当前位置： SCI文献检索 > NATURE MEDICINE期刊下所有文献 > A C-terminal HSP90 inhibitor restores glucocorticoid sensitivity and relieves a mouse allograft model of Cushing disease.

A C-terminal HSP90 inhibitor restores glucocorticoid sensitivity and relieves a mouse allograft model of Cushing disease.

Abstract：

:One function of the glucocorticoid receptor (GR) in corticotroph cells is to suppress the transcription of the gene encoding proopiomelanocortin (POMC), the precursor of the stress hormone adrenocorticotropin (ACTH). Cushing disease is a neuroendocrine condition caused by partially glucocorticoid-resistant corticotroph adenomas that excessively secrete ACTH, which leads to hypercortisolism. Mutations that impair GR function explain glucocorticoid resistance only in sporadic cases. However, the proper folding of GR depends on direct interactions with the chaperone heat shock protein 90 (HSP90, refs. 7,8). We show here that corticotroph adenomas overexpress HSP90 compared to the normal pituitary. N- and C-terminal HSP90 inhibitors act at different steps of the HSP90 catalytic cycle to regulate corticotroph cell proliferation and GR transcriptional activity. C-terminal inhibitors cause the release of mature GR from HSP90, which promotes its exit from the chaperone cycle and potentiates its transcriptional activity in a corticotroph cell line and in primary cultures of human corticotroph adenomas. In an allograft mouse model, the C-terminal HSP90 inhibitor silibinin showed anti-tumorigenic effects, partially reverted hormonal alterations, and alleviated symptoms of Cushing disease. These results suggest that the pathogenesis of Cushing disease caused by overexpression of heat shock proteins and consequently misregulated GR sensitivity may be overcome pharmacologically with an appropriate HSP90 inhibitor.

journal_name

Nat Med

journal_title

Nature medicine

authors

Riebold M,Kozany C,Freiburger L,Sattler M,Buchfelder M,Hausch F,Stalla GK,Paez-Pereda M

doi

10.1038/nm.3776

subject

Has Abstract

pub_date

2015-03-01 00:00:00

pages

276-80

issue

3

eissn

1078-8956

issn

1546-170X

pii

nm.3776

journal_volume

21

pub_type

杂志文章

相关文献

NATURE MEDICINE文献大全
  • Thymosin beta 15: a novel regulator of tumor cell motility upregulated in metastatic prostate cancer.

    abstract：:The Dunning rat prostatic carcinoma is a model system where cell motility closely correlates with the metastatic phenotype. We have identified a novel gene, upregulated in the highly motile and metastatic Dunning cancer cell lines, that represents a new member of the thymosin-beta family, thymosin beta 15. Transfectio...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm1296-1322

    authors： Bao L,Loda M,Janmey PA,Stewart R,Anand-Apte B,Zetter BR

    更新日期：1996-12-01 00:00:00

  • Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial.

    abstract：:Preoperative immunotherapy with anti-PD1 plus anti-CTLA4 antibodies has shown remarkable pathological responses in melanoma1 and colorectal cancer2. In NABUCCO (ClinicalTrials.gov: NCT03387761 ), a single-arm feasibility trial, 24 patients with stage III urothelial cancer (UC) received two doses of ipilimumab and two ...

    journal_title：Nature medicine

    pub_type： 杂志文章,多中心研究

    doi：10.1038/s41591-020-1085-z

    authors： van Dijk N,Gil-Jimenez A,Silina K,Hendricksen K,Smit LA,de Feijter JM,van Montfoort ML,van Rooijen C,Peters D,Broeks A,van der Poel HG,Bruining A,Lubeck Y,Sikorska K,Boellaard TN,Kvistborg P,Vis DJ,Hooijberg E,Schumac

    更新日期：2020-12-01 00:00:00

  • A GABAergic system in airway epithelium is essential for mucus overproduction in asthma.

    abstract：:Gamma-aminobutyric acid (GABA) is an important neurotransmitter that, through the subtype A GABA receptor (GABAAR), induces inhibition in the adult brain. Here we show that an excitatory, rather than inhibitory, GABAergic system exists in airway epithelial cells. Both GABAARs and the GABA synthetic enzyme glutamic aci...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm1604

    authors： Xiang YY,Wang S,Liu M,Hirota JA,Li J,Ju W,Fan Y,Kelly MM,Ye B,Orser B,O'Byrne PM,Inman MD,Yang X,Lu WY

    更新日期：2007-07-01 00:00:00

  • Interleukin-6-deficient mice develop mature-onset obesity.

    abstract：:The immune-modulating cytokine interleukin-6 (IL-6) is expressed both in adipose tissue and centrally in hypothalamic nuclei that regulate body composition. We investigated the impact of loss of IL-6 on body composition in mice lacking the gene encoding IL-6 (Il6-/- mice) and found that they developed mature-onset obe...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm0102-75

    authors： Wallenius V,Wallenius K,Ahrén B,Rudling M,Carlsten H,Dickson SL,Ohlsson C,Jansson JO

    更新日期：2002-01-01 00:00:00

  • Thymosin α1 represents a potential potent single-molecule-based therapy for cystic fibrosis.

    abstract：:Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that compromise its chloride channel activity. The most common mutation, p.Phe508del, results in the production of a misfolded CFTR protein, which has residual channel activity but is prematu...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm.4305

    authors： Romani L,Oikonomou V,Moretti S,Iannitti RG,D'Adamo MC,Villella VR,Pariano M,Sforna L,Borghi M,Bellet MM,Fallarino F,Pallotta MT,Servillo G,Ferrari E,Puccetti P,Kroemer G,Pessia M,Maiuri L,Goldstein AL,Garaci E

    更新日期：2017-05-01 00:00:00

  • TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1.

    abstract：:T-helper type 17 cells (T(H)17) are implicated in rodent models of immune-mediated diseases. Here we report their involvement in human uveitis and scleritis, and validate our findings in experimental autoimmune uveoretinitis (EAU), a model of uveitis. T(H)17 cells were present in human peripheral blood mononuclear cel...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm1585

    authors： Amadi-Obi A,Yu CR,Liu X,Mahdi RM,Clarke GL,Nussenblatt RB,Gery I,Lee YS,Egwuagu CE

    更新日期：2007-06-01 00:00:00

  • NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages.

    abstract：:Altered metabolism has been implicated in the pathogenesis of inflammatory diseases. NADPH oxidase 4 (NOX4), a source of cellular superoxide anions, has multiple biological functions that may be of importance in inflammation and in the pathogenesis of human metabolic diseases, including diabetes. However, the mechanis...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm.4153

    authors： Moon JS,Nakahira K,Chung KP,DeNicola GM,Koo MJ,Pabón MA,Rooney KT,Yoon JH,Ryter SW,Stout-Delgado H,Choi AM

    更新日期：2016-09-01 00:00:00

  • Erratum: The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions.

    abstract：:This corrects the article DOI: 10.1038/nm.4439. ...

    journal_title：Nature medicine

    pub_type： 已发布勘误

    doi：10.1038/nm0418-526b

    authors： Bolouri H,Farrar JE,Triche T Jr,Ries RE,Lim EL,Alonzo TA,Ma Y,Moore R,Mungall AJ,Marra MA,Zhang J,Ma X,Liu Y,Liu Y,Auvil JMG,Davidsen TM,Gesuwan P,Hermida LC,Salhia B,Capone S,Ramsingh G,Zwaan CM,Noort S,Pic

    更新日期：2018-04-10 00:00:00

  • Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation.

    abstract：:Surgery or radiation therapy of metastatic cancer often damages lymph nodes, leading to secondary lymphedema. Here we show, using a newly established mouse model, that collecting lymphatic vessels can be regenerated and fused to lymph node transplants after lymph node removal. Treatment of lymph node-excised mice with...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm1689

    authors： Tammela T,Saaristo A,Holopainen T,Lyytikkä J,Kotronen A,Pitkonen M,Abo-Ramadan U,Ylä-Herttuala S,Petrova TV,Alitalo K

    更新日期：2007-12-01 00:00:00

  • Protectin DX alleviates insulin resistance by activating a myokine-liver glucoregulatory axis.

    abstract：:We previously demonstrated that low biosynthesis of ω-3 fatty acid-derived proresolution mediators, termed protectins, is associated with an impaired global resolution capacity, inflammation and insulin resistance in obese high-fat diet-fed mice. These findings prompted a more direct study of the therapeutic potential...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm.3549

    authors： White PJ,St-Pierre P,Charbonneau A,Mitchell PL,St-Amand E,Marcotte B,Marette A

