title: Tubulin glycylases are required for primary cilia, control of cell proliferation and tumor development in colon.
abstract: TTLL3 and TTLL8 are tubulin glycine ligases catalyzing posttranslational glycylation of microtubules. We show here for the first time that these enzymes are required for robust formation of primary cilia. We further discover the existence of primary cilia in colon and demonstrate that TTLL3 is the only glycylase in this organ. As a consequence, colon epithelium shows a reduced number of primary cilia accompanied by an increased rate of cell division in TTLL3-knockout mice. Strikingly, higher proliferation is compensated by faster tissue turnover in normal colon. In a mouse model for tumorigenesis, lack of TTLL3 strongly promotes tumor development. We further demonstrate that decreased levels of TTLL3 expression are linked to the development of human colorectal carcinomas. Thus, we have uncovered a novel role for tubulin glycylation in primary cilia maintenance, which controls cell proliferation of colon epithelial cells and plays an essential role in colon cancer development.
authors.affiliation: Institut Curie, Orsay, France PSL Research University, Paris, France CNRS UMR3306, Orsay, France INSERM U1005, Orsay, France IGMM CNRS UMR5535, Montpellier, France Université Montpellier Sud de France, Montpellier, France.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Rocha
authors.affiliation: IGMM CNRS UMR5535, Montpellier, France Université Montpellier Sud de France, Montpellier, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Papon
authors.affiliation: Institut Curie Hospital, Paris, France.
authors.forename: Wulfran
authors.initials: W
authors.lastname: Cacheux
authors.affiliation: Institut Curie, Orsay, France PSL Research University, Paris, France CNRS UMR3306, Orsay, France INSERM U1005, Orsay, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Marques Sousa
authors.affiliation: Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Valeria
authors.initials: V
authors.lastname: Lascano
authors.affiliation: Institut Curie, Orsay, France PSL Research University, Paris, France CNRS UMR3306, Orsay, France INSERM U1005, Orsay, France Institut de Biotecnologia i de Biomedicina, Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.
authors.forename: Olivia
authors.initials: O
authors.lastname: Tort
authors.affiliation: Institut Curie, Orsay, France PSL Research University, Paris, France CNRS UMR3306, Orsay, France INSERM U1005, Orsay, France.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Giordano
authors.affiliation: Institut Curie Hospital, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Vacher
authors.affiliation: IGMM CNRS UMR5535, Montpellier, France Université Montpellier Sud de France, Montpellier, France.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Lemmers
authors.affiliation: Institut Curie Hospital, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Mariani
authors.affiliation: Institut Curie Hospital, Paris, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Meseure
authors.affiliation: Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: Medema
authors.affiliation: Institut Curie Hospital, Paris, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.affiliation: IGMM CNRS UMR5535, Montpellier, France Université Montpellier Sud de France, Montpellier, France Academic Medical Center, Amsterdam, The Netherlands carsten.janke@curie.fr hahne@igmm.cnrs.fr.
authors.forename: Michael
authors.initials: M
authors.lastname: Hahne
authors.affiliation: Institut Curie, Orsay, France PSL Research University, Paris, France CNRS UMR3306, Orsay, France INSERM U1005, Orsay, France carsten.janke@curie.fr hahne@igmm.cnrs.fr.
authors.forename: Carsten
authors.initials: C
authors.lastname: Janke
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation; D002478:Cells, Cultured; D002923:Cilia / Q000378:metabolism*; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005998:Glycine / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism; D010453:Peptide Synthases / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014404:Tubulin / Q000502:physiology*
chemical_list: D002273:Carcinogens; D012333:RNA, Messenger; D014404:Tubulin; D010453:Peptide Synthases; D005998:Glycine
keywords: colorectal cancer; microtubule glycylation; primary cilia; proliferation; tubulin posttranslational modification