DOCSLIB.ORG

Mast Cell STAT6 IL-4 Induces the Proteolytic Processing Of

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mast Cell STAT6 IL-4 Induces the Proteolytic Processing Of IL-4 Induces the Proteolytic Processing of Mast Cell STAT6 Melanie A. Sherman, Doris R. Powell and Melissa A. Brown This information is current as J Immunol 2002; 169:3811-3818; ; of September 28, 2021. doi: 10.4049/jimmunol.169.7.3811 http://www.jimmunol.org/content/169/7/3811 Downloaded from References This article cites 74 articles, 47 of which you can access for free at: http://www.jimmunol.org/content/169/7/3811.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 28, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology IL-4 Induces the Proteolytic Processing of Mast Cell STAT61 Melanie A. Sherman, Doris R. Powell, and Melissa A. Brown2 IL-4 is a potent, pleiotropic cytokine that, in general, directs cellular activation, differentiation, and rescue from apoptosis. However, in mast cells, IL-4 induces the down-regulation of activation receptors and promotes cell death. Mast cells have been shown to transduce IL-4 signals through a unique C-terminally truncated isoform of STAT6. In this study, we examine the mechanism through which STAT6 is processed to generate this isoform. We demonstrate that STAT6 processing in mast cells is initiated by IL-4-induced phosphorylation and nuclear translocation of full-length STAT6 and subsequent cleavage by a nuclear serine-family protease. The location of the protease in the nucleus ensures that the truncated STAT6 has preferential access to bind DNA. IL-4-responsive target genes in mast cells are identified by chromatin immunoprecipitation of STAT6, including the IL-4 gene itself. These results suggest a molecular explanation for the suppressive effects of IL-4 on STAT6-regulated genes in mast cells. The Journal of Immunology, 2002, 169: 3811–3818. Downloaded from ignal transducer and activator or transcription 6, a latent protein and thus acts relatively late in the STAT6 signaling cas- cytoplasmic transcription factor, is a member of a family cade to inhibit JAK1 and limit the duration of STAT6 activation S of signaling molecules that mediate responses to cyto- (10). Second, alternate isoforms of STAT proteins have been de- kines. IL-4 (and IL-13) binding to its receptor results in the acti- scribed for several STAT family members (11–15). These ␤ iso- vation of Janus kinase (JAK)3 1 and JAK3, receptor-associated forms (identified for STATs 1, 3, 5A, and 5B) lack the transacti- tyrosine kinases (1, 2). JAK1 and 3 directly phosphorylate tyrosine vation domain (TAD) but retain DNA binding ability. Therefore, http://www.jimmunol.org/ residues within STAT6 Src homology (SH)2 domains leading to by competing with the transcriptionally active form of STAT for dimerization and translocation to the nucleus where STAT6 can binding to DNA, they effectively inhibit the early transcription of associate with regulatory elements that control IL-4 (and/or IL-13) cytokine-responsive genes. Ϫ Ϫ responsive genes. Numerous studies using STAT6 / mice have The biological significance of STAT isoforms that act as dom- demonstrated the importance of this molecule in providing immu- inant negative transcription factors is clearly evident from studies nological competence (3–5). For example, the STAT6 signaling of STAT5, a signaling molecule activated in response to IL-2, pathway is of particular significance in the development of Th2 IL-3, IL-5, stem cell factor, and IL-15 (16–18). The truncated Ϫ Ϫ immunity to extracellular pathogens. STAT6 / mice are ex- STAT5␤ isoforms are expressed uniquely in myeloid progenitor tremely vulnerable to these infections, and