    更新日期：2014-06-01 00:00:00

  • In vivo imaging and tracking of host-microbiota interactions via metabolic labeling of gut anaerobic bacteria.

    abstract：:The intestine is densely populated by anaerobic commensal bacteria. These microorganisms shape immune system development, but understanding of host-commensal interactions is hampered by a lack of tools for studying the anaerobic intestinal environment. We applied metabolic oligosaccharide engineering and bioorthogonal...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm.3929

    authors： Geva-Zatorsky N,Alvarez D,Hudak JE,Reading NC,Erturk-Hasdemir D,Dasgupta S,von Andrian UH,Kasper DL

    更新日期：2015-09-01 00:00:00

  • An immunological epitope selective for pathological monomer-misfolded SOD1 in ALS.

    abstract：:Misfolding of Cu/Zn-superoxide dismutase (SOD1) is emerging as a mechanism underlying motor neuron degeneration in individuals with amyotrophic lateral sclerosis (ALS) who carry a mutant SOD1 gene (SOD1 ALS). Here we describe a structure-guided approach to developing an antibody that specifically recognizes monomer-mi...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm1559

    authors： Rakhit R,Robertson J,Vande Velde C,Horne P,Ruth DM,Griffin J,Cleveland DW,Cashman NR,Chakrabartty A

    更新日期：2007-06-01 00:00:00

  • A new activity for SAMHD1 in HIV restriction.

    abstract：:Restriction factors are host cell proteins that inhibit retroviral infection. A new study using mutants of human HIV-1 restriction factor SAMHD1 suggests that it inhibits infection through degradation of viral RNA rather than through its dNTPase activity as previously suggested. ...

    journal_title：Nature medicine

    pub_type： 评论,杂志文章

    doi：10.1038/nm.3657

    authors： Yang Z,Greene WC

    更新日期：2014-08-01 00:00:00

  • Clinical microfluidics for neutrophil genomics and proteomics.

    abstract：:Neutrophils have key roles in modulating the immune response. We present a robust methodology for rapidly isolating neutrophils directly from whole blood with 'on-chip' processing for mRNA and protein isolation for genomics and proteomics. We validate this device with an ex vivo stimulation experiment and by compariso...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm.2205

    authors： Kotz KT,Xiao W,Miller-Graziano C,Qian WJ,Russom A,Warner EA,Moldawer LL,De A,Bankey PE,Petritis BO,Camp DG 2nd,Rosenbach AE,Goverman J,Fagan SP,Brownstein BH,Irimia D,Xu W,Wilhelmy J,Mindrinos MN,Smith RD,Davis RW

    更新日期：2010-09-01 00:00:00

  • The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure.

    abstract：:Hypertension is one of the most frequent pathologies in the industrialized world. Although recognized to be dependent on a combination of genetic and environmental factors, its molecular basis remains elusive. Increased activity of the monomeric G protein RhoA in arteries is a common feature of hypertension. However, ...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm.2079

    authors： Guilluy C,Brégeon J,Toumaniantz G,Rolli-Derkinderen M,Retailleau K,Loufrani L,Henrion D,Scalbert E,Bril A,Torres RM,Offermanns S,Pacaud P,Loirand G

    更新日期：2010-02-01 00:00:00

  • Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL.

    abstract：:Relapse is the leading cause of mortality in children with acute lymphoblastic leukemia (ALL). Among chemotherapeutics, thiopurines are key drugs in ALL combination therapy. Using whole-exome sequencing, we identified relapse-specific mutations in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1), which encod...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm.3840

    authors： Li B,Li H,Bai Y,Kirschner-Schwabe R,Yang JJ,Chen Y,Lu G,Tzoneva G,Ma X,Wu T,Li W,Lu H,Ding L,Liang H,Huang X,Yang M,Jin L,Kang H,Chen S,Du A,Shen S,Ding J,Chen H,Chen J,von Stackelberg A,Gu L,Zhang J,

    更新日期：2015-06-01 00:00:00

  • TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity.

    abstract：:We formulate a two-phase paradigm of autoimmunity associated with systemic lupus erythematosus, the archetypal autoimmune disease. The initial Toll-like receptor (TLR)-independent phase is mediated by dendritic cell uptake of apoptotic cell debris and associated nucleic acids, whereas the subsequent TLR-dependent phas...

