ann Berger, Susan Hankey, Sherry A. Rovinsky, W. Scott Moye-Rowley et Laurie A. Stargell. « TFIIA Plays a Role in the Response to Oxidative Stress ». Eukaryotic Cell 5, n^o 7 (juillet 2006) : 1081–90. http://dx.doi.org/10.1128/ec.00071-06.

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ABSTRACT To characterize the role of the general transcription factor TFIIA in the regulation of gene expression by RNA polymerase II, we examined the transcriptional profiles of TFIIA mutants of Saccharomyces cerevisiae using DNA microarrays. Whole-genome expression profiles were determined for three different mutants with mutations in the gene coding for the small subunit of TFIIA, TOA2. Depending on the particular mutant strain, approximately 11 to 27% of the expressed genes exhibit altered message levels. A search for common motifs in the upstream regions of the pool of genes decreased in all three mutants yielded the binding site for Yap1, the transcription factor that regulates the response to oxidative stress. Consistent with a TFIIA-Yap1 connection, the TFIIA mutants are unable to grow under conditions that require the oxidative stress response. Underexpression of Yap1-regulated genes in the TFIIA mutant strains is not the result of decreased expression of Yap1 protein, since immunoblot analysis indicates similar amounts of Yap1 in the wild-type and mutant strains. In addition, intracellular localization studies indicate that both the wild-type and mutant strains localize Yap1 indistinguishably in response to oxidative stress. As such, the decrease in transcription of Yap1-dependent genes in the TFIIA mutant strains appears to reflect a compromised interaction between Yap1 and TFIIA. This hypothesis is supported by the observations that Yap1 and TFIIA interact both in vivo and in vitro. Taken together, these studies demonstrate a dependence of Yap1 on TFIIA function and highlight a new role for TFIIA in the cellular mechanism of defense against reactive oxygen species.

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Xu, Wei-guo, Jing Zhu, Lin Li, Dongsheng Chen, Qin Zhang, Qianqian Duan, Si Li et Mingzhe Xiao. « YAP1 mutation as a novel predictor of response to anti-PD-1/PD-L1 treatment in pan-cancers. » Journal of Clinical Oncology 39, n^o 15_suppl (20 mai 2021) : 2604. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.2604.

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2604 Background: YAP1 is the main downstream target of the Hippo pathway and acts as a transcriptional coactivator to regulate development processes. YAP1 amplification is a potentially useful biomarker for predicting treatment outcomes and identifying patients with a high risk of relapse who should be closely monitored in nonsurgical esophageal squamous cell carcinoma (ESCC). YAP1 overexpression has been identified in multiple solid cancers, which consistently correlated with unfavorable clinical outcomes. Previous work suggested that YAP1 alterations may enrich for responses to immune checkpoint inhibitors (ICI), validation of these findings in needed. Methods: Using 539-gene target-capture next generation sequencing, we analyzed the YAP1 mutation in 3547 tumor tissue or plasma ctDNA samples from different patients, and the public database of TACG was also compared. Data from MSK-IMPACT study (n = 1661, anti-PD-(L)1/CTLA-4 mono/ combined therapy) was retrieved and analysed. In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model. Results: In clinical cohort, the frequency of YAP1 mutation in 3547 tumor tissue or plasma ctDNA samples from different patients was 0.62 % (22 in 3547). Meanwhile, the frequency of YAP1 mutation in TCGA cohort was 0.90 % (99 in 10953). We further analyzed Kaplan-Meier curves from MSK-IMPACT study (n = 1661, anti-PD-(L)1/CTLA-4 mono/ combined therapy). In MSK-IMPACT cohort, mutation of YAP1 was associated with higher TMB (P = 0.022) and higher mutation count (P = 0.017) in pan-cancers. YAP1 mutation was associated with prolonged overall survival (OS) trend compared with YAP1 wt in pan-cancers (P = 0.15; HR, 2.209, 95% CI, 0.7109-6.8639). Conclusions: In our study, the frequency of YAP1 mutation was investigated in clinical and TCGA cohort, which might provide useful information to guide precision medicine. YAP1 mutation may serve as a novel predictor of response to anti-PD-1/PD-L1 treatment in pan-cancers via upregulating TMB and mutation count.

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Owonikoko, Taofeek K., Andrew Elliott, Andrey Ivanov, Bhakti Dwivedi, Phillip Walker, Ari M. Vanderwalde, Sonam Puri et al. « Pan-cancer analysis of YAP1 expression as a predictive biomarker for cancer immunotherapy. » Journal of Clinical Oncology 40, n^o 16_suppl (1 juin 2022) : 2629. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.2629.

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2629 Background: High YAP1 expression correlates with the ‘T-cell inflamed’ expression phenotype in small cell lung cancer (SCLC), but its association with other biomarkers of immune checkpoint vulnerability and in tumor types beyond SCLC is not known. We examined whether YAP1 expression correlates with other established markers of immune checkpoint blockade (ICB) efficacy (PDL1 expression and TMB) in a tumor agnostic manner to determine clinical relevance. Methods: Next-generation sequencing of DNA (592 gene panel or whole exome) and RNA (whole transcriptome) was performed for patient samples (n = 57,134), representing 13 cancer types, submitted to a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ). The ‘T-cell inflamed’ signature (TIS) score was calculated as an 18-gene weighted coefficient composite value (Cristescu, 2018). PDL1 expression was assessed by immunohistochemistry (IHC) with cancer type-specific antibodies and thresholds, and high tumor mutational burden was defined as ≥10 mut/Mb. Patients were stratified into subgroups based on median YAP1 expression (YAP1-High/YAP-Low) within each cancer type. Significance was tested by Chi-square, Fisher’s exact test, or Mann-Whitney U test. Results: YAP1-High tumors were associated with significantly increased TIS scores compared to YAP1-Low across all 13 cancer types examined, with the largest fold increase observed in SCLC (1.33-fold, p < 0.0001), followed by pancreatic cancer (1.28-fold, p < 0.0001), while the smallest occurred in melanoma (1.13-fold, p < 0.0001). Spearman correlation strength (range 0.23-0.57) between YAP expression and TIS scores was consistent with increased TIS scores in YAP1-High samples. TMB-High rates were similar in YAP-High and YAP1-Low subgroups for most cancer types, with slightly lower rates in YAP1-High tumors observed for endometrial (23.0 vs 26.6%, p < 0.001) and esophageal (7.0 vs 9.5%, p < 0.05) cancers. YAP1 expression was not significantly increased in PDL1+ (IHC) tumors for most cancer types. However, significantly decreased YAP1 expression was associated with PDL1+ samples in RCC (Renal Cell Carcinoma) (0.91-fold change, P < 0.05), MM (0.90-fold change, P < 0.001), and ENCA (0.80-fold change, P < 0.0001) Conclusions: Our analyses provide confirmation that YAP1 expression positively correlates with the ‘T-cell inflamed’ phenotype across many cancer types, including those with approvals for (ICB) therapy. YAP1 expression was independent of established markers of ICB response, including TMB and PDL1. Further analysis of YAP1 expression as an additional tumor agnostic predictive biomarker is warranted.

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Cheng, Siyuan, Shu Yang, Yingli Shi et Xiuping Yu. « Abstract 3751 : Altered prostatic HOX code is associated with decreased YAP1 expression during neuroendocrine prostate cancer development ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 3751. http://dx.doi.org/10.1158/1538-7445.am2022-3751.

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Abstract Background: Neuroendocrine (NE) phenotype contributes to 25 to 30% androgen deprivation resistant prostate cancer cases. Until now, this aggressive phenotype is untreatable. Therefore, it is urgent to study the molecular mechanism of NE development to reveal therapeutic strategies. Methods: Data were downloaded from CCLE, cBioPortal, and GEO and analyzed by R. RT-qPCR, western-blot, Immunohistochemistry, and Immunofluorescence were used to assess gene expression. Results: Neuroendocrine prostate cancer (NEPCa) develops from prostate adenocarcinoma (AdPCa). We screened and identified the consensus differentially expressed genes across all public NEPCa transcriptome datasets. We found several HOX genes are included. HOXB13 is deceased but HOXB3, HOXD8 are increased in NEPCa. Based on the HOX code (total 39 HOX genes expression) theory, different cell lineages have distinct HOX codes and HOX codes can represent tissue identities, we established 42 HOX codes for 42 cells lineages including prostate through bioinformatics analysis of 1019 cancer cell lines transcriptome. We found NEPCa samples have changed prostatic HOX code. We also found YAP1, a previously characterized oncogene, is decreased in mRNA level in NEPCa than AdPCa. We confirmed the YAP1 protein is not detected in NEPCa human/mouse samples, PDX samples, and cell line samples (NCI-H660). We used YAP1 as a model. We hypothesized that the signaling involved in silencing YAP1 expression can also contribute to NE development. We first confirmed the loss of YAP1 expression in NEPCa cells is under epigenetic control by inducing YAP1 mRNA expression in primary mouse NEPCa cells through epigenetic inhibitors treatments (HDACs/DNA methyltransferase inhibitors). We characterized the YAP1 promoter through data mining chromatin ChIP-seq data and DNA methylation-seq data. We identified and cloned a 3kb DNA fragment across the YAP1 transcription start site as YAP1 regulatory element. We then built a YAP1-promoter-luciferase reporter using this fragment. We also generated a list of transcription factors that can bind the YAP1 regulatory element. We will then confirm the roles of these transcriptional factors in both regulating YAP1 and NE development. We also found YAP1 expression is co-expressed with many HOX genes in human samples. This suggested the potential regulatory function of HOX code to YAP1 expression. Conclusion: We proposed 2 critical events during NE development, changed prostatic HOX code and loss of YAP expression. We identified HOX code change as one of the potential regulatory mechanisms of YAP1. We then proposed to use YAP1 regulatory element as a model system to study the NE development mechanism. Funding: The LSUHS Office of Research SEED awards, NIH R01 CA226285, and Feist-Weiller Cancer Center pre-doc fellowship to SC. Acknowledgment: We acknowledge Feist-Weiller Cancer Center for travel support to SC. Citation Format: Siyuan Cheng, Shu Yang, Yingli Shi, Xiuping Yu. Altered prostatic HOX code is associated with decreased YAP1 expression during neuroendocrine prostate cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3751.

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Hu, Yi, Yan Ma, Guifang Luo, Wenyan Liao, Shufen Zhang et Genlin Li. « Effect of MiR-375 Regulates YAP1 on the Invasion, Apoptosis, and Epithelial-Mesenchymal Transition of Cervical Cancer HeLa Cells ». Evidence-Based Complementary and Alternative Medicine 2021 (1 septembre 2021) : 1–8. http://dx.doi.org/10.1155/2021/3088723.

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Yes-associated protein 1 (YAP1) is an important signaling pathway activator molecule. Studies have shown that it is involved in the occurrence of malignant tumors. This study identified a microRNA (miR/miRNA) targeting the 3′ untranslated region (3″ utr) of the YAP1 gene and evaluated its biological impact on human cervical cancer cells and related molecular mechanisms. qPCR and western blotting were used to detect the levels of miR-375 and YAP1 in HeLa cells. TargetScan software was used to identify the binding sites of YAP1 and miR-375. The MTT method was used to determine the viability of HeLa cells transfected with miR-375 mimic and YAP1 interference vector, the Transwell chamber experiment was used to detect the invasion of HeLa cells after transfection, the apoptosis of HeLa cells after transfection was detected by flow cytometry, and the western blotting was used to detect the epithelial mesenchymal transition (EMT) of HeLa cells after transfection. The expression of miR-375 in HeLa cells was significantly lower than that of normal control cervical cells, and the expression of YAP1 in HeLa cells was significantly higher than that of normal control cervical cells. TargetScan analysis showed that miR-375 was bound to the 3′ UTR of YAP1. qPCR and western blot analysis showed that transfection of miR-375 mimics inhibited YAP1 expression in HeLa cells. Transfection of miR-375 mimic and YAP1 interference vector inhibited HeLa cell invasion and EMT and promoted HeLa cell apoptosis. These findings indicate that miR-375 inhibits the malignant development of human cervical cancer cells by regulating the expression of YAP1.

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Zhang, Y.-H., B. Li, L. Shen, Y. Shen et X.-D. Chen. « The Role and Clinical Significance of Yes-Associated Protein 1 in Human Osteosarcoma ». International Journal of Immunopathology and Pharmacology 26, n^o 1 (janvier 2013) : 157–67. http://dx.doi.org/10.1177/039463201302600115.

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Yes-associated protein 1 (YAP1) is an oncogene that plays multiple roles in the tumorigenesis and progression of many malignances. The present study aimed to investigate the clinical significance of YAP1 expression in human osteosarcoma (OS) and explore the molecular mechanisms of YAP1 activity in OS MG-63 cells. The expression of YAP1 was assessed by immunohistochemical assay using a tissue microarray procedure. A loss-of-function approach was used to investigate the effects of small hairpin RNA-mediated knockdown of YAP1 on the expression of RUNX2, CyclinD1, and matrix metalloproteinase-9 (MMP-9) as well as the proliferative activities and invasive potential in OS MG-63 cells (evaluated by MTT and Transwell assays, respectively). The expression of YAP1 protein in OS tissues was significantly higher than that in ANCT, and was closely associated with gender ( P = 0.013) and Enneking staging ( P = 0.035), but it did not correlate with age, tumor location, or distant metastases of OS patients ( P > 0.05, each). Knockdown of YAP1 resulted in downregulation of the expression of RUNX2, CyclinD1, and MMP-9 and inhibited the proliferation and invasion of MG-63 cells. Our findings suggest that YAP1 is highly expressed in OS tissues, and increased expression of this molecule is correlated with the gender and Enneking staging of osteosarcoma patients. Knockdown of YAP1 may inhibit the proliferation and invasion of OS cells through downregulation of the RUNX2 pathway, thereby representing a potential therapeutic target for the treatment of cancer.

