206,492 research outputs found
Fibroblasts in head neck squamous cell carcinoma associated with perineural invasion have high level nuclear Yes-Associated Protein (YAP) expression
No full textPaul A. Reynolds, PhD, is supported by the Melville Trust for the Care and cure of Cancer.We retrospectively studied the expression of Yes-associated protein (YAP) using immunohistochemical staining in 10 cases of head and neck squamous cell carcinoma with associated perineural invasion. We find that fibroblasts in areas associated with perineural invasion show higher levels of nuclear YAP compared to fibroblasts in the stroma of normal mucosa, with a median cell count of 35.4 per high-power field in the former and 3.9 in the latter. No differences were observed between the expression of YAP phosphorylated at Ser127 in the tumoral stroma compared to that in the normal mucosa, with a median cell count expression of 4.9 in the former versus 5.0 in the latter. Therefore, a strong and increased nuclear YAP expression in fibroblasts associated with perineural invasion in head and neck squamous cell carcinoma suggests that YAP-mediated transcription programs in these fibroblasts may contribute to perineural invasion.Peer reviewe
Willin, an upstream component of the Hippo signaling pathway, orchestrates mammalian peripheral nerve fibroblasts
No full textWillin/FRMD6 was first identified in the rat sciatic nerve, which is composed of neurons, Schwann cells, and fibroblasts. Willin is an upstream component of the Hippo signaling pathway, which results in the inactivation of the transcriptional coactivator YAP through Ser127 phosphorylation. This in turn suppresses the expression of genes involved in cell growth, proliferation and cancer development ensuring the control of organ size, cell contact inhibition and apoptosis. Here we show that in the mammalian sciatic nerve, Willin is predominantly expressed in fibroblasts and that Willin expression activates the Hippo signaling cascade and induces YAP translocation from the nucleus to the cytoplasm. In addition within these cells, although it inhibits cellular proliferation, Willin expression induces a quicker directional migration towards scratch closure and an increased expression of factors linked to nerve regeneration. These results show that Willin modulates sciatic nerve fibroblast activity indicating that Willin may have a potential role in the regeneration of the peripheral nervous system.Peer reviewe
Emerging role of Hpo signaling and YAP in hepatocellular carcinoma
No full textVicente Valero III,1 Timothy M Pawlik,1 Robert A Anders21Department of Surgery, Division of Surgical Oncology, 2Department of Pathology, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USAAbstract: Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related mortality worldwide. Due to the poor prognosis and limited therapeutic options, there is great interest in further understanding better the molecular underpinnings and potential molecular targets associated with HCC. The Hippo (Hpo) signaling pathway and YAP, its principal downstream effector, represent an innovative area of research in HCC. Pioneered in Drosophila melanogaster, the Hpo cascade controls tissue homeostasis including organ size, cell proliferation, apoptosis, as well as cell-cycle regulation and differentiation. This conserved kinase cascade in mammals depends on central control by the tumor suppressor mammalian sterile 20-like kinase 1/2 (Mst1/2). The Mst1/2 commences the downstream kinase cascade, ultimately activating the oncoprotein YAP and allowing its physical association with downstream targets to enhance the gene expression signatures that are involved in proliferation and survival. Alterations in YAP expression and defective regulation of other key Hpo pathway members, such as Mst1/2, Salvador, neurofibromatosis and Mer (Nf2/mer), large tumor suppressor homolog 1/2 (Lats1/2), and Mps one binder kinase activator-like 1A and 1B (Mob1) drive carcinogenesis in animal models. The dysregulation of the Hpo pathway – resulting in an unchecked activation of YAP – culminates in the development of a broad range of human tumor types, including HCC. The abrogation of Mst1/2-mediated YAP phosphorylation permits YAP entry into the nucleus in murine models and functions similarly in human HCCs. Chemoresistance mechanisms displayed by HCC tumors occur in a YAP-dependent manner. The HCC specimens exhibit YAP overexpression, and YAP serves as an independent prognostic marker for disease-free survival and overall survival in patients with HCC. Recently, the small molecule inhibitor, verteporfin has been shown to attenuate YAP activity in murine models, perhaps offering a novel therapeutic approach for patients with advanced HCC.Keywords: hepatocellular carcinoma, yes-associated-protein, Hippo signaling, liver cancer, hepatic malignanc
Post-translational inhibition of YAP oncogene expression by 4-hydroxynonenal in bladder cancer cells
No full textThe transcriptional regulator YAP plays an important role in cancer progression and is negatively controlled by the Hippo pathway. YAP is frequently overexpressed in human cancers, including bladder cancer. Interestingly, YAP expression and activity can be inhibited by pro-oxidant conditions; moreover, YAP itself can also affect the cellular redox status through multiple mechanisms. 4-Hydroxynonenal (HNE), the most intensively studied end product of lipid peroxidation, is a pro-oxidant agent able to deplete GSH and has an anti-tumoral effect by affecting multiple signal pathways, including the down-regulation of oncogene expressions. These observations prompted us to investigate the effect of HNE on YAP expression and activity. We demonstrated that HNE inhibited YAP expression and its target genes in bladder cancer cells through a redox-dependent mechanism. Moreover, the YAP down-regulation was accompanied by an inhibition of proliferation, migration, invasion, and angiogenesis, as well as by an accumulation of cells in the G2/M phase of cell cycle and by an induction of apoptosis. We also established the YAP role in inhibiting cell viability and inducing apoptosis in HNE-treated cells by using an expression vector for YAP. Furthermore, we identified a post-translational mechanism for the HNE-induced YAP expression inhibition, involving an increase of YAP phosphorylation and ubiquitination, leading to proteasomal degradation. Our data established that HNE can post-translationally down-regulate YAP through a redox-dependent mechanism and that this modulation can contribute to determining the specific anti-cancer effects of HNE
Caveolin-1 Modulates Mechanotransduction Responses to Substrate Stiffness through Actin-Dependent Control of YAP
No full textThe transcriptional regulator YAP orchestrates many cellular functions, including tissue homeostasis, organ growth control, and tumorigenesis. Mechanical stimuli are a key input to YAP activity, but the mechanisms controlling this regulation remain largely uncharacterized. We show that CAV1 positively modulates the YAP mechanoresponse to substrate stiffness through actin-cytoskeleton-dependent and Hippo-kinase-independent mechanisms. RHO activity is necessary, but not sufficient, for CAV1-dependent mechanoregulation of YAP activity. Systematic quantitative interactomic studies and image-based small interfering RNA (siRNA) screens provide evidence that this actin-dependent regulation is determined by YAP interaction with the 14-3-3 protein YWHAH. Constitutive YAP activation rescued phenotypes associated with CAV1 loss, including defective extracellular matrix (ECM) remodeling. CAV1-mediated control of YAP activity was validated in vivo in a model of pancreatitis-driven acinar-to-ductal metaplasia. We propose that this CAV1-YAP mechanotransduction system controls a significant share of cell programs linked to these two pivotal regulators, with potentially broad physiological and pathological implications. Moreno-Vicente et al. report that CAV1, a key component of PM mechanosensing caveolae, mediates adaptation to ECM rigidity by modulating YAP activity through the control of actin dynamics and phosphorylation-dependent interaction of YAP with the 14-3-3-domain protein YWHAH. Cav1-dependent YAP regulation drives two pathophysiological processes: ECM remodeling and pancreatic ADM. © 2018 The Author
Paranisitra leytensis Robillard & Yap 2015
No full textParanisitra leytensis Robillard, 2015 (Fig. 1) Paranisitra leytensis Robillard & Yap, 2015: 85; Baroga et al. 2016: 94 (taxonomic key). Type material. Holotype male. Philippines. [Visayas]: Leyte [Island], Burauen, Barangay Villa Corazon, zone herbacée [herbaceous area] (GPS Bar1), 10°57’50.5”N 124°46’ 35.3”E, 282 m (TR14), iii.2013, coll. T. Robillard (UPLBMNH). Allotype female. Philippines. [Visayas]: Leyte [Island]: Buo, zone secondaire près de la route [secondary area near road], (TR34), iii.2013, coll. T. Robillard (UPLBMNH). Paratypes (1 male, 5 females). Philippines. same information as HT and AT (MNHN-EO-ENSIF-3162–3166). [examined] Other material examined. Philippines. [Mindanao]: [Surigao del Norte]: Siargao Island, Del Carmen, Brgy. Esperanza, 1♂ (JBB139), 01–05.x.2016, coll. S.A. Yap (UPLBMNH), right middle leg for molecular analysis (N40); Del Carmen, Brgy. Katipunan, 2♀, 07.iv.2018, rainy, coll. J.B. Baroga-Barbecho, S.A. Yap, M.K. Tan, & H. Yeo (UPLBMNH, ZRC); 2♀ (Siargao18_44, 84), 14–17.x.2018, coll. M.K. Tan, J.B. Baroga-Barbecho & S.A. Yap (ZRC). [Mindanao Island: Agusan del Sur]: Casawangan Lake, 1♂ (JBB363), 22.vii.2015, coll. N.M. Barbecho (NMP 13579), left middle leg for molecular analysis (N39). Type locality. Philippines. Visayas, Leyte Island, Burauen, Barangay Villa Corazon, 10°57’50.5”N 124°46’ 35.3”E, 282 m. Distribution. Philippines. Visayas: Leyte Island; Mindanao: Siargao Island (new record); Mindanao