T cells from these mice cells and are responsible for maintaining an IL-3-refractive state by guest on September 28, 2021 are unable to produce adequate amounts of the Th2 cytokines IL-4, (15). Upon differentiation, these cells lose expression of STAT5␤ IL-13, and IL-5 (3–5). B cell isotype switching, immunity to some and express only full-length STAT5, coincident with a gain of IL-3 tumors (6, 7), and development of contact hypersensitivity (8) are responsiveness (19). The truncated STAT5 proteins are generated Ϫ Ϫ also compromised in STAT6 / mice. through proteolysis of full-length STAT5 by a nuclear protease Because IL-4 plays a central role in the regulation of immune found only in immature myelocytes (20). This protease, termed responses, the magnitude and duration of STAT6-induced re- modulator of STAT activity (MSA) is a 25-kDa member of the sponses must be tightly controlled. At least two mechanisms have serine protease family. Its recognition and cleavage site in STAT5 been described to accomplish this regulation. First, suppressor of has been identified, and mutation of this site results in a STAT5 cytokine signaling (SOCS) proteins are up-regulated by cytokine- protein that resists proteolysis (19). induced STAT activation and either compete with STAT for bind- We previously identified a STAT6 isoform that shares charac- ing to receptors or bind to and inhibit JAK kinase activity (re- teristics with the ␤ forms of the other STAT family members (21). viewed by Chen et al. in Ref. 9). SOCS-1 is an IL-4-inducible In contrast to the 100-kDa full-length STAT6 molecule, STAT6␤ is truncated to ϳ65 kDa. Results from epitope mapping studies demonstrate that STAT6␤ lacks the C-terminal TAD, but it ap- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA ␤ 30322 pears to retain a high affinity for DNA. STAT6 is expressed in a cell type-specific manner and is present in mast cells, but not in B Received for publication June 17, 2002. Accepted for publication July 31, 2002. or T cells. Interestingly, while IL-4-induced STAT6 is associated The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with an activating phenotype in B cells and T cells, it is often with 18 U.S.C. Section 1734 solely to indicate this fact. suppressive for mast cell gene expression. Mast cell receptors c-kit 1 This work was supported by National Institutes of Health Grants AR02157 (to and Fc⑀RI are down-regulated in response to IL-4 stimulation (22– M.A.S.) and CA47992 (to M.A.B.). 24) and the induction of several cytokines is inhibited upon long- 2 Address correspondence and reprint requests to Dr. Melissa A. Brown, 7311 Wood- term IL-4 exposure (23). ruff Memorial Research Building, Department of Pathology and Laboratory Medicine, Emory University, 1639 Pierce Drive, Atlanta, GA 30322. E-mail address: In this study, we set out to 1) characterize the STAT6 protein in [email protected] mast cells with regard to the mechanism of isoform generation, 3 Abbreviations used in this paper: JAK, Janus kinase; SH, Src homology; SOCS, phosphorylation status, and cellular localization, and 2) identify a suppressor of cytokine signaling; TAD, transactivation domain; MSA, modulator of role of STAT6␤ in mast cell gene transcription. We demonstrate STAT activity; BMMC, bone marrow-derived mast cells; USF, upstream stimulatory ␤ ␤ factor; IP, immunoprecipitation; ChIP, chromatin IP; SHP-1, sulfhydryl-2 domain- that analogous to STAT5 , STAT6 is also generated by proteo- containing tyrosine phosphatase-1. lytic processing. Although distinct from STAT5 MSA, the mast Copyright © 2002 by The American Association of Immunologists, Inc. 0022-1767/02/$02.00 3812 MAST CELL STAT6 PROTEASE cell STAT6 protease is a member of the serine protease family and ferred to nylon membrane. The blot was blocked in 5% milk/TBST (10 is located in the nucleus. We show that mast cell STAT6 is phos- mM Tris, pH 8.0, 150 mM NaCl, 0.5% Tween) overnight at 4°C. Abs (1 ␮ phorylated in response to IL-4 and binds in vivo to a STAT6 bind- g/ml) were added in 2% milk/TBST (the phospho-STAT6 Ab was diluted in 3% BSA/Tween 20 ϩ TBS) and incubated1hatroom temperature. ing site in the IL-4 promoter in mast cells. Mast cell STAT6 is also HRP-conjugated donkey anti-rabbit secondary Abs (Amersham, Arlington associated with the promoters of apoptosis regulator genes bax and Heights, IL) were added at a 1/5000 dilution in 2% milk/TBST and incu- bcl-2. The restricted expression and binding of this isoform to IL-4 bated1hatroom temperature. Reactive proteins were visualized by ECL responsive genes in mast cells could account for the cell-type spe- (DuPont, Boston, MA) and radiography. cific inhibitory effects of IL-4. Northern blot analysis For analysis of STAT6 expression in cell lines, 10 ␮g of total RNA was Materials and Methods electrophoresed on a 1% formaldehyde gel and transferred to nitrocellu- Cell culture and stimulation lose. The STAT6 DNA probe (bp 1–384 from STAT6 sequence, Accession CFTL-15, a murine IL-3 dependent mast cell line (C15; Ref. 25), WEHI- no. AF481809) was labeled by random hexamer priming. 3B, an immature myeloid cell line (26), and M12.4.1, a transformed B cell RNase protection analysis line (27), were cultured in complete RPMI (10% heat-inactivated FBS, 0.5% penicillin/streptomycin, 2 mM glutamine, 1.0 mM sodium pyruvate, Total RNA samples from C15 and M12 cell lines were isolated using the 50 ␮M 2-ME).
Load more

Recommended publications
  • Targeting Il13ralpha2 Activates STAT6-TP63 Pathway to Suppress Breast Cancer Lung Metastasis Panagiotis Papageorgis1,2,3*, Sait Ozturk2, Arthur W
    Papageorgis et al. Breast Cancer Research (2015) 17:98 DOI 10.1186/s13058-015-0607-y RESEARCH ARTICLE Open Access Targeting IL13Ralpha2 activates STAT6-TP63 pathway to suppress breast cancer lung metastasis Panagiotis Papageorgis1,2,3*, Sait Ozturk2, Arthur W. Lambert2, Christiana M. Neophytou1, Alexandros Tzatsos4, Chen K. Wong2, Sam Thiagalingam2*† and Andreas I. Constantinou1*† Abstract Introduction: Basal-like breast cancer (BLBC) is an aggressive subtype often characterized by distant metastasis, poor patient prognosis, and limited treatment options. Therefore, the discovery of alternative targets to restrain its metastatic potential is urgently needed. In this study, we aimed to identify novel genes that drive metastasis of BLBC and to elucidate the underlying mechanisms of action. Methods: An unbiased approach using gene expression profiling of a BLBC progression model and in silico leveraging of pre-existing tumor transcriptomes were used to uncover metastasis-promoting genes. Lentiviral- mediated knockdown of interleukin-13 receptor alpha 2 (IL13Ralpha2) coupled with whole-body in vivo bioluminescence imaging was performed to assess its role in regulating breast cancer tumor growth and lung metastasis. Gene expression microarray analysis was followed by in vitro validation and cell migration assays to elucidate the downstream molecular pathways involved in this process. Results: We found that overexpression of the decoy receptor IL13Ralpha2 is significantly enriched in basal compared with luminal primary breast tumors as well as in a subset of metastatic basal-B breast cancer cells. Importantly, breast cancer patients with high-grade tumors and increased IL13Ralpha2 levels had significantly worse prognosis for metastasis-free survival compared with patients with low expression.
    [Show full text]
  • An Immunoevasive Strategy Through Clinically-Relevant Pan-Cancer Genomic and Transcriptomic Alterations of JAK-STAT Signaling Components
    bioRxiv preprint doi: https://doi.org/10.1101/576645; this version posted March 14, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. An immunoevasive strategy through clinically-relevant pan-cancer genomic and transcriptomic alterations of JAK-STAT signaling components Wai Hoong Chang1 and Alvina G. Lai1, 1Nuffield Department of Medicine, University of Oxford, Old Road Campus, Oxford, OX3 7FZ, United Kingdom Since its discovery almost three decades ago, the Janus ki- Although cytokines are responsible for inflammation in nase (JAK)-signal transducer and activator of transcription cancer, spontaneous eradication of tumors by endoge- (STAT) pathway has paved the road for understanding inflam- nous immune processes rarely occurs. Moreover, the matory and immunity processes related to a wide range of hu- dynamic interaction between tumor cells and host immu- man pathologies including cancer. Several studies have demon- nity shields tumors from immunological ablation, which strated the importance of JAK-STAT pathway components in overall limits the efficacy of immunotherapy in the clinic. regulating tumor initiation and metastatic progression, yet, the extent of how genetic alterations influence patient outcome is far from being understood. Focusing on 133 genes involved in Cytokines can be pro- or anti-inflammatory and are inter- JAK-STAT signaling, we found that copy number alterations dependent on each other’s function to maintain immune underpin transcriptional dysregulation that differs within and homeostasis(3).
    [Show full text]
  • The Effect of STAT5 on Inflammation-Related Gene Expression in Diabetic Mouse
    The Effect of STAT5 on Inflammation-Related Gene Expression in Diabetic Mouse Kidneys A thesis presented to the faculty of the College of Arts and Sciences of Ohio University In partial fulfillment of the requirements for the degree Master of Science Samantha J. Shaw May 2014 © 2014 Samantha J. Shaw. All Rights Reserved. 2 This thesis titled The Effect of STAT5 on Inflammation-Related Gene Expression in Diabetic Mouse Kidneys by SAMANTHA J. SHAW has been approved for the Department of Biological Sciences and the College of Arts and Sciences by Karen T. Coschigano Associate Professor of Biomedical Sciences Robert Frank Dean, College of Arts and Sciences 3 ABSTRACT SHAW, SAMANTHA J., M.S., May 2014, Biological Sciences The Effect of STAT5 on Inflammation-Related Gene Expression in Diabetic Mouse Kidneys Director of Thesis: Karen T. Coschigano Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and renal failure in humans. The molecular pathways that lead to DN are not well known. This research investigates possible roles of several signal transducers and activators of transcription (STAT) proteins in this disease using a STAT5A/B knockout (SKO) mouse model. Based on previous observations of increased inflammation-related gene expression in the kidneys of diabetic SKO mice, the hypothesis of the current project was that the combination of the loss of STAT5 repression and increase of STAT3 activity escalates inflammation-related gene expression in the kidneys of diabetic SKO mice. In support of this hypothesis, an increase of IRF-1 RNA expression, reflective of the loss of STAT5 repression, was observed in the kidneys of diabetic SKO mice.
    [Show full text]
  • Myeloid-Derived Suppressor Cell Development Is Regulated by a STAT/IRF-8 Axis
    Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis Jeremy D. Waight, … , Kebin Liu, Scott I. Abrams J Clin Invest. 2013;123(10):4464-4478. https://doi.org/10.1172/JCI68189. Research Article Immunology Myeloid-derived suppressor cells (MDSCs) comprise immature myeloid populations produced in diverse pathologies, including neoplasia. Because MDSCs can impair antitumor immunity, these cells have emerged as a significant barrier to cancer therapy. Although much research has focused on how MDSCs promote tumor progression, it remains unclear how MDSCs develop and why the MDSC response is heavily granulocytic. Given that MDSCs are a manifestation of aberrant myelopoiesis, we hypothesized that MDSCs arise from perturbations in the regulation of interferon regulatory factor–8 (IRF-8), an integral transcriptional component of myeloid differentiation and lineage commitment. Overall, we demonstrated that (a) Irf8-deficient mice generated myeloid populations highly homologous to tumor-induced MDSCs with respect to phenotype, function, and gene expression profiles; (b) IRF-8 overexpression in mice attenuated MDSC accumulation and enhanced immunotherapeutic efficacy; (c) the MDSC-inducing factors G-CSF and GM-CSF facilitated IRF-8 downregulation via STAT3- and STAT5-dependent pathways; and (d) IRF-8 levels in MDSCs of breast cancer patients declined with increasing MDSC frequency, implicating IRF-8 as a negative regulator in human MDSC biology. Together, our results reveal a previously unrecognized role for IRF-8 expression in MDSC subset development, which may provide new avenues to target MDSCs in neoplasia. Find the latest version: https://jci.me/68189/pdf Research article Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis Jeremy D.
    [Show full text]
  • Interferons Inhibit Activation of STAT6 by Interleukin 4 in Human Monocytes by Inducing SOCS-1 Gene Expression
    Proc. Natl. Acad. Sci. USA Vol. 96, pp. 10800–10805, September 1999 Immunology Interferons inhibit activation of STAT6 by interleukin 4 in human monocytes by inducing SOCS-1 gene expression HAROLD L. DICKENSHEETS*, CHANDRASEKAR VENKATARAMAN†,ULRIKE SCHINDLER†, AND RAYMOND P. DONNELLY*‡ *Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892; and †Tularik, Inc., South San Francisco, CA 94080 Edited by William E. Paul, National Institutes of Health, Bethesda, MD, and approved July 8, 1999 (received for review February 16, 1999) ABSTRACT Interferons (IFNs) inhibit induction by IL-4 12), 15-lipoxygenase (15-LO) (13, 14), IL-1 receptor antago- of multiple genes in human monocytes. However, the mecha- nist (IL-1ra) (15–17), and types I and II IL-1 receptors (IL-1R) nism by which IFNs mediate this inhibition has not been (18, 19). Type I IFNs (IFN-␣ and IFN-␤) and type II IFN defined. IL-4 activates gene expression by inducing tyrosine (IFN-␥) inhibit IL-4͞IL-13-induced gene expression in mono- phosphorylation, homodimerization, and nuclear transloca- cytes and B cells. For example, IFN-␥ suppresses IgE synthesis tion of the latent transcription factor, STAT6 (signal trans- by IL-4-stimulated B cells (20–22). IFNs also inhibit IL-4- ducer and activator of transcription-6). STAT6-responsive induced CD23 expression in both B cells (23, 24) and mono- elements are characteristically present in the promoters of cytes (25, 26). Furthermore, IFN-␥ inhibits IL-4- and IL-13- IL-4-inducible genes. Because STAT6 activation is essential induced expression of 15-LO and IL-1ra in monocytes (13, 14, for IL-4-induced gene expression, we examined the ability of 27).
    [Show full text]
  • Modulation of STAT Signaling by STAT-Interacting Proteins
    Oncogene (2000) 19, 2638 ± 2644 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Modulation of STAT signaling by STAT-interacting proteins K Shuai*,1 1Departments of Medicine and Biological Chemistry, University of California, Los Angeles, California, CA 90095, USA STATs (signal transducer and activator of transcription) play important roles in numerous cellular processes Interaction with non-STAT transcription factors including immune responses, cell growth and dierentia- tion, cell survival and apoptosis, and oncogenesis. In Studies on the promoters of a number of IFN-a- contrast to many other cellular signaling cascades, the induced genes identi®ed a conserved DNA sequence STAT pathway is direct: STATs bind to receptors at the named ISRE (interferon-a stimulated response element) cell surface and translocate into the nucleus where they that mediates IFN-a response (Darnell, 1997; Darnell function as transcription factors to trigger gene activa- et al., 1994). Stat1 and Stat2, the ®rst known members tion. However, STATs do not act alone. A number of of the STAT family, were identi®ed in the transcription proteins are found to be associated with STATs. These complex ISGF-3 (interferon-stimulated gene factor 3) STAT-interacting proteins function to modulate STAT that binds to ISRE (Fu et al., 1990, 1992; Schindler et signaling at various steps and mediate the crosstalk of al., 1992). ISGF-3 consists of a Stat1:Stat2 heterodimer STATs with other cellular signaling pathways. This and a non-STAT protein named p48, a member of the article reviews the roles of STAT-interacting proteins in IRF (interferon regulated factor) family (Levy, 1997).
    [Show full text]
  • Batf3 and Id2 Have a Synergistic Effect on Irf8-Directed Classical Cd8α+ Dendritic Cell Development
    Batf3 and Id2 Have a Synergistic Effect on Irf8-Directed Classical CD8α+ Dendritic Cell Development This information is current as Hemant Jaiswal, Monika Kaushik, Rachid Sougrat, Monica of October 3, 2021. Gupta, Anup Dey, Rohit Verma, Keiko Ozato and Prafullakumar Tailor J Immunol 2013; 191:5993-6001; Prepublished online 13 November 2013; doi: 10.4049/jimmunol.1203541 http://www.jimmunol.org/content/191/12/5993 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2013/11/13/jimmunol.120354 Material 1.DC1 http://www.jimmunol.org/ References This article cites 57 articles, 38 of which you can access for free at: http://www.jimmunol.org/content/191/12/5993.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 3, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Batf3 and Id2 Have a Synergistic Effect on Irf8-Directed Classical CD8a+ Dendritic Cell Development Hemant Jaiswal,* Monika Kaushik,* Rachid Sougrat,† Monica Gupta,‡ Anup Dey,‡ Rohit Verma,* Keiko Ozato,‡ and Prafullakumar Tailor* Dendritic cells (DCs) are heterogeneous cell populations represented by different subtypes, each varying in terms of gene expression patterns and specific functions.
    [Show full text]
  • STAT6-Dependent Fashion CCL23 Expression Is Induced by IL-4 in A
    CCL23 Expression Is Induced by IL-4 in a STAT6-Dependent Fashion Hermann Novak, Anke Müller, Nathalie Harrer, Claudia Günther, Jose M. Carballido and Maximilian Woisetschläger This information is current as of September 28, 2021. J Immunol 2007; 178:4335-4341; ; doi: 10.4049/jimmunol.178.7.4335 http://www.jimmunol.org/content/178/7/4335 Downloaded from References This article cites 47 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/178/7/4335.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 28, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology CCL23 Expression Is Induced by IL-4 in a STAT6-Dependent Fashion Hermann Novak, Anke Mu¨ller, Nathalie Harrer, Claudia Gu¨nther, Jose M. Carballido, and Maximilian Woisetschla¨ger1 The chemokine CCL23 is primarily expressed in cells of the myeloid lineage but little information about its regulation is available.
    [Show full text]
  • Mutation of Thyroid Hormone Receptor-&Beta
    Oncogene (2011) 30, 3381–3390 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc ORIGINAL ARTICLE Mutation of thyroid hormone receptor-b in mice predisposes to the development of mammary tumors CJ Guigon1, DW Kim1, MC Willingham2 and S-y Cheng1 1Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA and 2Department of Pathology, Wake Forest University, Winston-Salem, NC, USA Correlative data suggest that thyroid hormone receptor-b Introduction (TRb) mutations could increase the risk of mammary tumor development, but unequivocal evidence is still Thyroid hormone receptors (TRs) belong to the lacking. To explore the role of TRb mutants in vivo in superfamily of nuclear receptors that are ligand- breast tumor development and progression, we took dependent transcription factors. Two TR genes, THRA advantage of a knock-in mouse model harboring a and THRB, located on chromosomes 17 and 3, respec- mutation in the Thrb gene encoding TRb (ThrbPV mouse). tively, encode four thyroid hormone (T3)-binding Although in adult nulliparous females, a single ThrbPV receptors: TRa1, TRb1, TRb2 and TRb3. They bind allele did not contribute to mammary gland abnormalities, T3 that has critical roles in differentiation, growth and the presence of two ThrbPV alleles led to mammary metabolism (Yen, 2001). hyperplasia in B36% ThrbPV/PV mice. The ThrbPV Several findings support the notion that mutations of mutation further markedly augmented the risk of TRs can be associated with cancer. Early evidence mammary hyperplasia in a mouse model with high suggested that mutated TRs could be involved in susceptibility to mammary tumors (Pten þ /À mouse), as carcinogenesis came from the discovery that v-erbA, a demonstrated by the occurrence of mammary hyperplasia highly mutated chicken THRA1 that has lost the ability in B60% of ThrbPV/ þ Pten þ /À and B77% of ThrbPV/PV to activate gene transcription, leads to neoplastic trans- Pten þ /À mice versus B33% of Thrb þ / þ Pten þ /À mice.
    [Show full text]
  • Allen Gao, M.D., Ph.D
    Allen Gao, M.D., Ph.D. Research/Academic Interests Dr. Gao’s research interests focus on understanding molecular mechanisms associated with progression of castration-resistant prostate cancer and metastasis to bone with the goal of identification of potential therapeutic targets for prostate cancer. Particular emphasis includes microRNAs, aberrant androgen receptor activation by cytokines and transcriptional factors such as Stat3 and NF-kB, targeting cell signaling pathways (AR, IL-6 and Stat3), and mechanisms of drug resistance in prostate cancer. Dr. Gao’s lab was among the first to find that selenium regulates androgen signaling and that IL-4 activates the androgen receptor mediated by NF-B and Stat6, made the discovery that IL-6 signaling in prostate cancer involves Stat3, defined Stat3 and NF-B interactions in prostate cancer, discovered niclosamide as a novel inhibitor of androgen receptor variants (AR-V7), and identified several novel resistance mechanisms to enzalutamide/abiraterone/docetaxel including p52, IL- 6/Stat3, intracrine androgens/AKR1C3, and ABCB1. Dr. Gao has published over 100 peer-reviewed articles in the area of prostate cancer. His research findings such as the discovery of niclosamide as a novel inhibitor of androgen receptor variants have translated into several clinical trials (NCT02807805, NCT03123978) that test the combination treatments with current therapies to advanced resistant prostate cancer. Another recent discovery of indomethacin as an inhibitor of AKR1C3 and synergizing enzalutamide has also translated into clinical trial (NCT02935205) to test the combination treatments with current therapies to advanced resistant prostate cancer. Dr. Gao has served numerous NIH, NCI, DOD and VA merits, and American Cancer Society (ACS) review panels including SPORE and PPG study sections.
    [Show full text]
  • Locus IL-10 Enhancer in the Through a STAT5-Responsive Intronic Regulatory T Cells Is Enhanced by IL-2 the Production of IL-10 B
    The Production of IL-10 by Human Regulatory T Cells Is Enhanced by IL-2 through a STAT5-Responsive Intronic Enhancer in the IL-10 Locus This information is current as of September 26, 2021. Kazue Tsuji-Takayama, Motoyuki Suzuki, Mayuko Yamamoto, Akira Harashima, Ayumi Okochi, Takeshi Otani, Toshiya Inoue, Akira Sugimoto, Terumasa Toraya, Makoto Takeuchi, Fumiyuki Yamasaki, Shuji Nakamura and Masayoshi Kibata Downloaded from J Immunol 2008; 181:3897-3905; ; doi: 10.4049/jimmunol.181.6.3897 http://www.jimmunol.org/content/181/6/3897 http://www.jimmunol.org/ References This article cites 51 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/181/6/3897.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 26, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767
    [Show full text]
  • STAT6 Nuclear Trafficking Live Cell Imaging Reveals Continuous
    Live Cell Imaging Reveals Continuous STAT6 Nuclear Trafficking Hui-Chen Chen and Nancy C. Reich This information is current as J Immunol 2010; 185:64-70; Prepublished online 24 May of September 24, 2021. 2010; doi: 10.4049/jimmunol.0903323 http://www.jimmunol.org/content/185/1/64 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2010/05/21/jimmunol.090332 Material 3.DC1 References This article cites 42 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/185/1/64.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 24, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Live Cell Imaging Reveals Continuous STAT6 Nuclear Trafficking Hui-Chen Chen and Nancy C. Reich The STAT6 transcription factor is essential for the development of protective immunity; however, the consequences of its activity can also contribute to the pathogenesis of autoimmune disease.
    [Show full text]