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Kogure, Hiroyuki, Yoshihiro Handa, Masahiro Nagata, Naoto Kanai, Peter Güntert, Kenji Kubota et Nobukazu Nameki. « Identification of residues required for stalled-ribosome rescue in the codon-independent release factor YaeJ ». Nucleic Acids Research 42, n^o 5 (9 décembre 2013) : 3152–63. http://dx.doi.org/10.1093/nar/gkt1280.

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Abstract The YaeJ protein is a codon-independent release factor with peptidyl-tRNA hydrolysis (PTH) activity, and functions as a stalled-ribosome rescue factor in Escherichia coli. To identify residues required for YaeJ function, we performed mutational analysis for in vitro PTH activity towards rescue of ribosomes stalled on a non-stop mRNA, and for ribosome-binding efficiency. We focused on residues conserved among bacterial YaeJ proteins. Additionally, we determined the solution structure of the GGQ domain of YaeJ from E. coli using nuclear magnetic resonance spectroscopy. YaeJ and a human homolog, ICT1, had similar levels of PTH activity, despite various differences in sequence and structure. While no YaeJ-specific residues important for PTH activity occur in the structured GGQ domain, Arg118, Leu119, Lys122, Lys129 and Arg132 in the following C-terminal extension were required for PTH activity. All of these residues are completely conserved among bacteria. The equivalent residues were also found in the C-terminal extension of ICT1, allowing an appropriate sequence alignment between YaeJ and ICT1 proteins from various species. Single amino acid substitutions for each of these residues significantly decreased ribosome-binding efficiency. These biochemical findings provide clues to understanding how YaeJ enters the A-site of stalled ribosomes.

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Zhang, Huan, Xiaorui Song, Peisheng Wang, Runxia Lv, Shuangshuang Ma et Lingyan Jiang. « YaeB, Expressed in Response to the Acidic pH in Macrophages, Promotes Intracellular Replication and Virulence of Salmonella Typhimurium ». International Journal of Molecular Sciences 20, n^o 18 (4 septembre 2019) : 4339. http://dx.doi.org/10.3390/ijms20184339.

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Salmonella enterica serovar Typhimurium is a facultative intracellular pathogen that infects humans and animals. Survival and growth in host macrophages represents a crucial step for S. Typhimurium virulence. Many genes that are essential for S. Typhimurium proliferation in macrophages and associated with virulence are highly expressed during the intracellular lifecycle. yaeB, which encodes an RNA methyltransferase, is also upregulated during S. Typhimurium growth in macrophages. However, the involvement of YaeB in S. Typhimurium pathogenicity is still unclear. In this study, we investigated the role of YaeB in S. Typhimurium virulence. Deletion of yaeB significantly impaired S. Typhimurium growth in macrophages and virulence in mice. The effect of yaeB on pathogenicity was related to its activation of pstSCAB, a phosphate (Pi)-specific transport system that is verified here to be important for bacterial replication and virulence. Moreover, qRT-PCR data showed YaeB was induced by the acidic pH inside macrophages, and the acidic pH passed to YeaB through inhibiting global regulator histone-like nucleoid structuring (H-NS) which confirmed in this study can repress the expression of yaeB. Overall, these findings identified a new virulence regulatory network involving yaeB and provided valuable insights to the mechanisms through which acidic pH and low Pi regulate virulence.

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Wu, Lei, Si Cheng, Yong Meng et Yahui Huang. « miR-194 Regulates Cisplatin Resistance in Colorectal Cancer Cells Through Targeting Yes-Associated Protein ». Journal of Biomaterials and Tissue Engineering 10, n^o 2 (1 février 2020) : 157–62. http://dx.doi.org/10.1166/jbt.2020.2239.

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Elevated Yes-associated protein (YAP1) expression is associated with colorectal cancer. Bioinfor-matics analysis showed a targeting relationship between miR-194 and YAP13′-UTR. Our study assessed miR-194’s role in proliferation, apoptosis, and CDDP resistance of colorectal cancer cells. The CDDP-resistant cell line SW480/CDDP was established and miR-194 and YAP1 level in parental SW480 cells and normal intestinal epithelial HCoEpiC cells was measured. SW480/CDDP cells were separated into control group, miR-NC group and miR-194 mimic group followed by analysis of miR-194 and YAP1 level, cell apoptosis and proliferation by flow cytometry. There was a targeted regulatory relationship between miR-194 and YAP1 mRNA. miR-194 was significantly upregulated in SW480/CDDP cells compared to SW480 cells and downregulated in SW480 cells compared to HCoEpiC cells. Whereas, opposite YAP1 expression profiles were found in SW480/CDDP, SW480 and HCoEpiC cells. miR-194 mimic significantly upregulated miR-194 in the SW480/CDDP cells, with decreased YAP1 expression, increased cell apoptosis, decreased cell proliferation and reduced IC50. Decreased miR-194 and increased YAP1 expression involve in CDDP resistance of colorectal cancer. Increase of miR-194 expression can inhibit colorectal cancer cell proliferation, promote apoptosis and reduce CDDP resistance by down-regulating YAP1 expression.

