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Laura D Attardi - One of the best experts on this subject based on the ideXlab platform.
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abstract 62 loss of PERP p53 p63 target gene may indicate tumorigenesis at the margin and local recurrence
Clinical Cancer Research, 2017Co-Authors: Amanda Simmons, Laura D Attardi, Christina S Kong, Rie Von Eyben, Quynhthu Le, Cherieann O NathanAbstract:Objectives: PERP (p53 apoptosis effector related to PMP22) localizes to the desmosomal adhesion complexes and is involved in suppressing squamous cell carcinoma (SCC) development. Loss of PERP expression leads to destabilization of desmosome complexes, resulting in enhanced tumor aggressiveness and worse local control in head and neck SCC (HNSCC). We had previously examined PERP loss at surgical margins in a small cohort of HNSCC patients. Results suggested that the loss of PERP may serve as a marker for persistent tumor and predictive of local relapse. Here we validate these findings in an independent patient cohort and report on the combined results of both groups. Materials and Methods: We previously examined the PERP protein expression by immunohistochemistry (IHC) in the surgical mucosal margins of 17 HNSCC patients. The validation cohort consists of 31 patients (15 oral cavity, 11 hypopharynx, 5 larynx). PERP expression was similarly assessed by IHC in the surgical margins of these patients. Finally, we combined the results of both groups to yield 48 patients with HNSCC (18 oral cavity, 12 hypopharynx, 4 oral pharynx, 14 larynx) for competing risk analysis. The relationship between local relapse and PERP expression (positive or negative) was analyzed in a competing risk model with death as a competing risk. Results: In the initial cohort, the 2-year cumulative incidence rate of local relapse was 37.5% for the negative PERP group compared to a 20% for the positive PERP group (p = 0.177). In the validation cohort, the 2-year cumulative incidence rate of local relapse was 50% for the negative PERP group compared to a 15% for the positive PERP group (p = 0.063). Since the results were similar between two groups, we combined them together for additional analyses. In this combined dataset, PERP expression was negative in 18, positive in 26, and not assessable in three patients. Of the 45 analyzable patients, the 2-year cumulative incidence rate of local relapse was 44.4% for the negative PERP group compared to a 16.4% for the positive PERP group (p = 0.010). There was also a trend for worse progression-free survival (p = 0.059) and overall survival (p = 0.085) with the loss of PERP. Conclusions: PERP loss at the surgical margins appears to be associated with a higher risk of local recurrence in HNSCC. These promising results need to be tested in a larger prospective study. Citation Format: Amanda Simmons, Christina Kong, Rie von Eyben, Laura Attardi, Xiaohui Ma, Quynh-Thu Le, Cherie-Ann Nathan. Loss of PERP p53/p63 target gene may indicate tumorigenesis at the margin and local recurrence [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 62.
