title: The BTB-zinc finger transcription factor abrupt acts as an epithelial oncogene in Drosophila melanogaster through maintaining a progenitor-like cell state.
abstract: The capacity of tumour cells to maintain continual overgrowth potential has been linked to the commandeering of normal self-renewal pathways. Using an epithelial cancer model in Drosophila melanogaster, we carried out an overexpression screen for oncogenes capable of cooperating with the loss of the epithelial apico-basal cell polarity regulator, scribbled (scrib), and identified the cell fate regulator, Abrupt, a BTB-zinc finger protein. Abrupt overexpression alone is insufficient to transform cells, but in cooperation with scrib loss of function, Abrupt promotes the formation of massive tumours in the eye/antennal disc. The steroid hormone receptor coactivator, Taiman (a homologue of SRC3/AIB1), is known to associate with Abrupt, and Taiman overexpression also drives tumour formation in cooperation with the loss of Scrib. Expression arrays and ChIP-Seq indicates that Abrupt overexpression represses a large number of genes, including steroid hormone-response genes and multiple cell fate regulators, thereby maintaining cells within an epithelial progenitor-like state. The progenitor-like state is characterised by the failure to express the conserved Eyes absent/Dachshund regulatory complex in the eye disc, and in the antennal disc by the failure to express cell fate regulators that define the temporal elaboration of the appendage along the proximo-distal axis downstream of Distalless. Loss of scrib promotes cooperation with Abrupt through impaired Hippo signalling, which is required and sufficient for cooperative overgrowth with Abrupt, and JNK (Jun kinase) signalling, which is required for tumour cell migration/invasion but not overgrowth. These results thus identify a novel cooperating oncogene, identify mammalian family members of which are also known oncogenes, and demonstrate that epithelial tumours in Drosophila can be characterised by the maintenance of a progenitor-like state.
authors.affiliation: Cell Cycle and Development Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Nezaket
authors.initials: N
authors.lastname: Turkel
authors.forename: Virender K
authors.initials: VK
authors.lastname: Sahota
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Bolden
authors.forename: Karen R
authors.initials: KR
authors.lastname: Goulding
authors.forename: Karen
authors.initials: K
authors.lastname: Doggett
authors.forename: Lee F
authors.initials: LF
authors.lastname: Willoughby
authors.forename: Enrique
authors.initials: E
authors.lastname: Blanco
authors.forename: Enrique
authors.initials: E
authors.lastname: Martin-Blanco
authors.forename: Montserrat
authors.initials: M
authors.lastname: Corominas
authors.forename: Jason
authors.initials: J
authors.lastname: Ellul
authors.forename: Toshiro
authors.initials: T
authors.lastname: Aigaki
authors.forename: Helena E
authors.initials: HE
authors.lastname: Richardson
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Brumby
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D049109:Cell Proliferation; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics*; D005134:Eye Neoplasms / Q000235:genetics / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008565:Membrane Proteins; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D016759:Oncogene Protein p65(gag-jun) / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D016759:Oncogene Protein p65(gag-jun); D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C404683:Scrib protein, Drosophila; C422002:TAI protein, Drosophila; C531978:ab protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases