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https://www.readbyqxmd.com/read/28441737/commitment-of-scaffold-proteins-in-the-onco-biology-of-human-colorectal-cancer-and-liver-metastases-after-oxaliplatin-based-chemotherapy
#1
Deborah Rotoli, Manuel Morales, Julio Ávila, María Del Carmen Maeso, María Del Pino García, Ali Mobasheri, Pablo Martín-Vasallo
Scaffold proteins play pivotal roles in the regulation of signaling pathways, integrating external and internal stimuli to various cellular outputs. We report the pattern of cellular and subcellular expression of scaffoldins angiomotin-like 2 (AmotL2), FK506 binding protein 5 (FKBP51) and IQ motif containing GTPase-activating protein 1 (IQGAP1) in colorectal cancer (CRC) and metastases in liver resected after oxaliplatin-based chemotherapy (CT). Positive immunostaining for the three scaffoldins was found in most cells in healthy colon, tumor, healthy liver and metastasized liver...
April 22, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28377614/the-hsp90-machinery-facilitates-the-transport-of-diphtheria-toxin-into-human-cells
#2
Manuel Schuster, Leonie Schnell, Peter Feigl, Carina Birkhofer, Katharina Mohr, Maurice Roeder, Stefan Carle, Simon Langer, Franziska Tippel, Johannes Buchner, Gunter Fischer, Felix Hausch, Manfred Frick, Carsten Schwan, Klaus Aktories, Cordelia Schiene-Fischer, Holger Barth
Diphtheria toxin kills human cells because it delivers its enzyme domain DTA into their cytosol where it inhibits protein synthesis. After receptor-mediated uptake of the toxin, DTA translocates from acidic endosomes into the cytosol, which might be assisted by host cell factors. Here we investigated the role of Hsp90 and its co-chaperones during the uptake of native diphtheria toxin into human cells and identified the components of the Hsp90 machinery including Hsp90, Hsp70, Cyp40 and the FK506 binding proteins FKBP51 and FKBP52 as DTA binding partners...
April 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28363942/usp49-negatively-regulates-tumorigenesis-and-chemoresistance-through-fkbp51-akt-signaling
#3
Kuntian Luo, Yunhui Li, Yujiao Yin, Lei Li, Chenming Wu, Yuping Chen, Somaira Nowsheen, Qi Hu, Lizhi Zhang, Zhenkun Lou, Jian Yuan
The AKT pathway is a fundamental signaling pathway that mediates multiple cellular processes, such as cell proliferation and survival, angiogenesis, and glucose metabolism. We recently reported that the immunophilin FKBP51 is a scaffolding protein that can enhance PHLPP-AKT interaction and facilitate PHLPP-mediated dephosphorylation of AKT at Ser473, negatively regulating AKT activation. However, the regulation of FKBP51-PHLPP-AKT pathway remains unclear. Here we report that a deubiquitinase, USP49, is a new regulator of the AKT pathway...
March 31, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28283554/impaired-dual-specificity-protein-phosphatase-dusp4-reduces-corticosteroid-sensitivity
#4
Yoshiki Kobayashi, Kazuhiro Ito, Akira Kanda, Koich Tomoda, Nicolas Mercado, Peter Barnes
We have reported that phosphorylation of glucocorticoid receptor (GR) at Ser(226) reduces GR nuclear translocation resulting in corticosteroid insensitivity in patients with severe asthmas. A serine/threonine protein phosphatase, PP2A, which regulates JNK1 and GR-Ser(226) signaling, is involved in this mechanism. Here, we further explored dual-specificity protein kinases (DUSPs) with the ability to dephosphorylate JNK, and identified DUSP4 as a phosphatase involved in the regulation of corticosteroid sensitivity...
March 10, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28254433/loss-of-fkbp5-impedes-adipocyte-differentiation-under-both-normoxia-and-hypoxic-stress
#5
Lingling Zhang, Bin Qiu, Tingting Wang, Jun Wang, Ming Liu, Yuxue Xu, Chao Wang, Ran Deng, Kent Williams, Zhiwei Yang, Tiebing Liang, Weidong Yong
FK506-binding protein 51 (FKBP51) is one of the most important regulators in the GR-mediated stress response, and we previously demonstrated that loss of FKBP5 arrests adipogenesis and renders mice resistant to diet-induced obesity (DIO). However, the exact role of FKBP5 in the process of adipocyte differentiation under hypoxic conditions (the common microenvironment where adipocytes reside in obese individuals) is still unclear. Here, by isolating and culturing WT- and Fkbp5-knockout mouse embryonic fibroblasts (MEFs), and treat them at normal oxygen environment (21% O2, nomorxia) or low oxygen environment (5% O2, hypoxia)...
April 15, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28218707/fkbp51-immunohistochemical-expression-a-new-prognostic-biomarker-for-oscc
#6
Daniela Russo, Francesco Merolla, Massimo Mascolo, Gennaro Ilardi, Simona Romano, Silvia Varricchio, Virginia Napolitano, Angela Celetti, Loredana Postiglione, Pier Paolo Di Lorenzo, Luigi Califano, Giovanni Orabona Dell'Aversana, Fabio Astarita, Maria Fiammetta Romano, Stefania Staibano
Up-to-date, several molecular markers of prognosis have been studied in Oral Squamous Cell Carcinoma (OSCC), but none entered in the clinical setting. Therapy of OSCC tumors mainly relies on surgery, radiotherapy and partially on chemotherapy; there is an urgent need for biomarkers able to better stratify OSCC patients' risk to address targeted therapeutic strategies. The role of immune response in the pathogenesis and biological behavior of OSCC has been investigated by several authors, and promising results have been obtained with immune checkpoint inhibitors...
February 18, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28147277/regulation-of-serine-threonine-kinase-akt-activation-by-nad-dependent-deacetylase-sirt7
#7
Jia Yu, Bo Qin, Fengying Wu, Sisi Qin, Somaira Nowsheen, Shan Shan, Jacqueline Zayas, Huadong Pei, Zhenkun Lou, Liewei Wang
The Akt pathway is a central regulator that promotes cell survival in response to extracellular signals. Depletion of SIRT7, an NAD(+)-dependent deacetylase that is the least-studied sirtuin, is known to significantly increase Akt activity in mice through unknown mechanisms. In this study, we demonstrate that SIRT7 depletion in breast cancer cells results in Akt hyper-phosphorylation and increases cell survival following genotoxic stress. Mechanistically, SIRT7 specifically interacts with and deacetylates FKBP51 at residue lysines 28 and 155 (K28 and K155), resulting in enhanced interactions among FKBP51, Akt, and PHLPP, as well as Akt dephosphorylation...
January 31, 2017: Cell Reports
https://www.readbyqxmd.com/read/28032931/fkbp51-regulates-cell-motility-and-invasion-via-rhoa-signaling
#8
Miho Takaoka, Shun Ito, Yoshio Miki, Akira Nakanishi
FK506 binding protein 51 (FKBP51), a member of the immunophilin family, is involved in multiple signaling pathways, tumorigenesis, and chemoresistance. FKBP51 expression correlates with metastatic potential in melanoma and prostate cancer. However, the functions of FKBP51, particularly involving the regulation of cell motility and invasion, are not fully understood. We discovered two novel interacting partner proteins of FKBP51, i.e., deleted in liver cancer 1 (DLC1) and deleted in liver cancer 2 (DLC2), using immunoprecipitation and mass spectrometry...
March 2017: Cancer Science
https://www.readbyqxmd.com/read/27844058/western-high-fat-diet-consumption-during-adolescence-increases-susceptibility-to-traumatic-stress-while-selectively-disrupting-hippocampal-and-ventricular-volumes
#9
Priya Kalyan-Masih, Julio David Vega-Torres, Christina Miles, Elizabeth Haddad, Sabrina Rainsbury, Mohsen Baghchechi, Andre Obenaus, Johnny D Figueroa
Psychological trauma and obesity co-occur frequently and have been identified as major risk factors for psychiatric disorders. Surprisingly, preclinical studies examining how obesity disrupts the ability of the brain to cope with psychological trauma are lacking. The objective of this study was to determine whether an obesogenic Western-like high-fat diet (WD) predisposes rats to post-traumatic stress responsivity. Adolescent Lewis rats (postnatal day 28) were fed ad libitum for 8 weeks with either the experimental WD diet (41...
September 2016: ENeuro
https://www.readbyqxmd.com/read/27829158/amygdalar-microrna-15a-is-essential-for-coping-with-chronic-stress
#10
Naama Volk, Julius C Pape, Mareen Engel, Anthony S Zannas, Nadia Cattane, Annamaria Cattaneo, Elisabeth B Binder, Alon Chen
MicroRNAs are important regulators of gene expression and associated with stress-related psychiatric disorders. Here, we report that exposing mice to chronic stress led to a specific increase in microRNA-15a levels in the amygdala-Ago2 complex and a concomitant reduction in the levels of its predicted target, FKBP51, which is implicated in stress-related psychiatric disorders. Reciprocally, mice expressing reduced levels of amygdalar microRNA-15a following exposure to chronic stress exhibited increased anxiety-like behaviors...
November 8, 2016: Cell Reports
https://www.readbyqxmd.com/read/27822288/xiao-yao-san-against-corticosterone-induced-stress-injury-via-upregulating-glucocorticoid-receptor-reaction-element-transcriptional-activity
#11
Guoping Cao, Shenglan Gong, Fengxue Zhang, Wenjun Fu
Previous studies have revealed that uncontrollable stress can impair the synaptic plasticity and firing property of hippocampal neurons, which influenced various hippocampal-dependent tasks including memory, cognition, behavior, and mood. In this work, we had investigated the effects and mechanisms of the Chinese herbal medicine Xiao Yao San (XYS) against corticosterone-induced stress injury in primary hippocampal neurons (PHN) cells. We found that XYS and RU38486 could increase cell viabilities and decrease cell apoptosis by MTT, immunofluorescence, and flow cytometry assays...
2016: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/27718274/the-prognostic-value-of-stromal-fk506-binding-protein-1-and-androgen-receptor-in-prostate-cancer-outcome
#12
Damien A Leach, Andrew P Trotta, Eleanor F Need, Gail P Risbridger, Renea A Taylor, Grant Buchanan
BACKGROUND: Improving our ability to predict cancer progression and response to conservative or radical intent therapy is critical if we are to prevent under or over treatment of individual patients. Whereas the majority of solid tumors now have a range of molecular and/or immunological markers to help define prognosis and treatment options, prostate cancer still relies mainly on histological grading and clinical parameters. We have recently reported that androgen receptor (AR) expression in stroma inversely associates with prostate cancer-specific survival, and that stromal AR reduces metastasis...
February 2017: Prostate
https://www.readbyqxmd.com/read/27462449/the-interchange-of-immunophilins-leads-to-parallel-pathways-and-different-intermediates-in-the-assembly-of-hsp90-glucocorticoid-receptor-complexes
#13
Ima-Obong Ebong, Victoria Beilsten-Edmands, Nisha A Patel, Nina Morgner, Carol V Robinson
Hormone receptors require participation of the chaperones Hsp40/Hsp70 to form client-transfer complexes with Hsp90/Hop. Interaction with the co-chaperone p23 releases Hop and Hsp70, and the immunophilin FKBP52 mediates transfer of the Hsp90-receptor complex to the nucleus. Inhibition of glucocorticoid receptor (GR) transport by FKBP51, but not by FKBP52, has been observed at the cellular level, but the subunit composition of the intermediates involved has not been deduced. Here we use mass spectrometry to show that FKBP51/52 form analogous complexes with GR/Hsp90/Hop/Hsp70/ATP, but differences emerge upon addition of p23 to client-transfer complexes...
2016: Cell Discovery
https://www.readbyqxmd.com/read/27462022/id4-promotes-ar-expression-and-blocks-tumorigenicity-of-pc3-prostate-cancer-cells
#14
Shravan Kumar Komaragiri, Dhanushka H Bostanthirige, Derrick J Morton, Divya Patel, Jugal Joshi, Sunil Upadhyay, Jaideep Chaudhary
Deregulation of tumor suppressor genes is associated with tumorigenesis and the development of cancer. In prostate cancer, ID4 is epigenetically silenced and acts as a tumor suppressor. In normal prostate epithelial cells, ID4 collaborates with androgen receptor (AR) and p53 to exert its tumor suppressor activity. Previous studies have shown that ID4 promotes tumor suppressive function of AR whereas loss of ID4 results in tumor promoter activity of AR. Previous study from our lab showed that ectopic ID4 expression in DU145 attenuates proliferation and promotes AR expression suggesting that ID4 dependent AR activity is tumor suppressive...
September 9, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27446431/expression-and-localization-of-the-immunophilin-fkbp51-in-colorectal-carcinomas-and-primary-metastases-and-alterations-following-oxaliplatin-based-chemotherapy
#15
Deborah Rotoli, Manuel Morales, María Del Carmen Maeso, María Del Pino García, Araceli Morales, Julio Ávila, Pablo Martín-Vasallo
The immunophilin FK506-binding protein 5 (FKBP51) is a scaffold protein that serves a pivotal role in the regulation of multiple signaling pathways, integrating external and internal stimuli into distinct signal outputs. In a previous study, we identified several genes that are significantly up- or downregulated in the peripheral white cells (PWCs) of colorectal adenocarcinoma (CRC) patients undergoing oxaliplatin-based chemotherapy. In our screening, FKBP51 gene expression was downregulated following chemotherapy...
August 2016: Oncology Letters
https://www.readbyqxmd.com/read/27442117/fkbp51-null-mice-are-resistant-to-diet-induced-obesity-and-the-ppar%C3%AE-agonist-rosiglitazone
#16
Lance A Stechschulte, Bin Qiu, Manya Warrier, Terry D Hinds, Man Zhang, Hao Gu, Yuxue Xu, Saja S Khuder, Lucia Russo, Sonia M Najjar, Beata Lecka-Czernik, Weidong Yong, Edwin R Sanchez
FK506-binding protein-51 (FKBP51) is a molecular cochaperone recently shown to be a positive regulator of peroxisome proliferator-activated receptor (PPAR)γ, the master regulator of adipocyte differentiation and function. In cellular models of adipogenesis, loss of FKBP51 not only reduced PPARγ activity but also reduced lipid accumulation, suggesting that FKBP51 knock-out (KO) mice might have insufficient development of adipose tissue and lipid storage ability. This model was tested by examining wild-type (WT) and FKBP51-KO mice under regular and high-fat diet conditions...
October 2016: Endocrinology
https://www.readbyqxmd.com/read/27421688/the-fkbp5-polymorphism-rs1360780-is-associated-with-lower-weight-loss-after-bariatric-surgery-26-months-of-follow-up
#17
Ingrid Borba Hartmann, Gabriel Rodrigo Fries, Joana Bücker, Ellen Scotton, Lisia von Diemen, Marcia Kauer-Sant'Anna
BACKGROUND: Bariatric surgery is the most effective treatment choice for severe obesity. Recent literature indicates that FK506-binding protein 51 (FKBP51) could play a role in energy homeostasis, influencing adipogenesis and weight. OBJECTIVE: To evaluate if the presence of the T allele of the FKBP5 SNP rs1360780, associated with increased FKBP51 expression, could influence weight loss after bariatric surgery. SETTING: Hospital de Clínicas de Porto Alegre, Brazil...
September 2016: Surgery for Obesity and related Diseases: Official Journal of the American Society for Bariatric Surgery
https://www.readbyqxmd.com/read/27374865/fk506-binding-protein-51-integrates-pathways-of-adaptation-fkbp51-shapes-the-reactivity-to-environmental-change
#18
Theo Rein
This review portraits FK506 binding protein (FKBP) 51 as "reactivity protein" and collates recent publications to develop the concept of FKBP51 as contributor to different levels of adaptation. Adaptation is a fundamental process that enables unicellular and multicellular organisms to adjust their molecular circuits and structural conditions in reaction to environmental changes threatening their homeostasis. FKBP51 is known as chaperone and co-chaperone of heat shock protein (HSP) 90, thus involved in processes ensuring correct protein folding in response to proteotoxic stress...
September 2016: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/27334923/microrna-511-binds-to-fkbp5-mrna-which-encodes-a-chaperone-protein-and-regulates-neuronal-differentiation
#19
Dali Zheng, Jonathan J Sabbagh, Laura J Blair, April L Darling, Xiaoqi Wen, Chad A Dickey
Single nucleotide polymorphisms in the FKBP5 gene increase the expression of the FKBP51 protein and have been associated with increased risk for neuropsychiatric disorders such as major depression and post-traumatic stress disorder. Moreover, levels of FKBP51 are increased with aging and in Alzheimer disease, potentially contributing to disease pathogenesis. However, aside from its glucocorticoid responsiveness, little is known about what regulates FKBP5 In recent years, non-coding RNAs, and in particular microRNAs, have been shown to modulate disease-related genes and processes...
August 19, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27233944/hsp90-binding-immunophilin-fkbp51-forms-complexes-with%C3%A2-htert-enhancing-telomerase-activity
#20
Mariana Lagadari, Nadia R Zgajnar, Luciana I Gallo, Mario D Galigniana
FK506-binding proteins are members of the immunophilin family of proteins. Those immunophilins associated to the 90-kDa-heat-shock protein, Hsp90, have been proposed as potential modulators of signalling cascade factors chaperoned by Hsp90. FKBP51 and FKBP52 are the best characterized Hsp90-bound immunophilins first described associated to steroid-receptors. The reverse transcriptase subunit of telomerase, hTERT, is also an Hsp90 client-protein and is highly expressed in cancer cells, where it is required to compensate the loss of telomeric DNA after each successive cell division...
August 2016: Molecular Oncology
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