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Abstract 62: Loss of PERP p53/p63 target gene may indicate tumorigenesis at the margin and local recurrence
Clinical Cancer Research, 2017Co-Authors: Amanda Simmons, Laura D Attardi, Christina S Kong, Rie Von Eyben, Quynhthu Le, Xiaohui Ma, Cherieann O NathanAbstract:Objectives: PERP (p53 apoptosis effector related to PMP22) localizes to the desmosomal adhesion complexes and is involved in suppressing squamous cell carcinoma (SCC) development. Loss of PERP expression leads to destabilization of desmosome complexes, resulting in enhanced tumor aggressiveness and worse local control in head and neck SCC (HNSCC). We had previously examined PERP loss at surgical margins in a small cohort of HNSCC patients. Results suggested that the loss of PERP may serve as a marker for persistent tumor and predictive of local relapse. Here we validate these findings in an independent patient cohort and report on the combined results of both groups. Materials and Methods: We previously examined the PERP protein expression by immunohistochemistry (IHC) in the surgical mucosal margins of 17 HNSCC patients. The validation cohort consists of 31 patients (15 oral cavity, 11 hypopharynx, 5 larynx). PERP expression was similarly assessed by IHC in the surgical margins of these patients. Finally, we combined the results of both groups to yield 48 patients with HNSCC (18 oral cavity, 12 hypopharynx, 4 oral pharynx, 14 larynx) for competing risk analysis. The relationship between local relapse and PERP expression (positive or negative) was analyzed in a competing risk model with death as a competing risk. Results: In the initial cohort, the 2-year cumulative incidence rate of local relapse was 37.5% for the negative PERP group compared to a 20% for the positive PERP group (p = 0.177). In the validation cohort, the 2-year cumulative incidence rate of local relapse was 50% for the negative PERP group compared to a 15% for the positive PERP group (p = 0.063). Since the results were similar between two groups, we combined them together for additional analyses. In this combined dataset, PERP expression was negative in 18, positive in 26, and not assessable in three patients. Of the 45 analyzable patients, the 2-year cumulative incidence rate of local relapse was 44.4% for the negative PERP group compared to a 16.4% for the positive PERP group (p = 0.010). There was also a trend for worse progression-free survival (p = 0.059) and overall survival (p = 0.085) with the loss of PERP. Conclusions: PERP loss at the surgical margins appears to be associated with a higher risk of local recurrence in HNSCC. These promising results need to be tested in a larger prospective study. Citation Format: Amanda Simmons, Christina Kong, Rie von Eyben, Laura Attardi, Xiaohui Ma, Quynh-Thu Le, Cherie-Ann Nathan. Loss of PERP p53/p63 target gene may indicate tumorigenesis at the margin and local recurrence [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 62.
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erbb2 dependent downregulation of a pro apoptotic protein PERP is required for oncogenic transformation of breast epithelial cells
Oncogene, 2016Co-Authors: Iman Aftab Khan, Laura D Attardi, Olivier Masson, Sylvain Baron, Dale P Corkery, Graham Dellaire, Kirill V RosenAbstract:The ability of breast cancer cells to resist anoikis, apoptosis caused by detachment of the non-malignant epithelial cells from the extracellular matrix (ECM), is thought to be critical for breast tumor growth, invasion and metastasis. ErbB2, an oncoprotein that is often overproduced in breast tumors, can block breast cancer cell anoikis via mechanisms that are understood only in part. In an effort to understand them better we found that detachment of the non-malignant human breast epithelial cells from the ECM upregulates a protein PERP in these cells. PERP is a component of the desmosomes, multiprotein complexes involved in cell-to-cell adhesion. PERP can cause apoptosis via unknown mechanisms. We demonstrated that PERP upregulation by cell detachment is driven by detachment-induced loss of epidermal growth factor receptor (EGFR). We also found that PERP knockdown by RNA interference (RNAi) rescues detached cells from death which indicates that PERP contributes to their anoikis. We observed that ErbB2, when overexpressed in detached breast epithelial cells, causes PERP downregulation. Furthermore, ErbB2-directed RNAi or treatment with lapatinib, an ErbB2/EGFR small-molecule inhibitor used for breast cancer therapy, upregulated PERP in ErbB2-positive human breast and ovarian carcinoma cells. We established that ErbB2 downregulates PERP by activating an ErbB2 effector protein kinase Mek that blocks detachment-induced EGFR loss in a manner that requires the presence of a signaling protein Sprouty-2. Finally, we observed that restoration of the wild-type PERP levels in ErbB2-overproducing breast epithelial cells increases their anoikis susceptibility and blocks their clonogenicity in the absence of adhesion to the ECM. In summary, we have identified a novel mechanism of ErbB2-mediated mechanism of anoikis resistance of ErbB2-overproducing breast epithelial cells. This mechanism allows such cells to grow without adhesion to the ECM and is driven by ErbB2-induced activation of Mek, subsequent EGFR upregulation and further EGFR-dependent PERP loss.
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loss of the p53 p63 target PERP is an early event in oral carcinogenesis and correlates with higher rate of local relapse
Oral Surgery Oral Medicine Oral Pathology and Oral Radiology, 2013Co-Authors: Christina S Kong, Veronica G Beaudry, Laura D Attardi, Shirley Kwok, Catherine M Nguyen, Richard C K Jordan, Quynhthu LeAbstract:Background PERP is a p53/p63-regulated gene encoding a desmosomal protein that plays a critical role in cell-cell adhesion and tumor suppression. Study Design We evaluated PERP expression in different grades of oral dysplasia (34 cases) and at different stages of invasive squamous cell carcinoma (SCC), and correlated the latter with clinical outcome. A tissue microarray consisting of nondysplastic mucosa, carcinoma in situ, SCC, and nodal metastases from 33 patients with human papilloma virus–negative SCC was stained for PERP and E-cadherin. Results Complete loss of PERP expression was associated with worse local control in patients with SCC. The 5-year local control rate was 91% for patients with partial PERP loss versus 31% for those with complete loss ( P = .01). Conclusions This is the first study to show that loss of PERP expression correlates with the transition to SCC and with increased local relapse in patients with oral cavity SCC.
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Loss of the p53/p63 Target PERP is an Early Event in Oral Carcinogenesis and Correlates with Higher Rate of Local Relapse
Oral Surgery Oral Medicine Oral Pathology and Oral Radiology, 2012Co-Authors: Christina S Kong, Veronica G Beaudry, Laura D Attardi, Shirley Kwok, Catherine M Nguyen, Richard C K Jordan, Quynhthu LeAbstract:Background PERP is a p53/p63-regulated gene encoding a desmosomal protein that plays a critical role in cell-cell adhesion and tumor suppression. Study Design We evaluated PERP expression in different grades of oral dysplasia (34 cases) and at different stages of invasive squamous cell carcinoma (SCC), and correlated the latter with clinical outcome. A tissue microarray consisting of nondysplastic mucosa, carcinoma in situ, SCC, and nodal metastases from 33 patients with human papilloma virus–negative SCC was stained for PERP and E-cadherin. Results Complete loss of PERP expression was associated with worse local control in patients with SCC. The 5-year local control rate was 91% for patients with partial PERP loss versus 31% for those with complete loss ( P = .01). Conclusions This is the first study to show that loss of PERP expression correlates with the transition to SCC and with increased local relapse in patients with oral cavity SCC.
Luminita Paraoan - One of the best experts on this subject based on the ideXlab platform.
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PERP ing into diverse mechanisms of cancer pathogenesis regulation and role of the p53 p63 effector PERP
Biochimica et Biophysica Acta, 2020Co-Authors: Owain Roberts, Luminita ParaoanAbstract:Abstract The tetraspan plasma membrane protein PERP ( p 53 apoptosis e ffector r elated to P MP22) is a lesser-known transcriptional target of p53 and p63. A member of the PMP22/GAS3/EMP membrane protein family, PERP was originally identified as a p53 target specifically trans-activated during apoptosis, but not during cell-cycle arrest. Several studies have since shown downregulation of PERP expression in numerous cancers, suggesting that PERP is a tumour suppressor protein. This review focusses on the important advances made in elucidating the mechanisms regulating PERP expression and its function as a tumour suppressor in diverse human cancers, including breast cancer and squamous cell carcinoma. Investigating PERP's role in clinically-aggressive uveal melanoma has revealed that PERP engages a positive-feedback loop with p53 to regulate its own expression, and that p63 is required beside p53 to achieve pro-apoptotic levels of PERP in this cancer. Furthermore, the recent discovery of apoptosis-mediating interaction of PERP with SERCA2b at the plasma membrane-endoplasmic reticulum interface demonstrates a novel mechanism of PERP stabilisation, and how PERP can mediate Ca2+ signalling to facilitate apoptosis. The multi-faceted role of PERP in cancer, involving well-documented functions in mediating apoptosis and cell-cell adhesion is discussed, alongside emerging roles in epithelial-mesenchymal transition, PERP's crosstalk with inflammation pathways, and other signalling pathways. The potential for restoring PERP expression as a means of cancer therapy is also considered.
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PERP-ing into diverse mechanisms of cancer pathogenesis: Regulation and role of the p53/p63 effector PERP.
Biochimica et Biophysica Acta, 2020Co-Authors: Owain Roberts, Luminita ParaoanAbstract:Abstract The tetraspan plasma membrane protein PERP ( p 53 apoptosis e ffector r elated to P MP22) is a lesser-known transcriptional target of p53 and p63. A member of the PMP22/GAS3/EMP membrane protein family, PERP was originally identified as a p53 target specifically trans-activated during apoptosis, but not during cell-cycle arrest. Several studies have since shown downregulation of PERP expression in numerous cancers, suggesting that PERP is a tumour suppressor protein. This review focusses on the important advances made in elucidating the mechanisms regulating PERP expression and its function as a tumour suppressor in diverse human cancers, including breast cancer and squamous cell carcinoma. Investigating PERP's role in clinically-aggressive uveal melanoma has revealed that PERP engages a positive-feedback loop with p53 to regulate its own expression, and that p63 is required beside p53 to achieve pro-apoptotic levels of PERP in this cancer. Furthermore, the recent discovery of apoptosis-mediating interaction of PERP with SERCA2b at the plasma membrane-endoplasmic reticulum interface demonstrates a novel mechanism of PERP stabilisation, and how PERP can mediate Ca2+ signalling to facilitate apoptosis. The multi-faceted role of PERP in cancer, involving well-documented functions in mediating apoptosis and cell-cell adhesion is discussed, alongside emerging roles in epithelial-mesenchymal transition, PERP's crosstalk with inflammation pathways, and other signalling pathways. The potential for restoring PERP expression as a means of cancer therapy is also considered.
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er stress linked autophagy stabilizes apoptosis effector PERP and triggers its co localization with serca2b at er plasma membrane junctions
Cell death discovery, 2019Co-Authors: Samantha J Mcdonnell, David G Spiller, Michael R H White, Ian A Prior, Luminita ParaoanAbstract:Specific molecular interactions that underpin the switch between ER stress-triggered autophagy-mediated cellular repair and cellular death by apoptosis are not characterized. This study reports the unexpected interaction elicited by ER stress between the plasma membrane (PM)-localized apoptosis effector PERP and the ER Ca2+ pump SERCA2b. We show that the p53 effector PERP, which specifically induces apoptosis when expressed above a threshold level, has a heterogeneous distribution across the PM of un-stressed cells and is actively turned over by the lysosome. PERP is upregulated following sustained starvation-induced autophagy, which precedes the onset of apoptosis indicating that PERP protein levels are controlled by a lysosomal pathway that is sensitive to cellular physiological state. Furthermore, ER stress stabilizes PERP at the PM and induces its increasing co-localization with SERCA2b at ER–PM junctions. The findings highlight a novel crosstalk between pro-survival autophagy and pro-death apoptosis pathways and identify, for the first time, accumulation of an apoptosis effector to ER–PM junctions in response to ER stress.