    journal_title：Nature medicine

    pub_type： 杂志文章,评审

    doi：10.1038/nm1590

    authors： Baccala R,Hoebe K,Kono DH,Beutler B,Theofilopoulos AN

    更新日期：2007-05-01 00:00:00

  • Epidermal growth factor regulates hematopoietic regeneration after radiation injury.

    abstract：:The mechanisms that regulate hematopoietic stem cell (HSC) regeneration after myelosuppressive injury are not well understood. We identified epidermal growth factor (EGF) to be highly enriched in the bone marrow serum of mice bearing deletion of Bak and Bax in TIE2-expressing cells in Tie2Cre; Bak1(-/-); Bax(flox/-) m...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm.3070

    authors： Doan PL,Himburg HA,Helms K,Russell JL,Fixsen E,Quarmyne M,Harris JR,Deoliviera D,Sullivan JM,Chao NJ,Kirsch DG,Chute JP

    更新日期：2013-03-01 00:00:00

  • Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1.

    abstract：:Hereditary hemochromatosis and transfusional iron overload are frequent clinical conditions associated with progressive iron accumulation in parenchymal tissues, leading to eventual organ failure. We have discovered a new mechanism to reverse iron overload-pharmacological modulation of the divalent metal transporter-1...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm1542

    authors： Ludwiczek S,Theurl I,Muckenthaler MU,Jakab M,Mair SM,Theurl M,Kiss J,Paulmichl M,Hentze MW,Ritter M,Weiss G

    更新日期：2007-04-01 00:00:00

  • A newly discovered human pneumovirus isolated from young children with respiratory tract disease.

    abstract：:From 28 young children in the Netherlands, we isolated a paramyxovirus that was identified as a tentative new member of the Metapneumovirus genus based on virological data, sequence homology and gene constellation. Previously, avian pneumovirus was the sole member of this recently assigned genus, hence the provisional...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/89098

    authors： van den Hoogen BG,de Jong JC,Groen J,Kuiken T,de Groot R,Fouchier RA,Osterhaus AD

    更新日期：2001-06-01 00:00:00

  • Deciphering the genomic, epigenomic, and transcriptomic landscapes of pre-invasive lung cancer lesions.

    abstract：:The molecular alterations that occur in cells before cancer is manifest are largely uncharted. Lung carcinoma in situ (CIS) lesions are the pre-invasive precursor to squamous cell carcinoma. Although microscopically identical, their future is in equipoise, with half progressing to invasive cancer and half regressing o...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/s41591-018-0323-0

    authors： Teixeira VH,Pipinikas CP,Pennycuick A,Lee-Six H,Chandrasekharan D,Beane J,Morris TJ,Karpathakis A,Feber A,Breeze CE,Ntolios P,Hynds RE,Falzon M,Capitanio A,Carroll B,Durrenberger PF,Hardavella G,Brown JM,Lynch AG,Fa

    更新日期：2019-03-01 00:00:00

  • Author Correction: Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition.

    abstract：:In the Supplementary Information originally published with this article, a lane was missing in the β-actin blot in Supplementary Fig. 2. The lane has been added. The error has been corrected in the Supplementary Information associated with this article. ...

    journal_title：Nature medicine

    pub_type： 已发布勘误

    doi：10.1038/s41591-018-0168-6

    authors： Wong GS,Zhou J,Bin Liu J,Wu Z,Xu X,Li T,Xu D,Schumacher SE,Puschhof J,McFarland J,Zou C,Dulak A,Henderson L,Xu P,O'Day E,Rendak R,Liao WL,Cecchi F,Hembrough T,Schwartz S,Szeto C,Rustgi AK,Wong KK,Diehl JA,

    更新日期：2018-10-01 00:00:00

  • CD8+ T cell efficacy in vaccination and disease.

    abstract：:Much effort has been devoted to the design of vaccines that induce adaptive cellular immunity, in particular CD8+ T cells, which have a central role in the host response to viral infections and cancers. To date, however, the development of effective T cell vaccines remains elusive. This is due, in part, to the lack of...

    journal_title：Nature medicine

    pub_type： 杂志文章,评审

    doi：10.1038/nm.f.1774

    authors： Appay V,Douek DC,Price DA

    更新日期：2008-06-01 00:00:00

  • AKT2 is essential to maintain podocyte viability and function during chronic kidney disease.

    abstract：:In chronic kidney disease (CKD), loss of functional nephrons results in metabolic and mechanical stress in the remaining ones, resulting in further nephron loss. Here we show that Akt2 activation has an essential role in podocyte protection after nephron reduction. Glomerulosclerosis and albuminuria were substantially...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm.3313

    authors： Canaud G,Bienaimé F,Viau A,Treins C,Baron W,Nguyen C,Burtin M,Berissi S,Giannakakis K,Muda AO,Zschiedrich S,Huber TB,Friedlander G,Legendre C,Pontoglio M,Pende M,Terzi F

    更新日期：2013-10-01 00:00:00

  • PTEN opposes negative selection and enables oncogenic transformation of pre-B cells.

    abstract：:Phosphatase and tensin homolog (PTEN) is a negative regulator of the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) signaling pathway and a potent tumor suppressor in many types of cancer. To test a tumor suppressive role for PTEN in pre-B acute lymphoblastic leukemia (ALL), we induced Cre-mediated de...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm.4062

    authors： Shojaee S,Chan LN,Buchner M,Cazzaniga V,Cosgun KN,Geng H,Qiu YH,von Minden MD,Ernst T,Hochhaus A,Cazzaniga G,Melnick A,Kornblau SM,Graeber TG,Wu H,Jumaa H,Müschen M

    更新日期：2016-04-01 00:00:00

  • Re-engineered CD40 receptor enables potent pharmacological activation of dendritic-cell cancer vaccines in vivo.

    abstract：:Modest clinical outcomes of dendritic-cell (DC) vaccine trials call for the refinement of DC vaccine design. Although many potential antigens have been identified, development of methods to enhance antigen presentation by DCs has lagged. We have engineered a potent, drug-inducible CD40 (iCD40) receptor that permits te...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm1183

    authors： Hanks BA,Jiang J,Singh RA,Song W,Barry M,Huls MH,Slawin KM,Spencer DM

    更新日期：2005-02-01 00:00:00

  • The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy.

    abstract：:Epigenetic reprogramming is a critical process of pathological gene induction during cardiac hypertrophy and remodeling, but the underlying regulatory mechanisms remain to be elucidated. Here we identified a heart-enriched long noncoding (lnc)RNA, named cardiac-hypertrophy-associated epigenetic regulator (Chaer), whic...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm.4179

    authors： Wang Z,Zhang XJ,Ji YX,Zhang P,Deng KQ,Gong J,Ren S,Wang X,Chen I,Wang H,Gao C,Yokota T,Ang YS,Li S,Cass A,Vondriska TM,Li G,Deb A,Srivastava D,Yang HT,Xiao X,Li H,Wang Y

    更新日期：2016-10-01 00:00:00

  • TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination.

    abstract：:Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by localized areas of demyelination. Although the etiology and pathogenesis of MS remain largely unknown, it is generally assumed that immune responses to myelin antigens contribute to the disease process. The exact se...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm0198-078

    authors： Liu J,Marino MW,Wong G,Grail D,Dunn A,Bettadapura J,Slavin AJ,Old L,Bernard CC

    更新日期：1998-01-01 00:00:00

  • The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress.

    abstract：:Autophagy, an evolutionarily conserved process for the bulk degradation of cytoplasmic components, serves as a cell survival mechanism in starving cells. Although altered autophagy has been observed in various heart diseases, including cardiac hypertrophy and heart failure, it remains unclear whether autophagy plays a...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm1574

    authors： Nakai A,Yamaguchi O,Takeda T,Higuchi Y,Hikoso S,Taniike M,Omiya S,Mizote I,Matsumura Y,Asahi M,Nishida K,Hori M,Mizushima N,Otsu K

    更新日期：2007-05-01 00:00:00

  • Preventing dysbiosis of the neonatal mouse intestinal microbiome protects against late-onset sepsis.

    abstract：:Late-onset sepsis (LOS) is thought to result from systemic spread of commensal microbes from the intestines of premature infants. Clinical use of probiotics for LOS prophylaxis has varied owing to limited efficacy, reflecting an incomplete understanding of relationships between development of the intestinal microbiome...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/s41591-019-0640-y

    authors： Singer JR,Blosser EG,Zindl CL,Silberger DJ,Conlan S,Laufer VA,DiToro D,Deming C,Kumar R,Morrow CD,Segre JA,Gray MJ,Randolph DA,Weaver CT

    更新日期：2019-11-01 00:00:00