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Alencastro Veiga Cruzeiro, Gustavo, Taciani de Almeida Magalhães, Graziella Ribeiro de Sousa, Ricardo Bonfim Silva, Carlos Alberto Oliveira de Biagi Junior, Pablo Ferreira das Chagas, Rosane Gomes de Paula Queiroz, Carlos Alberto Scrideli, Luiz Gonzaga Tone et Elvis Terci Valera. « YAP1 Is a Potential Predictive Molecular Biomarker for Response to SMO Inhibitor in Medulloblastoma Cells ». Cancers 13, n^o 24 (13 décembre 2021) : 6249. http://dx.doi.org/10.3390/cancers13246249.

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Advances in genomics have led to the identification of twelve relevant molecular subtypes within medulloblastoma (MB). The alpha subtype of Sonic hedgehog-driven MB is resistant to therapy (including smoothened inhibitors) due to activation of genes from the non-canonical SHH pathway, such as MYCN, YAP1, or TP53. Using retrospective cohort microarray data, we found that YAP1 is overexpressed in SHH alpha MB and patients profiled as resistant to SMO inhibitors compared to good responders. Here, we performed YAP1 depletion via CRISPR/Cas9 in two in vitro models of SHH-like MB cells and found that this protein is involved in responsiveness to the SMO inhibitor regarding proliferation, apoptosis, and colony formation. Further, considering the synergic combination of YAP1 depletion with SMO inhibition, we assessed single-cell RNA-seq data from five patients and found that SMO and YAP1 are enriched within cells of SHH MB. Importantly, our data suggest that YAP1 is not only a reliable biomarker for cellular response to SMOi but may indicate prospective testing of combination therapy using YAP1 and SMO inhibitors in preclinical models of SHH MB.

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Ogimoto, Tatsuya, Hiroaki Ozasa, Kentaro Hashimoto, Hiroshi Yoshida, Kazutaka Hosoya, Masatoshi Yamazoe, Hitomi Ajimizu et al. « Abstract 5335 : Elucidation of initial resistance mechanisms in EGFR mutation-positive lung cancer focusing on YAP1 and cancer stem cells ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 5335. http://dx.doi.org/10.1158/1538-7445.am2022-5335.

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Abstract Background: EGFR mutation-positive lung cancer has high response rates to EGFR-tyrosine kinase inhibitors (TKIs), but eventually acquires resistance to EGFR-TKIs. Acquired resistance mechanisms are diverse because of tumor heterogeneity, which makes it difficult to overcome acquired resistance. Initial resistance is the resistance mechanism of tumor cells that survive the initial treatment. If we could overcome the initial resistance, we could prevent cancer cells from developing various types of acquired resistance. We are now focusing on YAP1 and cancer stem cells, which have been also reported as acquired resistance mechanisms in various types of cancers. Methods: PC-9 cells and HCC827 cells which were EGFR mutation-positive lung cancer cell lines were mainly utilized in our experiments; they were purchased from ECACC and ATCC, respectively. We mainly utilized osimertinib as an EGFR-TKI and verteporfin as a YAP1 inhibitor. The nuclear translocation of YAP1 was confirmed by fluorescence immunostaining. siRNA was utilized to knock down YAP1. Cell viability assays were performed using CellTiter-Glo reagent. qRT-PCR was performed to confirm the gene expression of cancer stem cells. Results: YAP1 is activated by nuclear translocation. In PC-9 cells, YAP1 was localized in the nucleus after osimertinib exposure. In contrast, YAP1 was localized in the nucleus of HCC827 cells before osimertinib exposure and remained in the nucleus even after osimertinib exposure. These data suggest that YAP1 activation is correlated with initial resistance. Cell viability assay showed that both PC-9 cells and HCC827 cells became more sensitive to osimertinib with the knocking down of YAP1. In addition, cell viability assays using PC-9 cells with verteporfin and osimertinib showed increased sensitivity to osimertinib. The gene expression of ALDH1A1 and SOX2 which are involved in cancer stem cells were increased in PC-9 cells after osimertinib exposure. On the other hand, the gene expression of ALDH1A1 was up-regulated but SOX2 was down-regulated in HCC827 cells after osimertinib exposure. We hypothesized that increased gene expression of cancer stem cells occurred downstream of YAP1 followed by initial resistance, thus we are currently confirming the gene alteration of cancer stem cells associated with osimertinib exposure with the knocking down YAP1. We are also considering the investigation of combination therapy of EGFR-TKIs and YAP1 inhibitors in vivo studies. Conclusions: YAP1 and cancer stem cells may be involved in initial resistance mechanisms to EGFR-TKIs in EGFR mutation-positive lung cancer. Our results suggest that especially YAP1 can be a potential therapeutic target, thus we will continue additional studies of combination therapy of EGFR-TKIs and YAP1 inhibitors. In addition, we will continue to investigate whether the gene for cancer stem cells acts downstream of YAP1. Citation Format: Tatsuya Ogimoto, Hiroaki Ozasa, Kentaro Hashimoto, Hiroshi Yoshida, Kazutaka Hosoya, Masatoshi Yamazoe, Hitomi Ajimizu, Tomoko Funazo, Takahiro Tsuji, Hironori Yoshida, Ryo Itotani, Yuichi Sakamori, Toyohiro Hirai. Elucidation of initial resistance mechanisms in EGFR mutation-positive lung cancer focusing on YAP1 and cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5335.

