title: The LSD1 Family of Histone Demethylases and the Pumilio Posttranscriptional Repressor Function in a Complex Regulatory Feedback Loop.
abstract: The lysine (K)-specific demethylase (LSD1) family of histone demethylases regulates chromatin structure and the transcriptional potential of genes. LSD1 is frequently deregulated in tumors, and depletion of LSD1 family members causes developmental defects. Here, we report that reductions in the expression of the Pumilio (PUM) translational repressor complex enhanced phenotypes due to dLsd1 depletion in Drosophila. We show that the PUM complex is a target of LSD1 regulation in fly and mammalian cells and that its expression is inversely correlated with LSD1 levels in human bladder carcinoma. Unexpectedly, we find that PUM posttranscriptionally regulates LSD1 family protein levels in flies and human cells, indicating the existence of feedback loops between the LSD1 family and the PUM complex. Our results highlight a new posttranscriptional mechanism regulating LSD1 activity and suggest that the feedback loop between the LSD1 family and the PUM complex may be functionally important during development and in human malignancies.
authors.affiliation: Laboratory of Molecular Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Wayne O
authors.initials: WO
authors.lastname: Miles
authors.affiliation: LBCMCP, Université Paul Sabatier, CNRS, Toulouse, France.
authors.forename: Julie M J
authors.initials: JM
authors.lastname: Lepesant
authors.affiliation: LBCMCP, Université Paul Sabatier, CNRS, Toulouse, France.
authors.forename: Jessie
authors.initials: J
authors.lastname: Bourdeaux
authors.affiliation: LBCMCP, Université Paul Sabatier, CNRS, Toulouse, France.
authors.forename: Manuela
authors.initials: M
authors.lastname: Texier
authors.affiliation: Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Kerenyi
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakakido
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hamamoto
authors.affiliation: Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.affiliation: Laboratory of Molecular Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Dyson
authors.affiliation: LBCMCP, Université Paul Sabatier, CNRS, Toulouse, France luisa.di-stefano@univ-tlse3.fr.
authors.forename: Luisa
authors.initials: L
authors.lastname: Di Stefano
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004330:Drosophila; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000378:metabolism*; D025461:Feedback, Physiological; D006367:HeLa Cells; D056466:Histone Demethylases / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C412783:brat protein, Drosophila; C074333:pum protein, Drosophila; C070574:nos protein, Drosophila; D056466:Histone Demethylases; C524804:Lsd-1 protein, Drosophila; D010089:Oxidoreductases, N-Demethylating