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p63 is required beside p53 for PERP mediated apoptosis in uveal melanoma
British Journal of Cancer, 2016Co-Authors: Raheela Awais, David G Spiller, Michael R H White, Luminita ParaoanAbstract:PERP (p53 apoptosis effector related to PMP-22), a transcriptional target of p53, is downregulated and contributes to the impairment of apoptosis in uveal melanoma (UM). Intriguingly, PERP is not induced in UM despite functional p53. p63, located on chromosome 3, which is characteristically altered in high-risk UM, can transactivate PERP. Here, we determine the functional role of p63 expression in the initiation of p53/PERP-mediated apoptosis in UM. PERP expression was monitored by quantitative PCR (qPCR) and immunoblotting in UM cell lines treated with DNA-damaging agents. The functional role of p63 was assessed by transient expression of p63-turbo GFP (p63-tGFP) in the apoptosis- resistant, 3q-deficient OCM-1 cells. Expression and localisation of p63, PERP and p53, and induction of apoptosis were characterised by qPCR, immunoblotting and live cell confocal microscopy. PERP expression was significantly downregulated in all UM cell lines. DNA-damaging treatments failed to induce apoptosis and activate PERP in OCM-1 cells, which displayed non-functional levels of p63. Expression of p63-tGFP induced apoptosis with marked increase in PERP expression and associated p53 accumulation. Lack of p63 contributes to reduced PERP levels and impaired p53-mediated apoptosis in UM. p63 expression is required for PERP-mediated apoptosis in UM.
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PERP expression stabilizes active p53 via modulation of p53 mdm2 interaction in uveal melanoma cells
Cell Death and Disease, 2011Co-Authors: Lyndsay Davies, David G Spiller, Michael R H White, Ian Grierson, Luminita ParaoanAbstract:The activation and regulation of target genes by the tumour-suppressor p53 dictates the fate of a cell, with cell cycle arrest or apoptosis being two distinct outcomes. PERP (p53 apoptosis effector related to PMP-22), a p53 transcriptional target, is induced specifically during apoptosis but not cell cycle arrest. Downregulation of PERP is associated with the aggressive, monosomy 3-type of uveal melanoma (UM), the most common primary intraocular tumour in adults, and increased PERP expression has a pro-apoptotic effect in UM cells. Here, we identify a novel effect of PERP expression, as elevated PERP protein positively influences active levels of its own transcriptional regulator, p53. Using fluorescent fusion proteins of PERP, p53 and MDM2, we demonstrate in single living UM cells that PERP expression significantly enhances p53 activity and its nuclear localization, increases p53-dependent transcription (including that of MDM2) while allowing oscillatory nucleo-cytoplasmic shuttling of p53/MDM2 complexes. Phosphorylation of p53 serine residues that interfere with the interaction between p53 and its negative regulator MDM2 and enhance pro-apoptotic gene transcription also occurs subsequent to PERP expression. These results implicate a role for PERP in amplifying functional p53 levels that promote p53-dependent apoptosis, and reveal a potential target for exploitation in enhancing p53 activity.
Mehmet Akif Akyol - One of the best experts on this subject based on the ideXlab platform.
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On the Geometry of Conformal Anti-invariant $\xi^\PERP-$ Submersions
2018Co-Authors: Mehmet Akif Akyol, Yılmaz GündüzalpAbstract:Lee [Anti-invariant $\xi^{\PERP}-$ Riemannian submersions from almost contact manifolds, Hacettepe Journal of Mathematics and Statistic, 42(3), (2013), 231-241.] defined and studied anti-invariant $\xi^\PERP-$ Riemannian submersions from almost contact manifolds.The main goal of this paper is to consider conformal anti-invariant $\xi^\PERP-$ submersions (it means the Reeb vector field $\xi$ is a horizontal vector field) from almost contact metric manifolds onto Riemannian manifolds as a generalization of anti-invariant $\xi^\PERP-$ Riemannian submersions. More precisely, we obtain the geometries of the leaves of $\ker\pi_{*}$ and $(\ker\pi_{*})^\PERP,$ including the integrability of the distributions, the geometry of foliations, some conditions related to totally geodesicness and harmonicty of the submersions. Finally, we show that there are certain product structures on the total space of a conformal anti-invariant $\xi^\PERP-$ submersion.