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Ye, Haifeng, Xiaoyan Li, Tuochen Zheng, Chuan Hu, Zezheng Pan, Jian Huang, Jia Li, Wei Li et Yuehui Zheng. « The Hippo Signaling Pathway Regulates Ovarian Function via the Proliferation of Ovarian Germline Stem Cells ». Cellular Physiology and Biochemistry 41, n^o 3 (2017) : 1051–62. http://dx.doi.org/10.1159/000464113.

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Objective: To improve the separation, identification and cultivation of ovarian germline stem cells (OGSCs), to clarify the relationship between the Hippo signaling pathway effector YAP1 and the proliferation and differentiation of OGSCs in vitro and to identify the major contribution of Hippo signaling to ovarian function. Methods: Two-step enzymatic separation processes and magnetic separation were used to isolate and identify OGSCs by determining the expression of Mvh, Oct4, Nanog, Fragilis and Stella markers. Then, YAP1, as the main effector molecule in the Hippo signaling pathway, was chosen as the target gene of the study. Lentivirus containing overexpressed YAP1 or a YAP1-targeted shRNA was transduced into OGSCs. The effects of modulating the Hippo signaling pathway on the proliferation, differentiation, reproduction and endocrine function of ovaries were observed by microinjecting the lentiviral vectors with overexpressed YAP1 or YAP1 shRNA into infertile mouse models or natural mice of reproductive age. Results: (1) The specific expression of Mvh, Oct4, Nanog, Fragilis and Stella markers was observed in isolated stem cells. Thus, the isolated cells were preliminarily identified as OGSCs. (2) The co-expression of LATS2, MST1, YAP1 and MVH was observed in isolated OGSCs. Mvh and Oct4 expression levels were significantly increased in OGSCs overexpressing YAP1 compared to GFP controls. Consistently, Mvh and Oct4 levels were significantly decreased in cells expressing YAP1-targeted shRNA. (3) After 14-75 days of YAP1 overexpression in infertile mouse models, we detected follicle regeneration in ovaries, the activation of primordial follicles and increased birth rate, accompanied by increasing levels of E2 and FSH. (4) However, we detected decreasing follicles in ovaries, lower birth rate, and decreasing E2 and FSH in serum from healthy mice of reproductive age following YAP1 shRNA expression. Conclusion: Methods for the isolation, identification and culture of OGSCs were successfully established. Further results indicate that isolated OGSCs can specifically recognize Hippo signaling molecules and that manipulation of YAP1 expression can be used to regulate the proliferation and differentiation of OGSCs, as well as ovarian function in mice. This study suggests that the Hippo signaling pathway may represent a new molecular target for the regulation of mouse ovarian functional remodeling.

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Jaiswal, Praveen Kumar, Suman Mohajan, Sweaty Koul, Fengtian Wang, Runhua Shi et Hari K. Koul. « Prostate-Derived ETS Factor (PDEF) Modulates Yes Associated Protein 1 (YAP1) in Prostate Cancer Cells : A Potential Cross-Talk between PDEF and Hippo Signaling ». Pharmaceuticals 12, n^o 4 (10 décembre 2019) : 181. http://dx.doi.org/10.3390/ph12040181.

