The HSP90 inhibitor, 17AAG, protects the intestinal stem cell niche and inhibits graft versus host disease development.

Abstract:

:Graft versus host disease (GvHD), which is the primary complication of allogeneic bone marrow transplantation, can alter the intestinal barrier targeted by activated donor T-cells. Chemical inhibition of the stress protein HSP90 was demonstrated in vitro to inhibit T-cell activation and to modulate endoplasmic reticulum (ER) stress to which intestinal cells are highly susceptible. Since the HSP90 inhibitor 17-allylamino-demethoxygeldanamycin (17AAG) is developed in clinics, we explored here its ability to control intestinal acute GvHD in vivo in two mouse GvHD models (C57BL/6BALB/c and FVB/NLgr5-eGFP), ex vivo in intestine organoids and in vitro in intestinal epithelial cultures. We show that 17AAG decreases GvHD-associated mortality without impairing graft versus leukemia effect. While 17AAG effect in T-cell activation is just moderate at the dose used in vivo, we observe a striking intestinal integrity protection. At the intestine level, the drug promotes the splicing of the transcription factor X-box binding protein 1 (XBP1), which is a key component of the ER stress. This effect is associated with a decrease in intestinal damage and an increase in Lgr5(+) stem cells, Paneth cells and defensins production. The importance of XBP1 splicing control is further confirmed in cultured cells and organoids of primary intestinal epithelium where XBP1 is either shRNA depleted or inhibited with toyocamycin. In conclusion, 17AAG has a protective effect on the epithelial intestinal barrier in mouse models of acute GvHD. This compound deserves to be tested in the therapeutic control of acute GvHD.

journal_name

Oncogene

journal_title

Oncogene

authors

Joly AL,Deepti A,Seignez A,Goloudina A,Hebrard S,Schmitt E,Richaud S,Fourmaux E,Hammann A,Collura A,Svrcek M,Jego G,Robinet E,Solary E,Demidov O,Kohli E,Garrido C

doi

10.1038/onc.2015.242

subject

Has Abstract

pub_date

2016-06-02 00:00:00

pages

2842-51

issue

22

eissn

0950-9232

issn

1476-5594

pii

onc2015242

journal_volume

35

pub_type

杂志文章

相关文献

ONCOGENE文献大全
  • Radiation-induced apoptosis is not enhanced by expression of either p53 or BAX in SW626 ovarian cancer cells.

    abstract::The p53 protein is known to play a central role in mediating G1 arrest or apoptosis in response to ionizing radiation in some cell types. It has been proposed that the link between p53 and induction of apoptosis is provided in part by p53-mediated upregulation of BAX. In this study, we used the human SW626 ovarian can...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/sj.onc.1201132

    authors: Strobel T,Swanson L,Korsmeyer S,Cannistra SA

    更新日期:1997-06-12 00:00:00

  • Isolation of a new class of 'flat' revertants from ras-transformed NIH3T3 cells using cis-4-hydroxy-L-proline.

    abstract::A new class of nontransformed revertant cells has been isolated from the ras-transformed cell line DT using cis-4-hydroxy-L-proline (CHP) as a selective agent. The new revertants, CHP 9CJ and CHP CB4, each contain two copies of the v-Ki-ras gene, elevated levels of phosphorylated p21ras protein, and rescuable transfor...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:

    authors: Yanagihara K,Ciardiello F,Talbot N,McGeady ML,Cooper H,Benade L,Salomon DS,Bassin RH

    更新日期:1990-08-01 00:00:00

  • TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior.

    abstract::Treatment options for adenoid cystic carcinoma (ACC) of the salivary gland, a slowly growing tumor with propensity for neuroinvasion and late recurrence, are limited to surgery and radiotherapy. Based on expression analysis performed on clinical specimens of salivary cancers, we identified in ACC expression of the neu...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/onc.2012.377

    authors: Ivanov SV,Panaccione A,Brown B,Guo Y,Moskaluk CA,Wick MJ,Brown JL,Ivanova AV,Issaeva N,El-Naggar AK,Yarbrough WG

    更新日期:2013-08-08 00:00:00

  • FOXM1 is a transcriptional target of ERalpha and has a critical role in breast cancer endocrine sensitivity and resistance.

    abstract::In this study, we investigated the regulation of FOXM1 expression by estrogen receptor alpha (ERalpha) and its role in hormonal therapy and endocrine resistance. FOXM1 protein and mRNA expression was regulated by ER-ligands, including estrogen, tamoxifen (OHT) and fulvestrant (ICI182780; ICI) in breast carcinoma cell ...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/onc.2010.47

    authors: Millour J,Constantinidou D,Stavropoulou AV,Wilson MS,Myatt SS,Kwok JM,Sivanandan K,Coombes RC,Medema RH,Hartman J,Lykkesfeldt AE,Lam EW

    更新日期:2010-05-20 00:00:00

  • MacroH2A1.2 inhibits prostate cancer-induced osteoclastogenesis through cooperation with HP1α and H1.2.

    abstract::Osteoclasts are multinuclear bone-resorbing cells that differentiate from hematopoietic precursor cells. Prostate cancer cells frequently spread to bone and secrete soluble signaling factors to accelerate osteoclast differentiation and bone resorption. However, processes and mechanisms that govern the expression of os...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/s41388-018-0356-3

    authors: Kim JM,Shin Y,Lee S,Kim MY,Punj V,Shin HI,Kim K,Koh JM,Jeong D,An W

    更新日期:2018-10-01 00:00:00

  • Distinct methylation patterns of two APC gene promoters in normal and cancerous gastric epithelia.

    abstract::The adenomatous polyposis coli (APC) tumor suppressor gene is mutationally inactivated in both familial and sporadic forms of colorectal cancers. In addition, hypermethylation of CpG islands in the upstream portion of APC, a potential alternative mechanism of tumor suppressor gene inactivation, has been described in c...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/sj.onc.1203704

    authors: Tsuchiya T,Tamura G,Sato K,Endoh Y,Sakata K,Jin Z,Motoyama T,Usuba O,Kimura W,Nishizuka S,Wilson KT,James SP,Yin J,Fleisher AS,Zou T,Silverberg SG,Kong D,Meltzer SJ

    更新日期:2000-07-27 00:00:00

  • Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality.

    abstract::Recent evidence has implicated the transmembrane co-receptor neuropilin-1 (NRP1) in cancer progression. Primarily known as a regulator of neuronal guidance and angiogenesis, NRP1 is also expressed in multiple human malignancies, where it promotes tumor angiogenesis. However, non-angiogenic roles of NRP1 in tumor progr...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/onc.2016.482

    authors: Tse BWC,Volpert M,Ratther E,Stylianou N,Nouri M,McGowan K,Lehman ML,McPherson SJ,Roshan-Moniri M,Butler MS,Caradec J,Gregory-Evans CY,McGovern J,Das R,Takhar M,Erho N,Alshalafa M,Davicioni E,Schaeffer EM,Jenkins RB

    更新日期:2017-06-15 00:00:00

  • BHRF1, a viral homologue of the Bcl-2 oncogene, disturbs epithelial cell differentiation.

    abstract::Epstein-Barr virus (EBV) is associated with tumours of both lymphoid and epithelial origin. Whilst a role for EBV latent genes in the development of these malignancies is accepted, it is also possible that viral proteins involved in EBV replication may influence the oncogenic process. BHRF1 is an immediate early prote...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:

    authors: Dawson CW,Eliopoulos AG,Dawson J,Young LS

    更新日期:1995-01-05 00:00:00

  • Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells.

    abstract::The ability of glioma cells to migrate great distances from a primary tumor mass is the primary cause of tumor recurrence. The urokinase-type plasminogen activator (uPA) is a serine protease that can initiate proteolytic cascades, which result in remodeling of extracellular matrix and basement membrane, allowing cells...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/sj.onc.1206164

    authors: Chandrasekar N,Mohanam S,Gujrati M,Olivero WC,Dinh DH,Rao JS

    更新日期:2003-01-23 00:00:00

  • The adenovirus E1A 289R and 243R proteins inhibit the phosphorylation of p300.

    abstract::A protein of 300 kDa (p300) associates with the adenovirus E1A proteins and has been implicated in the control of cell cycle progression. In mammalian cells, p300 is actively phosphorylated in both quiescent and proliferating cells and its level of phosphorylation increases as it travels from late G1 into M phase. E1A...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:

    authors: Banerjee AC,Recupero AJ,Mal A,Piotrkowski AM,Wang DM,Harter ML

    更新日期:1994-06-01 00:00:00

  • Evidence for human DNA-mediated transfer of the suppressed phenotype into malignant Chinese hamster cells.

    abstract::Genetic suppression of the neoplastic phenotype has been demonstrated in somatic cell hybrids between tumor and normal cells. Suppression in whole-cell and microcell hybrids cannot, as yet, be attributed to specific elements defined at the molecular level. To identify a gene capable of suppressing the neoplastic pheno...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:

    authors: Schäfer R,Nirkko AC,Ambühl PM,Grzeschik KH,Schwarte-Waldhoff I

    更新日期:1991-12-01 00:00:00

  • Predominant requirement of Bax for apoptosis in HCT116 cells is determined by Mcl-1's inhibitory effect on Bak.

    abstract::The intrinsic mitochondrial apoptotic pathway acts through two core pro-apoptotic proteins Bax (Bcl2-associated X protein) and Bak (Bcl2-antagonist/killer 1). Although Bax and Bak seem to have redundant roles in apoptosis, accumulating evidence also suggests that they might not be interchangeable under certain conditi...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/onc.2011.497

    authors: Wang C,Youle RJ

    更新日期:2012-06-28 00:00:00

  • MET targeting: time for a rematch.

    abstract::MET, the receptor tyrosine kinase (RTK) for hepatocyte growth factor, is a proto-oncogene involved in embryonic development and throughout life in homeostasis and tissue regeneration. Deregulation of MET signaling has been reported in numerous malignancies, prompting great interest in MET targeting for cancer therapy....

    journal_title:Oncogene

    pub_type: 杂志文章,评审

    doi:10.1038/s41388-020-1193-8

    authors: Koch JP,Aebersold DM,Zimmer Y,Medová M

    更新日期:2020-04-01 00:00:00

  • CD97 amplifies LPA receptor signaling and promotes thyroid cancer progression in a mouse model.

    abstract::CD97, a member of the adhesion family of G-protein-coupled receptors (GPCRs), complexes with and potentiates lysophosphatidic acid (LPA) receptor signaling to the downstream effector RHOA. We show here that CD97 was expressed in a majority of thyroid cancers but not normal thyroid epithelium and that the level of CD97...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/onc.2012.301

    authors: Ward Y,Lake R,Martin PL,Killian K,Salerno P,Wang T,Meltzer P,Merino M,Cheng SY,Santoro M,Garcia-Rostan G,Kelly K

    更新日期:2013-05-30 00:00:00

  • Regulation of Fas-dependent activation-induced T cell apoptosis by cAMP signaling: a potential role for transcription factor NF-kappa B.

    abstract::TCR-mediated activation of T cell hybridomas induces programmed cell death by a Fas-dependent pathway. We now show that costimulation of 2B4 cells, in the absence or presence of transgenic Bcl-2, with anti-CD3 epsilon and forskolin, an activator of cAMP signaling, resulted in antagonism of Fas-dependent activation-ind...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/sj.onc.1201088

    authors: Ivanov VN,Lee RK,Podack ER,Malek TR

    更新日期:1997-05-22 00:00:00

  • TGFβ signaling in head and neck squamous cell carcinoma.

    abstract::Transforming growth factor beta (TGFβ) is a key regulator of epithelial cell proliferation, immune function and angiogenesis. Because TGFβ signaling maintains epithelial homeostasis, dysregulated TGFβ signaling is common in many malignancies, including head and neck squamous cell carcinoma (HNSCC). Defective TGFβ sign...

    journal_title:Oncogene

    pub_type: 杂志文章,评审

    doi:10.1038/onc.2010.306

    authors: White RA,Malkoski SP,Wang XJ

    更新日期:2010-10-07 00:00:00

  • Somatic mutations in the BRCA1 gene in Chinese sporadic breast and ovarian cancer.