Island: Agusan del Sur (new record). Diagnosis. Species close to P. longipes in terms of face coloration with a wide yellow band; differing by its smaller size and male genitalia with smaller and triangular pseudepiphallic lophi, shorter endophallic sclerite, and narrower endophallic apodemes. Remarks. The male specimens from Siargao Island and Mindanao Island (Agusan del Sur) were identified as P. leytensis based on the features of the body, face, size and male genitalia. They slightly differ from the specimens from Leyte by the following characters: in Siargao specimens, male genitalia wider than long, short and less setaceous lophi, and short rami; in Agusan specimen, thin and long male genitalia, ectophallic fold longer and narrowing basally. Male specimen from Mindanao Island is the smallest among examined specimens of the species.Published as part of Baroga-Barbecho, Jessica B., Yap, Sheryl A., Tan, Ming Kai & Robillard, Tony, 2019, Taxonomic review of the genus Paranisitra Chopard (Orthoptera: Gryllidae: Eneopterinae: Nisitrini) with description of a new species from Mindanao, pp. 81-96 in Zootaxa 4568 (1) on page 86, DOI: 10.11646/zootaxa.4568.1.5, http://zenodo.org/record/259926
Epithelial to mesenchymal transition in breast cancer : a novel murine model system and the regulatory role of tead transcription factors
No full textCancer is a leading cause of death worldwide, accounting for 7.6 million, or ~13% of all deaths in 2008. The majority of cancers arise from epithelia. Breast cancer, originating from the mammary epithelium, is the most frequent cancer in women worldwide. Breast cancer detection and treatment at early stages is an effective measure of counteracting the number of deaths, however at later stages, cancer cells may spread from the primary tumor to secondary organs, a multistage process called metastasis. This process involves the dissemination of cancer cells from the primary tumor, entrance into the vascular system, extravasation and re-growth (colonization) in the target organ. Metastasis is the actual cause of death in 90% of cancer patients.
Breast cancer treatment is complicated by the existence of substantial biological heterogeneity between and within tumors: At least five different subtypes of breast cancer with variable response to treatment and outcome have been proposed. The biological differences between these tumor subtypes are mainly determined by the nature of the oncogenic hit(s) and the cell type in which transformation originally occurred. In addition to different tumor types, progressing tumors (and also their metastatic outgrowth) consist of individual tumor cells with varying features, which can be evoked by acquisition of cumulative genetic/epigenetic alterations and/or by differential stimulation by components of the nearby tumor microenvironment.
These circumstances call for a better understanding of the underlying mechanisms that provide cancer cells with malignant features, such as the acquisition of a metastatic behavior and treatment resistance.
One mechanism that endows cancer cells with several pro-metastatic features and treatment resistance is the epithelial-mesenchymal transition (EMT). EMT is a latent embryonic program that can be aberrantly reactivated in epithelial tumor cells during tumor progression. Activation of EMT-like programs in tumor cells leads to dissolution of cell-cell adhesions, a loss of polarity and an acquisition of migratory, invasive and stem-cell-like traits.
Studies investigating the role of EMT in cancer have mainly employed a combination of different model systems for in vitro and in vivo experiments. Due to the lack of model systems that allow the study of breast cancer associated EMT in vitro and in vivo using the same cell line, I have established a stable cell line (Py2T) from a breast tumor of an MMTV-PyMT transgenic mouse. I show here that this epithelial cell line undergoes bona fide EMT under cell culture conditions when stimulated with the well-known EMT-inducer transforming growth factor β (TGFβ). TGFβ treatment of Py2T cells leads to downregulated expression of the epithelial marker E-cadherin and an upregulation of mesenchymal markers, concomitant with the induction of migratory and invasive properties. When orthotopically injected into mice, Py2T cells generate tumors that are highly invasive and display a mesenchymal phenotype characterized by the absence of E-cadherin expression, suggesting that these cells undergo spontaneous EMT-like changes in vivo. Interestingly, Py2T cells overexpressing a dominant-negative TGFβ-receptor, leading to a block of TGFβ responsiveness, also form tumors upon fat-pad transplantation, yet in these tumors a partial re-expression of E-cadherin can be observed, suggesting that TGFβ signaling contributes to the EMT phenotype in vivo. Together, my results show that the Py2T model system is a versatile tool to study EMT both in vitro and in vivo.