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on semi slant varvec xi PERP riemannian submersions
Mediterranean Journal of Mathematics, 2017Co-Authors: Mehmet Akif Akyol, Ramazan SariAbstract:The aim of the present paper is to define and study semi-slant \(\xi ^\PERP \)-Riemannian submersions from Sasakian manifolds onto Riemannian manifolds as a generalization of anti-invariant \(\xi ^\PERP \)-Riemannian submersions, semi-invariant \(\xi ^\PERP \)-Riemannian submersions and slant Riemannian submersions. We obtain characterizations, investigate the geometry of foliations which arise from the definition of this new submersion. After we investigate the geometry of foliations, we obtain necessary and sufficient condition for base manifold to be a locally product manifold and proving new conditions to be totally umbilical and totally geodesicness, respectively. Moreover, some examples of such submersions are mentioned.
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On Semi-Slant $${\varvec{\xi ^\PERP }}$$-Riemannian Submersions
Mediterranean Journal of Mathematics, 2017Co-Authors: Mehmet Akif Akyol, Ramazan SariAbstract:The aim of the present paper is to define and study semi-slant \(\xi ^\PERP \)-Riemannian submersions from Sasakian manifolds onto Riemannian manifolds as a generalization of anti-invariant \(\xi ^\PERP \)-Riemannian submersions, semi-invariant \(\xi ^\PERP \)-Riemannian submersions and slant Riemannian submersions. We obtain characterizations, investigate the geometry of foliations which arise from the definition of this new submersion. After we investigate the geometry of foliations, we obtain necessary and sufficient condition for base manifold to be a locally product manifold and proving new conditions to be totally umbilical and totally geodesicness, respectively. Moreover, some examples of such submersions are mentioned.
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On semi-slant $\xi^\PERP-$Riemannian submersions
arXiv: Differential Geometry, 2017Co-Authors: Mehmet Akif Akyol, Ramazan SariAbstract:The aim of the present paper to define and study semi-slant $\xi^\PERP-$Riemannian submersions from Sasakian manifolds onto Riemannian manifolds as a generalization of anti-invariant $\xi^\PERP-$Riemannian submersions, semi-invariant $\xi^\PERP-$Riemannian submersions and slant Riemannian submersions. We obtain characterizations, investigate the geometry of foliations which arise from the definition of this new submersion. After we investigate the geometry of foliations, we obtain necessary and sufficient condition for base manifold to be a locally product manifold and proving new conditions to be totally umbilical and totally geodesicness, respectively. Moreover, some examples of such submersions are mentioned.
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Conformal anti-invariant $\xi^\PERP-$submersions
arXiv: Differential Geometry, 2017Co-Authors: Mehmet Akif Akyol, Yılmaz GündüzalpAbstract:As a generalization of anti-invariant $\xi^\PERP-$Riemannian submersions, we introduce conformal anti-invariant $\xi^\PERP-$submersions from almost contact metric manifolds onto Riemannian manifolds. We investigate the geometry of foliations which are arisen from the definition of a conformal submersion and find necessary and sufficient conditions for a conformal anti-invariant $\xi^\PERP-$submersion to be totally geodesic and harmonic, respectively. Moreover, we show that there are certain product structures on the total space of a conformal anti-invariant $\xi^\PERP-$submersion.
Ramazan Sari - One of the best experts on this subject based on the ideXlab platform.
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on semi slant varvec xi PERP riemannian submersions
Mediterranean Journal of Mathematics, 2017Co-Authors: Mehmet Akif Akyol, Ramazan SariAbstract:The aim of the present paper is to define and study semi-slant \(\xi ^\PERP \)-Riemannian submersions from Sasakian manifolds onto Riemannian manifolds as a generalization of anti-invariant \(\xi ^\PERP \)-Riemannian submersions, semi-invariant \(\xi ^\PERP \)-Riemannian submersions and slant Riemannian submersions. We obtain characterizations, investigate the geometry of foliations which arise from the definition of this new submersion. After we investigate the geometry of foliations, we obtain necessary and sufficient condition for base manifold to be a locally product manifold and proving new conditions to be totally umbilical and totally geodesicness, respectively. Moreover, some examples of such submersions are mentioned.
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On Semi-Slant $${\varvec{\xi ^\PERP }}$$-Riemannian Submersions
Mediterranean Journal of Mathematics, 2017Co-Authors: Mehmet Akif Akyol, Ramazan SariAbstract:The aim of the present paper is to define and study semi-slant \(\xi ^\PERP \)-Riemannian submersions from Sasakian manifolds onto Riemannian manifolds as a generalization of anti-invariant \(\xi ^\PERP \)-Riemannian submersions, semi-invariant \(\xi ^\PERP \)-Riemannian submersions and slant Riemannian submersions. We obtain characterizations, investigate the geometry of foliations which arise from the definition of this new submersion. After we investigate the geometry of foliations, we obtain necessary and sufficient condition for base manifold to be a locally product manifold and proving new conditions to be totally umbilical and totally geodesicness, respectively. Moreover, some examples of such submersions are mentioned.
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On semi-slant $\xi^\PERP-$Riemannian submersions
arXiv: Differential Geometry, 2017Co-Authors: Mehmet Akif Akyol, Ramazan SariAbstract:The aim of the present paper to define and study semi-slant $\xi^\PERP-$Riemannian submersions from Sasakian manifolds onto Riemannian manifolds as a generalization of anti-invariant $\xi^\PERP-$Riemannian submersions, semi-invariant $\xi^\PERP-$Riemannian submersions and slant Riemannian submersions. We obtain characterizations, investigate the geometry of foliations which arise from the definition of this new submersion. After we investigate the geometry of foliations, we obtain necessary and sufficient condition for base manifold to be a locally product manifold and proving new conditions to be totally umbilical and totally geodesicness, respectively. Moreover, some examples of such submersions are mentioned.
Rebecca A Ihrie - One of the best experts on this subject based on the ideXlab platform.
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PERP regulates enamel formation via effects on cell cell adhesion and gene expression
Journal of Cell Science, 2011Co-Authors: Andrew H Jheon, Laura D Attardi, Rebecca A Ihrie, Pasha Mostowfi, Malcolm L Snead, Eli D Sone, Tiziano Pramparo, Ophir D KleinAbstract:Little is known about the role of cell–cell adhesion in the development of mineralized tissues. Here we report that PERP, a tetraspan membrane protein essential for epithelial integrity, regulates enamel formation. PERP is necessary for proper cell attachment and gene expression during tooth development, and its expression is controlled by P63, a master regulator of stratified epithelial development. During enamel formation, PERP is localized to the interface between the enamel-producing ameloblasts and the stratum intermedium (SI), a layer of cells subjacent to the ameloblasts. PERP-null mice display dramatic enamel defects, which are caused, in part, by the detachment of ameloblasts from the SI. Microarray analysis comparing gene expression in teeth of wild-type and PERP-null mice identified several differentially expressed genes during enamel formation. Analysis of these genes in ameloblast-derived LS8 cells upon knockdown of PERP confirmed the role for PERP in the regulation of gene expression. Together, our data show that PERP is necessary for the integrity of the ameloblast–SI interface and that a lack of PERP causes downregulation of genes that are required for proper enamel formation.
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PERP regulates enamel formation via effects on cell–cell adhesion and gene expression
Journal of Cell Science, 2011Co-Authors: Andrew H Jheon, Laura D Attardi, Rebecca A Ihrie, Pasha Mostowfi, Malcolm L Snead, Eli D Sone, Tiziano Pramparo, Ophir D KleinAbstract:Little is known about the role of cell–cell adhesion in the development of mineralized tissues. Here we report that PERP, a tetraspan membrane protein essential for epithelial integrity, regulates enamel formation. PERP is necessary for proper cell attachment and gene expression during tooth development, and its expression is controlled by P63, a master regulator of stratified epithelial development. During enamel formation, PERP is localized to the interface between the enamel-producing ameloblasts and the stratum intermedium (SI), a layer of cells subjacent to the ameloblasts. PERP-null mice display dramatic enamel defects, which are caused, in part, by the detachment of ameloblasts from the SI. Microarray analysis comparing gene expression in teeth of wild-type and PERP-null mice identified several differentially expressed genes during enamel formation. Analysis of these genes in ameloblast-derived LS8 cells upon knockdown of PERP confirmed the role for PERP in the regulation of gene expression. Together, our data show that PERP is necessary for the integrity of the ameloblast–SI interface and that a lack of PERP causes downregulation of genes that are required for proper enamel formation.
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the requirement for PERP in postnatal viability and epithelial integrity reflects an intrinsic role in stratified epithelia
Journal of Investigative Dermatology, 2006Co-Authors: Michelle R Marques, Rebecca A Ihrie, Jennifer S Horner, Laura D AttardiAbstract:Mice lacking the desmosome protein PERP exhibit blistering in their stratified epithelia and display postnatal lethality. However, it is unclear if these phenotypes are strictly related to PERP function in stratified epithelia, as PERP expression is not restricted to these tissues during embryogenesis, and certain desmosomal blistering diseases such as pemphigus vulgaris and pemphigus foliaceus have non-cell-intrinsic bases. Furthermore, we show here that PERP is expressed in the heart, raising the possibility that defects in heart function could account for lethality in the PERP-deficient mice. To determine conclusively if PERP function in stratified epithelia is crucial for postnatal survival and epithelial adhesion, we specifically ablated PERP in stratified epithelia by breeding conditional PERP knockout mice to keratin 5 (K5)-Cre transgenic mice. We found that the majority of mice lacking PERP in stratified epithelia die within 10 days after birth, accompanied by blistering and hyPERProliferation in the epithelia, similar to the constitutive PERP null mice. Together, these findings indicate that PERP's requirement for both viability and epithelial integrity reflects a role in the stratified epithelial compartment.
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mice lacking the p53 p63 target gene PERP are resistant to papilloma development
Cancer Research, 2005Co-Authors: Michelle R Marques, Rebecca A Ihrie, Jennifer S Horner, Roderick T Bronson, Laura D AttardiAbstract:PERP is a target of the p53 tumor suppressor involved in the DNA damage-induced apoptosis pathway. In addition, PERP is a target of the p53-related transcription factor p63 during skin development, where it participates in cell-cell adhesion mediated through desmosomes. Here we test the role of PERP in tumorigenesis in a two-step skin carcinogenesis model system. We find that mice lacking PERP in the skin are resistant to papilloma development, displaying fewer and smaller papillomas than wild-type mice. Proliferation levels, apoptotic indices and differentiation patterns are similar in the skin of treated PERP-deficient and wild-type mice. Instead, impaired adhesion through aberrant desmosome assembly may explain the diminished tumor development in the absence of PERP. These studies indicate that in certain contexts, PERP is required for efficient carcinogenesis and suggest a role for intact cell-cell adhesion in supporting tumor development in these settings.
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Mice Lacking the p53/p63 Target Gene PERP Are Resistant to Papilloma Development
Cancer Research, 2005Co-Authors: Michelle R Marques, Rebecca A Ihrie, Jennifer S Horner, Roderick T Bronson, Laura D AttardiAbstract:PERP is a target of the p53 tumor suppressor involved in the DNA damage-induced apoptosis pathway. In addition, PERP is a target of the p53-related transcription factor p63 during skin development, where it participates in cell-cell adhesion mediated through desmosomes. Here we test the role of PERP in tumorigenesis in a two-step skin carcinogenesis model system. We find that mice lacking PERP in the skin are resistant to papilloma development, displaying fewer and smaller papillomas than wild-type mice. Proliferation levels, apoptotic indices and differentiation patterns are similar in the skin of treated PERP-deficient and wild-type mice. Instead, impaired adhesion through aberrant desmosome assembly may explain the diminished tumor development in the absence of PERP. These studies indicate that in certain contexts, PERP is required for efficient carcinogenesis and suggest a role for intact cell-cell adhesion in supporting tumor development in these settings.
