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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...
October 8, 2016: Prostate
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
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
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
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
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...
April 20, 2016: Surgery for Obesity and related Diseases: Official Journal of the American Society for Bariatric Surgery
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
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
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
M Antunica-Noguerol, M L Budziñski, J Druker, N C Gassen, M C Sokn, S Senin, F Aprile-Garcia, F Holsboer, T Rein, A C Liberman, E Arzt
FK506-binding protein 51 (FKBP51) regulates the activity of the glucocorticoid receptor (GR), and is therefore a key mediator of the biological actions of glucocorticoids. However, the understanding of the molecular mechanisms that govern its activity remains limited. Here, we uncover a novel regulatory switch for GR activity by the post-translational modification of FKBP51 with small ubiquitin-like modifier (SUMO). The major SUMO-attachment site, lysine 422, is required for FKBP51-mediated inhibition of GR activity in hippocampal neuronal cells...
October 2016: Cell Death and Differentiation
Andrea M Füchsl, Stefan O Reber
Chronic subordinate colony housing (CSC), a pre-clinically validated mouse model for chronic psychosocial stress, results in increased basal and acute stress-induced plasma adrenocorticotropic hormone (ACTH) levels. We assessed CSC effects on hippocampal glucocorticoid (GC) receptor (GR), mineralocorticoid receptor (MR), and FK506 binding protein (FKBP51) expression, acute heterotypic stressor-induced GR translocation, as well as GC effects on gene expression and cell viability in isolated hippocampal cells...
2016: PloS One
Sarah Crunkhorn
No abstract text is available yet for this article.
April 1, 2016: Nature Reviews. Drug Discovery
Steffen Gaali, Xixi Feng, Andreas Hähle, Claudia Sippel, Andreas Bracher, Felix Hausch
The FK506-binding protein 51 (FKBP51) is a key regulator of stress hormone receptors and an established risk factor for stress-related disorders. Drug development for FKBP51 has been impaired by the structurally similar but functionally opposing homologue FKBP52. High selectivity between FKBP51 and FKBP52 can be achieved by ligands that stabilize a recently discovered FKBP51-favoring conformation. However, drug-like parameters for these ligands remained unfavorable. In the present study, we replaced the potentially labile pipecolic ester group of previous FKBP51 ligands by various low molecular weight amides...
March 24, 2016: Journal of Medicinal Chemistry
Maria Maiarù, Keri K Tochiki, Marc B Cox, Leonette V Annan, Christopher G Bell, Xixi Feng, Felix Hausch, Sandrine M Géranton
Polymorphisms in FKBP51 are associated with stress-related psychiatric disorders and influence the severity of pain symptoms experienced after trauma. We report that FKBP51 (FK506 binding protein 51) is crucial for the full development and maintenance of long-term pain states. Indeed, FKBP51 knockout mice, as well as mice in which silencing of FKBP51 is restricted to the spinal cord, showed reduced hypersensitivity in several persistent pain models in rodents. FKBP51 deletion did not compromise the detection of acute painful stimuli, a critical protective mechanism...
February 10, 2016: Science Translational Medicine
Dan Wu, Xuanyu Tao, Zhi-Peng Chen, Jian-Ting Han, Wen-Juan Jia, Ning Zhu, Xiangkai Li, Zhiping Wang, Yong-Xing He
The compound p-nitrophenol, which shows the anti-androgenic activity, can easily become anthropogenic pollutants and pose a threat to the environment and human health. Previous work indicates that the anti-androgenic mechanism of p-nitrophenol is complex and may involve several components in the AR signaling pathway, but the molecular details of how p-nitrophenol inhibits AR signaling are still not quite clear. Here, we characterized p-nitrophenol binds to the FK1 domain of an AR positive regulator FKBP51 with micromolar affinity and structural analysis of FK1 domain in complex with p-nitrophenol revealed that p-nitrophenol occupies a hydrophobic FK1 pocket that is vital for AR activity enhancement...
April 15, 2016: Journal of Hazardous Materials
S Mokuda, H Oiwa
No abstract text is available yet for this article.
2016: Scandinavian Journal of Rheumatology
Nils C Gassen, Gabriel R Fries, Anthony S Zannas, Jakob Hartmann, Jürgen Zschocke, Kathrin Hafner, Tania Carrillo-Roa, Jessica Steinbacher, S Nicole Preißinger, Lianne Hoeijmakers, Matthias Knop, Frank Weber, Stefan Kloiber, Susanne Lucae, George P Chrousos, Thomas Carell, Marcus Ising, Elisabeth B Binder, Mathias V Schmidt, Joëlle Rüegg, Theo Rein
Epigenetic processes, such as DNA methylation, and molecular chaperones, including FK506-binding protein 51 (FKBP51), are independently implicated in stress-related mental disorders and antidepressant drug action. FKBP51 associates with cyclin-dependent kinase 5 (CDK5), which is one of several kinases that phosphorylates and activates DNA methyltransferase 1 (DNMT1). We searched for a functional link between FKBP51 (encoded by FKBP5) and DNMT1 in cells from mice and humans, including those from depressed patients, and found that FKBP51 competed with its close homolog FKBP52 for association with CDK5...
November 24, 2015: Science Signaling
Mate Toth, Elizabeth I Flandreau, Jessica Deslauriers, Mark A Geyer, Isabelle M Mansuy, Emilio Merlo Pich, Victoria B Risbrough
Although early-life stress is a significant risk factor for developing anxiety disorders, including posttraumatic stress disorder (PTSD), the underlying mechanisms are unclear. Corticotropin releasing hormone (CRH) is disrupted in individuals with PTSD and early-life stress and hence may mediate the effects of early-life stress on PTSD risk. We hypothesized that CRH hyper-signaling in the forebrain during early development is sufficient to increase response to trauma in adulthood. To test this hypothesis, we induced transient, forebrain-specific, CRH overexpression during early-life (pre-puberty, CRHOEdev) in double-mutant mice (Camk2a-rtta2 × tetO-Crh) and tested their behavioral and gene expression responses to the predator stress model of PTSD in adulthood...
May 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Judith Toneatto, Nancy L Charó, Natalia M Galigniana, Graciela Piwien-Pilipuk
Adipose tissue plays a central role in the control of energy balance as well as in the maintenance of metabolic homeostasis. It was not until recently that the first evidences of the role of heat shock protein (Hsp) 90 and high molecular weight immunophilin FKBP51 have been described in the process of adipocyte differentiation. Recent reports describe their role in the regulation of PPARγ, a key transcription factor in the control of adipogenesis and the maintenance of the adipocyte phenotype. In addition, novel roles have been uncovered for FKBP51 in the organization of the architecture of the nucleus through its participation in the reorganization of the nuclear lamina...
October 2015: Adipocyte
Ozlem Guzeloglu Kayisli, Umit A Kayisli, Murat Basar, Nihan Semerci, Frederick Schatz, Charles J Lockwood
Use of long-acting progestin only contraceptives (LAPCs) offers a discrete and highly effective family planning method. Abnormal uterine bleeding (AUB) is the major side effect of, and cause for, discontinuation of LAPCs. The endometria of LAPC-treated women display abnormally enlarged, fragile blood vessels, decreased endometrial blood flow and oxidative stress. To understanding to mechanisms underlying AUB, we propose to identify LAPC-modulated unique gene cluster(s) in human endometrial stromal cells (HESCs)...
2015: PloS One
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