The second project presented in this thesis aimed at the identification of critical transcription factors (TFs) that mediate the widespread changes in gene expression observed during EMT. A genome-wide bioinformatics analysis has uncovered that the DNA-binding motif of Tead transcription factors (MCAT motif) is present in a large number of promoters of EMT-regulated genes. Here I show that Tead transcriptional activity is increased during EMT. Moreover, the expression levels of several Tead family members are also upregulated during EMT, and my results demonstrate that elevated transcriptional activity of Tead2 is sufficient to induce EMT. Furthermore, inhibition or depletion of Teads attenuates the EMT process. Moreover, Tead2 levels also can control the subcellular localization of the Tead co-activators Yap and Taz, a mechanism that possibly contributes to the increased Tead activity observed during EMT. I further demonstrate that Zyxin, a focal adhesion component and regulator of actin remodeling, which has previously been shown to be required for EMT-induced migration, is a direct target gene of Tead2. Collectively, these results demonstrate an important regulatory role of Tead transcription factors in the EMT process
yap
No full textyapKeep your yap shut! Explanation: mouthmouthYesJ.D.A. WIDDOWSON COLLECTOR'S PERMANENT FILENot usedNot usedWithdraw
Aerobic glycolysis tunes YAP/TAZ transcriptional activity
No full textIncreased glucose metabolism and reprogramming toward aerobic glycolysis are a hallmark of cancer cells, meeting their metabolic needs for sustained cell proliferation. Metabolic reprogramming is usually considered as a downstream consequence of tumor development and oncogene activation; growing evidence indicates, however, that metabolism on its turn can support oncogenic signaling to foster tumor malignancy. Here, we explored how glucose metabolism regulates gene transcription and found an unexpected link with YAP/TAZ, key transcription factors regulating organ growth, tumor cell proliferation and aggressiveness. When cells actively incorporate glucose and route it through glycolysis, YAP/TAZ are fully active; when glucose metabolism is blocked, or glycolysis is reduced, YAP/TAZ transcriptional activity is decreased. Accordingly, glycolysis is required to sustain YAP/TAZ pro‐tumorigenic functions, and YAP/TAZ are required for the full deployment of glucose growth‐promoting activity. Mechanistically we found that phosphofructokinase (PFK1), the enzyme regulating the first committed step of glycolysis, binds the YAP/TAZ transcriptional cofactors TEADs and promotes their functional and biochemical cooperation with YAP/TAZ. Strikingly, this regulation is conserved in Drosophila, where phosphofructokinase is required for tissue overgrowth promoted by Yki, the fly homologue of YAP. Moreover, gene expression regulated by glucose metabolism in breast cancer cells is strongly associated in a large dataset of primary human mammary tumors with YAP/TAZ activation and with the progression toward more advanced and malignant stages. These findings suggest that aerobic glycolysis endows cancer cells with particular metabolic properties and at the same time sustains transcription factors with potent pro‐tumorigenic activities such as YAP/TAZ
Tangent demet T(M) üzerinde liftlere göre yap lar n kovaryant türevleri
No full textThe differential geometry of tangent bundles was studied by several authors, for example: D. E. Blair (Blair 1976), V. Oproiu (Oproiu1973), A. Salimov (Salimov 2013), Yano and Ishihara (1973) and among others. It is well known that differant structures defined ona manifold M can be lifted to the same type of structures on its tangent bundle. Our goal is to study covariant derivatives of almostcontact structure and almost paracontact structure with respect to XV, XC and XH on tangent bundle T(M).Tanjant demetin diferensiyel geometrisi, D. E. Blair (Blair 1976), V. Oproiu (Oproiu 1973), A. Salimov (Salimov 2013), Yano veIshihara (1973) ve di er birçok bilim adamlar taraf ndan çal ld . Bir manifold üzerinde tan mlanan farkl yap lar, onun tanjant demetiüzerindeki ayn tip yap lara ta nabilindi i bilinmektedir. Bizim bu çal madaki amac m z tanjant demet üzerinde almost kontakt yap ve almost parakontakt yap lar n XC, XV ve XH ye göre kovaryant türevlerini hesaplamakt r
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