title: The tumour suppressor L(3)mbt inhibits neuroepithelial proliferation and acts on insulator elements.
abstract: In Drosophila, defects in asymmetric cell division often result in the formation of stem-cell-derived tumours. Here, we show that very similar terminal brain tumour phenotypes arise through a fundamentally different mechanism. We demonstrate that brain tumours in l(3)mbt mutants originate from overproliferation of neuroepithelial cells in the optic lobes caused by derepression of target genes in the Salvador-Warts-Hippo (SWH) pathway. We use ChIP-sequencing to identify L(3)mbt binding sites and show that L(3)mbt binds to chromatin insulator elements. Mutating l(3)mbt or inhibiting expression of the insulator protein gene mod(mdg4) results in upregulation of SWH pathway reporters. As l(3)mbt tumours are rescued by mutations in bantam or yorkie or by overexpression of Expanded, the deregulation of SWH pathway target genes is an essential step in brain tumour formation. Therefore, very different primary defects result in the formation of brain tumours, which behave quite similarly in their advanced stages.
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Science, Dr. Bohr-Gasse 3, 1030 Vienna, Austria.
authors.forename: Constance
authors.initials: C
authors.lastname: Richter
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Oktaba
authors.forename: Jonas
authors.initials: J
authors.lastname: Steinmann
authors.forename: Jürg
authors.initials: J
authors.lastname: Müller
authors.forename: Juergen A
authors.initials: JA
authors.lastname: Knoblich
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D038101:Insulator Elements / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009154:Mutation; D046569:Neuroepithelial Cells / Q000166:cytology / Q000378:metabolism; D009899:Optic Lobe, Nonmammalian / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA / Q000379:methods; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C555103:l(3)mbt protein, Drosophila; C101384:mod(mdg4) protein, Drosophila; C465504:sav protein, Drosophila; C093503:wts protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases