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Amy S. Lee - One of the best experts on this subject based on the ideXlab platform.
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Glucose Regulated Protein 94 deficiency induces squamous cell metaplasia and suppresses pten null driven endometrial epithelial tumor development
Oncotarget, 2016Co-Authors: Jieli Shen, Lijing Yao, Yvonne G Lin, Francesco J Demayo, John P Lydon, Louis Dubeau, Amy S. LeeAbstract:// Jieli Shen 1 , Lijing Yao 1 , Yvonne G. Lin 2 , Francesco J. DeMayo 3 , John P. Lydon 3 , Louis Dubeau 4 , Amy S. Lee 1 1 Department of Biochemistry and Molecular Biology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA 2 Division of Gynecologic Oncology, Department of Obstetrics-Gynecology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA 3 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA 4 Department of Pathology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA Correspondence to: Amy S. Lee, e-mail: amylee@usc.edu Keywords: endometrial cancer, PTEN, Glucose-Regulated Protein 94 (GRP94), squamous cell metaplasia, β-catenin Received: December 23, 2015 Accepted: January 30, 2016 Published: February 17, 2016 ABSTRACT Endometrial carcinoma is the most prevalent gynecologic cancer in the United States. The tumor suppressor gene Pten (phosphatase and tensin homolog) is commonly mutated in the more common type 1 (endometrioid) subtype. The Glucose-Regulated Protein 94 (GRP94) is emerging as a novel regulator for cancer development. Here we report that expression profiles from the Cancer Genome Atlas (TCGA) showed significantly increased Grp94 mRNA levels in endometrial tumor versus normal tissues, correlating with highly elevated GRP94 Protein expression in patient samples and the requirement of GRP94 for maintaining viability of human endometrioid adenocarcinoma (EAC) cell lines. Through generation of uterus-specific knockout mouse models with deletion of Grp94 alone ( c94 f/f ) or in combination with Pten ( cP f/f 94 f/f ), we discovered that c94 f/f uteri induced squamous cell metaplasia (SCM) and reduced active nuclear β-catenin. The cP f/f 94 f/f uteri showed accelerated SCM and suppression of PTEN-null driven EAC, with reduced cellular proliferation, attenuated β-catenin signaling and decreased AKT/S6 activation in the SCM. In contrast to single PTEN knockout uteri ( cP f/f ), cP f/f 94 f/f uteri showed no decrease in E-cadherin level and no invasive lesion. Collectively, our study implies that GRP94 downregulation induces SCM in EAC and suppresses AKT/S6 signaling, providing a novel mechanism for suppressing EAC progression.
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characterization and mechanism of stress induced translocation of 78 kilodalton Glucose Regulated Protein grp78 to the cell surface
Journal of Biological Chemistry, 2015Co-Authors: Yuanli Tsai, Yi Zhang, Chunchih Tseng, Ramunas Stanciauskas, Fabien Pinaud, Amy S. LeeAbstract:Glucose-Regulated Protein (GRP78)/BiP, a major chaperone in the endoplasmic reticulum, is recently discovered to be preferably expressed on the surface of stressed cancer cells, where it regulates critical oncogenic signaling pathways and is emerging as a target for anti-cancer therapy while sparing normal organs. However, because GRP78 does not contain classical transmembrane domains, its mechanism of transport and its anchoring at the cell surface are poorly understood. Using a combination of biochemical, mutational, FACS, and single molecule super-resolution imaging approaches, we discovered that GRP78 majorly exists as a peripheral Protein on plasma membrane via interaction with other cell surface Proteins including glycosylphosphatidylinositol-anchored Proteins. Moreover, cell surface GRP78 expression requires its substrate binding activity but is independent of ATP binding or a membrane insertion motif conserved with HSP70. Unexpectedly, different cancer cell lines rely on different mechanisms for GRP78 cell surface translocation, implying that the process is cell context-dependent.
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Glucose Regulated Protein 78 as a novel effector of brca1 for inhibiting stress induced apoptosis
Oncogene, 2008Co-Authors: B H Y Yeung, Amy S. Lee, B W Y Kwan, Jinsong Liu, Ast WongAbstract:The tumor suppressor BRCA1 is mutated in a high percentage of familial breast and ovarian cancer, but our understanding of its mechanisms of action remains incomplete. We report here that Glucose-Regulated Protein (GRP)-78, a critical regulator of the unfolded Protein response (UPR), is a novel downstream target of BRCA1. We showed that overexpression of wild-type BRCA1 suppressed the expression of GRP78, whereas expression of mutant BRCA1 gene or targeted inhibition of endogenous BRCA1 using small-interfering RNA (siRNA) enhanced GRP78 expression. Knockdown of BRCA1 also led to induction of other components of UPR, such as GRP94 and CHOP. Consistent with a role of BRCA1 knockdown in mediating cell survival, forced expression of GRP78 stimulated cell proliferation and prevented apoptosis, including that induced by endoplasmic reticulum stress and chemotherapy, in ovarian OVCAR-3 and breast MCF-7 cancer cells. Overexpression of wild-type BRCA1 could increase the apoptosis of GRP78-overexpressing cells. Conversely, knockdown GRP78 by siRNA sensitized ovarian and breast cancer cells to apoptosis. This effect was reduced when the expression of BRCA1 was simultaneously knockdown by siRNA, indicating that BRCA1 also negatively regulates GRP78-mediated cell survival and resistance to apoptosis.
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Mammalian stress response: induction of the Glucose-Regulated Protein family.
Current opinion in cell biology, 1992Co-Authors: Amy S. LeeAbstract:The Glucose-Regulated Protein family consists of a set of stress-inducible Proteins localized in the endoplasmic reticulum. Since their discovery in 1977, significant advances in our understanding of their structure, function and regulation have been made. Recent findings concerning the physiological roles played by the Glucose-Regulated Proteins, and their regulations at the transcriptional, post-transcriptional, translational and post-translational levels are summarized.
Yu Jia Chang - One of the best experts on this subject based on the ideXlab platform.
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Glucose-Regulated Protein 94 Modulates the Response of Osteosarcoma to Chemotherapy.
Disease markers, 2019Co-Authors: Chien Yu Huang, Po Li Wei, Ming-te Huang, Jin Wun Wang, Precious Takondwa Makondi, Hsin An Chen, Yu Jia ChangAbstract:Background. Osteosarcoma (OS) is the most common and most aggressive primary solid malignant bone tumor in children and young adults and has high rates of recurrence and metastasis. The endoplasmic reticulum (ER) stress pathway is important in regulating the chemo-responsiveness of cancer. However, the role of Glucose-Regulated Protein 94 (GRP94) in regulating the response of OS to chemotherapy has never been explored. Methods. In this study, two OS cell lines, MG63 and 143B cells, were used to evaluate the mechanism by which GRP94 modulates the response of osteosarcoma to chemotherapy. GRP94-knockdown (GRP94-KD) OS cells were generated using short hairpin RNAs, and the response to chemotherapy was assessed using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Cell apoptosis was quantified with propidium iodide (PI) staining and flow cytometry. Results. Silencing of GRP94 in MG63 and 143B cells did not influence the growth and migration of the cells, but reduced the colony formation. GRP94-KD OS cells were more resistant to paclitaxel, gemcitabine, and epirubicin treatments than cells transfected with the scrambled control, and more cells transfected with the scrambled control underwent apoptosis after paclitaxel, gemcitabine, and epirubicin treatments than GRP94-KD cells. Conclusions. Therefore, GRP94 silencing may increase the resistance of MG63 and 143B cells to paclitaxel, gemcitabine, and epirubicin treatments by inhibiting the induction of apoptosis. Thus, GRP94 may be a key biomarker for the chemotherapeutic response of OS.
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Silencing of Glucose-Regulated Protein 78 (GRP78) enhances cell migration through the upregulation of vimentin in hepatocellular carcinoma cells.
Annals of Surgical Oncology, 2011Co-Authors: Po Li Wei, Li Jen Kuo, Weu Wang, Feng-yen Lin, Hui-hsiung Liu, Tseng How, Ming-te Huang, Yu Jia ChangAbstract:Background Glucose-Regulated Protein 78 (GRP78) plays an important role in embryonic development and cancer progression. However, there is little information regarding the regulation of GRP78 in hepatocellular carcinoma (HCC) metastasis.
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Glucose-Regulated Protein 78 (GRP78) mediated the efficacy to curcumin treatment on hepatocellular carcinoma.
Annals of surgical oncology, 2011Co-Authors: Yu Jia Chang, Cheng Jeng Tai, Li Jen Kuo, Po Li Wei, Hung Hua Liang, Tsan Zon Liu, Weu Wang, Chen Jei TaiAbstract:Background Glucose-Regulated Protein 78 (GRP78) plays an important role in the therapeutic treatment and progression of cancer. However, little is known about the effect of GRP78 expression to curcumin in hepatocellular carcinoma (HCC).
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Glucose-Regulated Protein 78 Is a Novel Contributor to Acquisition of Resistance to Sorafenib in Hepatocellular Carcinoma
Annals of surgical oncology, 2009Co-Authors: Jeng-fong Chiou, Cheng Jeng Tai, Po Li Wei, Tsan Zon Liu, Ming-te Huang, Yu Huei Wang, Yu Jia ChangAbstract:Background Sorafenib is a newly established cancer drug found to be an effective systemic treatment for advanced hepatocellular carcinoma (HCC). However, little is known about any potential effectors that modify tumor cell sensitivity towards sorafenib. Here, we present the first evidence that Glucose-Regulated Protein 78 (GRP78) is intimately associated with acquisition of resistance towards sorafenib.
Marie-benoîte Cohen - One of the best experts on this subject based on the ideXlab platform.
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The Interplay between Glucose-Regulated Protein 78 (GRP78) and Steroids in the Reproductive System.
International journal of molecular sciences, 2018Co-Authors: Marylise Hebert-schuster, Belinda Elisabeth Rotta, Brenna Kirkpatrick, Jean Guibourdenche, Marie-benoîte CohenAbstract:The Glucose-Regulated Protein 78 (GRP78) is a molecular chaperone that is responsible for Protein folding, which belongs to the heat shock Protein 70 kDa (HSPA/HSP70). Because of the conjunction of GRP78 transcription with endoplasmic reticulum stress, the chaperone plays an important role in the unfolded Protein response (UPR), which is induced after the accumulation of misfolded Proteins. In the last years, a significant body of research concentrated on interplay between GRP78 and sexual steroid hormones. Throughout this review, we describe the mechanisms by which GRP78 regulates steroidogenesis at multiple levels and how steroids modulate GRP78 expression in different mammalian reproductive organs. Finally, we discuss the cooperation between GRP78 and steroids for cell survival and proliferation in the context of reproduction and tumorigenesis. This new paradigm offers significant opportunities for future exploration.
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Purified autoantibodies against Glucose-Regulated Protein 78 (GRP78) promote apoptosis and decrease invasiveness of ovarian cancer cells
Cancer letters, 2011Co-Authors: Marie-benoîte Cohen, Patrick PetignatAbstract:Circulating Glucose-Regulated Protein 78 (GRP78) autoantibodies represent potential biomarker of epithelial ovarian cancer. However there is relatively limited identification of these antibodies in response to ovarian cancer. Here, we were interested in characterization of these antibodies and into their role in tumor development. We first purified GRP78 autoantibodies from sera of patients with ovarian cancer, and then tested them on SKOV-3 ovarian cancer cell line. A decrease of invasion and an increase of H2O2-induced apoptosis of SKOV-3 cells were observed, suggesting their protective role against ovarian cancer cells.
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Glucose-Regulated Protein 78: a new partner of p53 in trophoblast.
Proteomics, 2009Co-Authors: Serge Arnaudeau, Patrizia Arboit, Paul Bischof, Kasuo Shin-ya, Akihiro Tomida, Takashi Tsuruo, Olivier Irion, Marie-benoîte CohenAbstract:Although wild-type p53 Protein is overexpressed in first trimester trophoblast, it is inactive towards its target genes MetalloProteinase 2 and 9. This seems to be due to a complex mechanism of inactivation and stabilization of p53 relying on the formation of Protein complexes involving the N-terminus of p53. To detect the Proteins associated with this sequence, we incubated biotinylated p53 N-terminal peptide in cytotrophoblastic cell medium 24 h before lysis of cells. We purified the Proteins retained on biotinylated peptide using a neutravidin affinity column. Proteins were then identified by peptide mass finger printing followed or not by peptide fragmentation sequencing. Among these Proteins, we identified Glucose-Regulated Protein 78 (GRP78) and verified its interaction with p53 in trophoblastic cells by immunoprecipitation and Western blot analysis. Moreover, the decreased expression of GRP78 induced by GRP78siRNA or versipelostatin decreased the formation of high molecular weight p53 complexes and p53 monomer and increased trophoblastic invasion. These results suggest that GRP78 is involved in inactivation and stabilization of p53 and in the regulation of trophoblastic invasion.
Greg R Collier - One of the best experts on this subject based on the ideXlab platform.
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Regulation of the selenoProtein SelS by Glucose deprivation and endoplasmic reticulum stress - SelS is a novel Glucose-Regulated Protein.
