title: Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway.
abstract: Tle1 (transducin-like enhancer of split 1) is a corepressor that interacts with a variety of DNA-binding transcription factors and has been implicated in many cellular functions; however, physiological studies are limited. Tle1-deficient (Tle1(Δ/Δ)) mice, although grossly normal at birth, exhibit skin defects, lung hypoplasia, severe runting, poor body condition, and early mortality. Tle1(Δ/Δ) mice display a chronic inflammatory phenotype with increased expression of inflammatory cytokines and chemokines in the skin, lung, and intestine and increased circulatory IL-6 and G-CSF, along with a hematopoietic shift toward granulocyte macrophage progenitor and myeloid cells. Tle1(Δ/Δ) macrophages produce increased inflammatory cytokines in response to Toll-like receptor (TLR) agonists and lipopolysaccharides (LPS), and Tle1(Δ/Δ) mice display an enhanced inflammatory response to ear skin 12-O-tetradecanoylphorbol-13-acetate treatment. Loss of Tle1 not only results in increased phosphorylation and activation of proinflammatory NF-κB but also results in decreased Hes1 (hairy and enhancer of split-1), a negative regulator of inflammation in macrophages. Furthermore, Tle1(Δ/Δ) mice exhibit accelerated growth of B6-F10 melanoma xenografts. Our work provides the first in vivo evidence, to our knowledge, that TLE1 is a major counterregulator of inflammation with potential roles in a variety of inflammatory diseases and in cancer progression.
authors.affiliation: Department of Pediatrics, Divisions of Medical Genetics and Pediatric Hematology/Oncology, MassGeneral Hospital for Children, Center for Human Genetics Research and MGH Cancer Center, Massachusetts General Hospital, Boston, MA 02114; dsweetser@mgh.harvard.edu sramasamy2@partners.org.
authors.forename: Selvi
authors.initials: S
authors.lastname: Ramasamy
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138; Harvard Stem Cell Institute, Cambridge, MA 02138;
authors.forename: Borja
authors.initials: B
authors.lastname: Saez
authors.affiliation: Microbial Pathogenesis Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Subhankar
authors.initials: S
authors.lastname: Mukhopadhyay
authors.affiliation: Department of Pediatrics, Divisions of Medical Genetics and Pediatric Hematology/Oncology, MassGeneral Hospital for Children, Center for Human Genetics Research and MGH Cancer Center, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Daching
authors.initials: D
authors.lastname: Ding
authors.affiliation: Department of Pediatric Surgery, MassGeneral Hospital for Children, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Alwiya M
authors.initials: AM
authors.lastname: Ahmed
authors.affiliation: Department of Pediatrics, Divisions of Medical Genetics and Pediatric Hematology/Oncology, MassGeneral Hospital for Children, Center for Human Genetics Research and MGH Cancer Center, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Pucci
authors.affiliation: Department of Pediatrics, Divisions of Medical Genetics and Pediatric Hematology/Oncology, MassGeneral Hospital for Children, Center for Human Genetics Research and MGH Cancer Center, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Rae'e
authors.initials: R
authors.lastname: Yamin
authors.affiliation: Department of Pediatrics, Divisions of Medical Genetics and Pediatric Hematology/Oncology, MassGeneral Hospital for Children, Center for Human Genetics Research and MGH Cancer Center, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Mikael J
authors.initials: MJ
authors.lastname: Pittet
authors.affiliation: Department of Pediatric Surgery, MassGeneral Hospital for Children, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Cassandra M
authors.initials: CM
authors.lastname: Kelleher
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138; Harvard Stem Cell Institute, Cambridge, MA 02138;
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.affiliation: Department of Pediatrics, Divisions of Medical Genetics and Pediatric Hematology/Oncology, MassGeneral Hospital for Children, Center for Human Genetics Research and MGH Cancer Center, Massachusetts General Hospital, Boston, MA 02114; dsweetser@mgh.harvard.edu sramasamy2@partners.org.
authors.forename: David A
authors.initials: DA
authors.lastname: Sweetser
mesh_terms: D000818:Animals; D056970:Co-Repressor Proteins / Q000235:genetics / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*
chemical_list: D056970:Co-Repressor Proteins; D016328:NF-kappa B; C434946:Tle1 protein, mouse
keywords: HES1; NF-κB; TLE1; inflammation; tumor suppressor
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