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PDEF (prostate-derived ETS factor, also known as SAM-pointed domain containing ETS transcription factor (SPDEF)) is expressed in luminal epithelial cells of the prostate gland and associates with luminal phenotype. The Hippo pathway regulates cell growth/proliferation, cellular homeostasis, and organ development by modulating phosphorylation of its downstream effectors. In previous studies, we observed decreased levels of PDEF during prostate cancer progression. In the present study, we evaluated the effects of the expression of PDEF on total/phosphoprotein levels of YAP1 (a downstream effector of the Hippo pathway). We observed that the PC3 and DU145 cells transfected with PDEF (PDEF-PC3 and PDEF-DU145) showed an increased phospho-YAP1 (Ser127) and total YAP1 levels as compared to the respective PC3 vector control (VC-PC3) and DU145 vector control cells (VC-DU145). We also observed an increased cytoplasmic YAP1 levels in PDEF-PC3 cells as compared to VC-PC3 cells. Moreover, our gene set enrichment analysis (GSEA) of mRNA expression in PDEF-PC3 and VC-PC3 cells revealed that PDEF resulted in inhibition of YAP1 target genes, directly demonstrating that PDEF plays a critical role in modulating YAP1 activity, and by extension in the regulation of the Hippo pathway. We also observed a decrease in YAP1 mRNA levels in prostate cancer tissues as compared to normal prostate tissues. Our analysis of multiple publicly available clinical cohorts revealed a gradual decrease in YAP1 mRNA expression during prostate cancer progression and metastasis. This decrease was similar to the decrease in PDEF levels, which we had reported earlier, and we observed a direct correlation between PDEF and YAP1 expression in CRPC data set. To the best of our knowledge, these results provide the first demonstration of inhibiting YAP1 activity by PDEF in any system and suggest a cross-talk between PDEF and the Hippo signaling pathway.

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Maeta, Kazuhiro, Shingo Izawa, Shoko Okazaki, Shusuke Kuge et Yoshiharu Inoue. « Activity of the Yap1 Transcription Factor in Saccharomyces cerevisiae Is Modulated by Methylglyoxal, a Metabolite Derived from Glycolysis ». Molecular and Cellular Biology 24, n^o 19 (1 octobre 2004) : 8753–64. http://dx.doi.org/10.1128/mcb.24.19.8753-8764.2004.

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ABSTRACT Methylglyoxal (MG) is synthesized during glycolysis, although it inhibits cell growth in all types of organisms. Hence, it has long been asked why such a toxic metabolite is synthesized in vivo. Glyoxalase I is a major enzyme detoxifying MG. Here we show that the Yap1 transcription factor, which is critical for the oxidative-stress response in Saccharomyces cerevisiae, is constitutively concentrated in the nucleus and activates the expression of its target genes in a glyoxalase I-deficient mutant. Yap1 contains six cysteine residues in two cysteine-rich domains (CRDs), i.e., three cysteine residues clustering near the N terminus (n-CRD) and the remaining three cysteine residues near the C terminus (c-CRD). We reveal that any of the three cysteine residues in the c-CRD is sufficient for MG to allow Yap1 to translocate into the nucleus and to activate the expression of its target gene. A Yap1 mutant possessing only one cysteine residue in the c-CRD but no cysteine in the n-CRD and deletion of the basic leucine zipper domain can concentrate in the nucleus with MG treatment. However, substitution of all the cysteine residues in Yap1 abolishes the ability of this transcription factor to concentrate in the nucleus following MG treatment. The redox status of Yap1 is substantially unchanged, and protein(s) interaction with Yap1 through disulfide bond is hardly detected in cells treated with MG. Collectively, neither intermolecular nor intramolecular disulfide bond formation seems to be involved in Yap1 activation by MG. Moreover, we show that nucleocytoplasmic localization of Yap1 closely correlates with growth phase and intracellular MG level. We propose a novel regulatory pathway underlying Yap1 activation by a natural metabolite in the cell.

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Hyun, Jeongeun, Seh-Hoon Oh, Richard T. Premont, Cynthia D. Guy, Carl L. Berg et Anna Mae Diehl. « Dysregulated activation of fetal liver programme in acute liver failure ». Gut 68, n^o 6 (22 janvier 2019) : 1076–87. http://dx.doi.org/10.1136/gutjnl-2018-317603.