FEBS letters, 2004Co-Authors: Yuan Gao, Helen C Feng, Ken Walder, Kristy Bolton, Terry Sunderland, Natalie Bishara, Melissa Quick, Lakshmi Kantham, Greg R CollierAbstract:SelS is a newly identified selenoProtein and its gene expression is up-Regulated in the liver of Psammomys obesus after fasting. We have examined whether SelS is Regulated by Glucose deprivation and endoplasmic reticulum (ER) stress in HepG2 cells. Glucose deprivation and the ER stress inducers tunicamycin and thapsigargin increased SelS gene expression and Protein content several-fold in parallel with Glucose-Regulated Protein 78. The overexpression of SelS increased Min6 cell resistance to oxidative stress-induced toxicity. These results indicate that SelS is a novel member of the Glucose-Regulated Protein family and its function is related to the regulation of cellular redox balance.
Po Li Wei - One of the best experts on this subject based on the ideXlab platform.
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Glucose-Regulated Protein 94 Modulates the Response of Osteosarcoma to Chemotherapy.
Disease markers, 2019Co-Authors: Chien Yu Huang, Po Li Wei, Ming-te Huang, Jin Wun Wang, Precious Takondwa Makondi, Hsin An Chen, Yu Jia ChangAbstract:Background. Osteosarcoma (OS) is the most common and most aggressive primary solid malignant bone tumor in children and young adults and has high rates of recurrence and metastasis. The endoplasmic reticulum (ER) stress pathway is important in regulating the chemo-responsiveness of cancer. However, the role of Glucose-Regulated Protein 94 (GRP94) in regulating the response of OS to chemotherapy has never been explored. Methods. In this study, two OS cell lines, MG63 and 143B cells, were used to evaluate the mechanism by which GRP94 modulates the response of osteosarcoma to chemotherapy. GRP94-knockdown (GRP94-KD) OS cells were generated using short hairpin RNAs, and the response to chemotherapy was assessed using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Cell apoptosis was quantified with propidium iodide (PI) staining and flow cytometry. Results. Silencing of GRP94 in MG63 and 143B cells did not influence the growth and migration of the cells, but reduced the colony formation. GRP94-KD OS cells were more resistant to paclitaxel, gemcitabine, and epirubicin treatments than cells transfected with the scrambled control, and more cells transfected with the scrambled control underwent apoptosis after paclitaxel, gemcitabine, and epirubicin treatments than GRP94-KD cells. Conclusions. Therefore, GRP94 silencing may increase the resistance of MG63 and 143B cells to paclitaxel, gemcitabine, and epirubicin treatments by inhibiting the induction of apoptosis. Thus, GRP94 may be a key biomarker for the chemotherapeutic response of OS.
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Silencing of Glucose-Regulated Protein 78 (GRP78) enhances cell migration through the upregulation of vimentin in hepatocellular carcinoma cells.
Annals of Surgical Oncology, 2011Co-Authors: Po Li Wei, Li Jen Kuo, Weu Wang, Feng-yen Lin, Hui-hsiung Liu, Tseng How, Ming-te Huang, Yu Jia ChangAbstract:Background Glucose-Regulated Protein 78 (GRP78) plays an important role in embryonic development and cancer progression. However, there is little information regarding the regulation of GRP78 in hepatocellular carcinoma (HCC) metastasis.
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Glucose-Regulated Protein 78 (GRP78) mediated the efficacy to curcumin treatment on hepatocellular carcinoma.
Annals of surgical oncology, 2011Co-Authors: Yu Jia Chang, Cheng Jeng Tai, Li Jen Kuo, Po Li Wei, Hung Hua Liang, Tsan Zon Liu, Weu Wang, Chen Jei TaiAbstract:Background Glucose-Regulated Protein 78 (GRP78) plays an important role in the therapeutic treatment and progression of cancer. However, little is known about the effect of GRP78 expression to curcumin in hepatocellular carcinoma (HCC).
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Glucose-Regulated Protein 78 Is a Novel Contributor to Acquisition of Resistance to Sorafenib in Hepatocellular Carcinoma
Annals of surgical oncology, 2009Co-Authors: Jeng-fong Chiou, Cheng Jeng Tai, Po Li Wei, Tsan Zon Liu, Ming-te Huang, Yu Huei Wang, Yu Jia ChangAbstract:Background Sorafenib is a newly established cancer drug found to be an effective systemic treatment for advanced hepatocellular carcinoma (HCC). However, little is known about any potential effectors that modify tumor cell sensitivity towards sorafenib. Here, we present the first evidence that Glucose-Regulated Protein 78 (GRP78) is intimately associated with acquisition of resistance towards sorafenib.