    abstract::Inherited mutations in the BRCA1 gene confer increased susceptibility to breast and ovarian cancer. Its role in sporadic carcinogenesis is not well defined. Somatic mutations in breast cancers have not been reported and to date there are only three reports of somatic mutations in sporadic ovarian cancers. To investiga...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/sj.onc.1202847

    authors: Khoo US,Ozcelik H,Cheung AN,Chow LW,Ngan HY,Done SJ,Liang AC,Chan VW,Au GK,Ng WF,Poon CS,Leung YF,Loong F,Ip P,Chan GS,Andrulis IL,Lu J,Ho FC

    更新日期:1999-08-12 00:00:00

  • DNA damage-related gene expression as biomarkers to assess cellular response after gamma irradiation of a human lymphoblastoid cell line.

    abstract::Since defects in molecular mechanisms controlling DNA repair, cell cycle checkpoint and apoptosis could modify cellular sensitivity to DNA damaging agents, we have conducted a multiparametric molecular analysis for better understanding the regulation pathways leading to cell survival or cell death after irradiation. U...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/sj.onc.1203405

    authors: Bishay K,Ory K,Lebeau J,Levalois C,Olivier MF,Chevillard S

    更新日期:2000-02-17 00:00:00

  • Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis.

    abstract::VEGFR-1 (Flt-1), VEGFR-2 (KDR) and VEGFR-3 (Flt4) are endothelial specific receptor tyrosine kinases, regulated by members of the vascular endothelial growth factor family. VEGFRs are indispensable for embryonic vascular development, and are involved in the regulation of many aspects of physiological and pathological ...

    journal_title:Oncogene

    pub_type: 杂志文章,评审

    doi:10.1038/sj.onc.1203855

    authors: Karkkainen MJ,Petrova TV

    更新日期:2000-11-20 00:00:00

  • Essential roles of Crk and CrkL in fibroblast structure and motility.

    abstract::Cytosolic proteins containing SH2 and SH3 domains, such as Crk and Crk-like (CrkL), are broadly expressed adapters that interact with a variety of proteins to fulfill key roles in signal transduction pathways triggered by activation of receptor and non-receptor tyrosine kinases. Crk and CrkL are similar to each other ...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/onc.2013.453

    authors: Park TJ,Curran T

    更新日期:2014-10-23 00:00:00

  • IL-3R-alpha blockade inhibits tumor endothelial cell-derived extracellular vesicle (EV)-mediated vessel formation by targeting the β-catenin pathway.

    abstract::The proangiogenic cytokine Interleukin-3 (IL-3) is released by inflammatory cells in breast and ovarian cancer tissue microenvironments and also acts as an autocrine factor for human breast and kidney tumor-derived endothelial cells (TECs). We have previously shown that IL-3-treated endothelial cells (ECs) release ext...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/s41388-017-0034-x

    authors: Lombardo G,Gili M,Grange C,Cavallari C,Dentelli P,Togliatto G,Taverna D,Camussi G,Brizzi MF

    更新日期:2018-03-01 00:00:00

  • Fstl1/DIP2A/MGMT signaling pathway plays important roles in temozolomide resistance in glioblastoma.

    abstract::Temozolomide was recognized as the first-line therapy for glioblastoma to prolong the survival of patients noticeably, while recent clinical studies found that some patients were not sensitive to temozolomide treatment. The possible mechanisms seemed to be methylguanine-DNA-methyltransferase (MGMT), mismatch repair, P...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/s41388-018-0596-2

    authors: Nie E,Miao F,Jin X,Wu W,Zhou X,Zeng A,Yu T,Zhi T,Shi Z,Wang Y,Zhang J,Liu N,You Y

    更新日期:2019-04-01 00:00:00

  • Interferon-α-secreting mesenchymal stem cells exert potent antitumor effect in vivo.

    abstract::Mesenchymal stem cells (MSCs) are a kind of adult stem cells that can be isolated easily from bone marrow, adipose tissue, umbilical cord and many other tissues. MSCs have been shown to specifically migrate to inflammatory sites, including tumors, and hold great promise as tumor-specific vectors to deliver antitumor a...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/onc.2013.458

    authors: Xu C,Lin L,Cao G,Chen Q,Shou P,Huang Y,Han Y,Wang Y,Shi Y

    更新日期:2014-10-16 00:00:00

  • Future prospects for oncolytic therapy.

    abstract::Viruses have been engineered to replicate selectively in cancer cells, based on a number of innovative principles. Several of these viruses have entered clinical trials and have proven relatively safe, and have shown evidence of efficacy. However, further research is required to enable these agents to function systemi...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/sj.onc.1209064

    authors: McCormick F

    更新日期:2005-11-21 00:00:00

  • MKP1/CL100 controls tumor growth and sensitivity to cisplatin in non-small-cell lung cancer.

    abstract::Non-small-cell lung cancer (NSCLC) represents the most frequent and therapy-refractive sub-class of lung cancer. Improving apoptosis induction in NSCLC represents a logical way forward in treating this tumor. Cisplatin, a commonly used therapeutic agent in NSCLC, induces activation of N-terminal-c-Jun kinase (JNK) tha...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/sj.onc.1209364

    authors: Chattopadhyay S,Machado-Pinilla R,Manguan-García C,Belda-Iniesta C,Moratilla C,Cejas P,Fresno-Vara JA,de Castro-Carpeño J,Casado E,Nistal M,Gonzalez-Barón M,Perona R

    更新日期:2006-06-01 00:00:00

  • Alu RNA accumulation induces epithelial-to-mesenchymal transition by modulating miR-566 and is associated with cancer progression.

    abstract::Alu sequences are the most abundant short interspersed repeated elements in the human genome. Here we show that in a cell culture model of colorectal cancer (CRC) progression, we observe accumulation of Alu RNA that is associated with reduced DICER1 levels. Alu RNA induces epithelial-to-mesenchymal transition (EMT) by...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/onc.2017.369

    authors: Di Ruocco F,Basso V,Rivoire M,Mehlen P,Ambati J,De Falco S,Tarallo V

    更新日期:2018-02-01 00:00:00

  • c-Myc inhibits myogenic differentiation and myoD expression by a mechanism which can be dissociated from cell transformation.

    abstract::The c-Myc oncoprotein is a basic-helix-loop-helix-leucine zipper (b-HLH-LZ) transcription factor involved in regulating cell proliferation and differentiation. We have used retrovirus-mediated gene transfer to investigate the effect of ectopic c-Myc expression on the spontaneous differentiation of primary quail myobla...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:

    authors: La Rocca SA,Crouch DH,Gillespie DA

    更新日期:1994-12-01 00:00:00

  • A human tumour-derived mutant p53 protein induces a p34cdc2 reversible growth arrest in fission yeast.

    abstract::We have expressed wild-type and human tumour-derived mutant p53 cDNA genes in the fission yeast Schizosaccharomyces pombe. In the case of one mutant this resulted in a growth arrest of recipient yeast cells. In contrast, wild-type p53 and three other mutant proteins tested did not block outgrowth of colonies. Human an...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:

    authors: Wagner P,Simanis V,Maimets T,Keenan E,Addison C,Brain R,Grimaldi M,Sturzbecher HW,Jenkins J

    更新日期:1991-09-01 00:00:00

  • EGF receptor binding and transformation by v-cbl is ablated by the introduction of a loss-of-function mutation from the Caenorhabditis elegans sli-1 gene.

    abstract::The 120 kD product of the c-cbl oncogene is rapidly tyrosine phosphorylated and recruited to the EGF receptor following ligand binding. Cbl's oncogenic potential is activated by a large carboxy-terminal truncation that generated v-cbl and removes the Ring finger and proline-rich SH3-binding domains. Here we show that ...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/sj.onc.1201193

    authors: Thien CB,Langdon WY

    更新日期:1997-05-08 00:00:00

  • An siRNA screen identifies the GNAS locus as a driver in 20q amplified breast cancer.

    abstract::Poor-prognosis oestrogen receptor-positive breast cancer is characterised by the presence of high-level focal amplifications. We utilised a focused small interfering RNA screen in 14 breast cancer cell lines to define genes that were pathogenic in three genomic regions focally amplified in oestrogen receptor-positive ...

    journal_title:Oncogene

    pub_type: 杂志文章

    doi:10.1038/onc.2013.202

    authors: Garcia-Murillas I,Sharpe R,Pearson A,Campbell J,Natrajan R,Ashworth A,Turner NC

    更新日期:2014-05-08 00:00:00