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ObjectiveUncertainty about acute liver failure (ALF) pathogenesis limits therapy. We postulate that ALF results from excessive reactivation of a fetal liver programme that is induced in hepatocytes when acutely injured livers regenerate. To evaluate this hypothesis, we focused on two molecules with known oncofetal properties in the liver, Yes-associated protein-1 (YAP1) and Insulin-like growth factor-2 RNA-binding protein-3 (IGF2BP3).DesignWe compared normal liver with explanted livers of patients with ALF to determine if YAP1 and IGF2BP3 were induced; assessed whether these factors are upregulated when murine livers regenerate; determined if YAP1 and IGF2BP3 cooperate to activate the fetal programme in adult hepatocytes; and identified upstream signals that control these factors and thereby hepatocyte maturity during recovery from liver injury.ResultsLivers of patients with ALF were massively enriched with hepatocytes expressing IGF2BP3, YAP1 and other fetal markers. Less extensive, transient accumulation of similar fetal-like cells that were proliferative and capable of anchorage-independent growth occurred in mouse livers that were regenerating after acute injury. Fetal reprogramming of hepatocytes was YAP1-dependent and involved YAP1-driven reciprocal modulation of let7 microRNAs and IGF2BP3, factors that negatively regulate each other to control fate decisions in fetal cells. Directly manipulating IGF2BP3 expression controlled the fetal-like phenotype regardless of YAP1 activity, proving that IGF2BP3 is the proximal mediator of this YAP1-directed fate.ConclusionAfter acute liver injury, hepatocytes are reprogrammed to fetal-like cells by a YAP1-dependent mechanism that differentially regulates let7 and IGF2BP3, identifying novel therapeutic targets for ALF.

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Ghosh, Ishita, Md Imtiaz Khalil, Rusella Mirza, Judy King, Damilola Olatunde et Arrigo De Benedetti. « NEK1-Mediated Phosphorylation of YAP1 Is Key to Prostate Cancer Progression ». Biomedicines 11, n^o 3 (28 février 2023) : 734. http://dx.doi.org/10.3390/biomedicines11030734.

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The key to preventing mCRPC progression is understanding how androgen-dependent PCa cells progress to independence and modify their transcriptional repertoire accordingly. We recently identified a novel axis of the Hippo pathway characterized by the sequential kinase cascade induced by androgen deprivation, AR−>TLK1B>NEK1>pYAP1-Y407, leading to CRPC adaptation. Phosphorylation of YAP1-Y407 increases upon ADT or induction of DNA damage, correlated with the known increase in NEK1 expression/activity, and this is suppressed in the Y407F mutant. Dominant expression of YAP1-Y407F in Hek293 cells reprograms the YAP1-mediated transcriptome to reduce TEAD- and p73-regulated gene expression and mediates sensitivity to MMC. NEK1 haploinsufficient TRAMP mice display reduced YAP1 expression and, if castrated, fail to progress to overt prostate carcinomas, even while displaying reduced E-Cadherin (E-Cad) expression in hyperplastic ductules. YAP1 overexpression, but not the Y407F mutant, transforms LNCaP cells to androgen-independent growth with a mesenchymal morphology. Immunohistochemical examination of prostate cancer biopsies revealed that the pYAP1-Y407 nuclear signal is low in samples of low-grade cancer but elevated in high GS specimens. We also found that J54, a pharmacological inhibitor of the TLK1>NEK1>YAP1 nexus leading to degradation of YAP1, can suppress the transcriptional reprogramming of LNCaP cells to androgen-independent growth and EMT progression, even when YAP1-WT is overexpressed.

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Molina, Laura, Kari Nejak-Bowen et Satdarshan P. Monga. « Role of YAP1 Signaling in Biliary Development, Repair, and Disease ». Seminars in Liver Disease 42, n^o 01 (24 janvier 2022) : 017–33. http://dx.doi.org/10.1055/s-0041-1742277.

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Yes-associated protein 1 (YAP1) is a transcriptional coactivator that activates transcriptional enhanced associate domain transcription factors upon inactivation of the Hippo signaling pathway, to regulate biological processes like proliferation, survival, and differentiation. YAP1 is most prominently expressed in biliary epithelial cells (BECs) in normal adult livers and during development. In the current review, we will discuss the multiple roles of YAP1 in the development and morphogenesis of bile ducts inside and outside the liver, as well as in orchestrating the cholangiocyte repair response to biliary injury. We will review how biliary repair can occur through the process of hepatocyte-to-BEC transdifferentiation and how YAP1 is pertinent to this process. We will also discuss the liver's capacity for metabolic reprogramming as an adaptive mechanism in extreme cholestasis, such as when intrahepatic bile ducts are absent due to YAP1 loss from hepatic progenitors. Finally, we will discuss the roles of YAP1 in the context of pediatric pathologies afflicting bile ducts, such as Alagille syndrome and biliary atresia. In conclusion, we will comprehensively discuss the spatiotemporal roles of YAP1 in biliary development and repair after biliary injury while describing key interactions with other well-known developmental pathways.

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