RRC ID 28075
Author Turkel N, Sahota VK, Bolden JE, Goulding KR, Doggett K, Willoughby LF, Blanco E, Martin-Blanco E, Corominas M, Ellul J, Aigaki T, Richardson HE, Brumby AM.
Title The BTB-zinc finger transcription factor abrupt acts as an epithelial oncogene in Drosophila melanogaster through maintaining a progenitor-like cell state.
Journal PLoS Genet
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.
Volume 9(7)
Pages e1003627
Published 2013-7-18
DOI 10.1371/journal.pgen.1003627
PII PGENETICS-D-13-00022
PMID 23874226
PMC PMC3715428
MeSH Animals Carcinogenesis* Cell Proliferation Disease Models, Animal Drosophila Proteins / genetics* Drosophila Proteins / metabolism Drosophila melanogaster / genetics* Eye Neoplasms / genetics Eye Neoplasms / pathology Humans Intracellular Signaling Peptides and Proteins / genetics Intracellular Signaling Peptides and Proteins / metabolism MAP Kinase Signaling System / genetics* Membrane Proteins Neoplasms, Experimental / genetics Neoplasms, Experimental / pathology Neoplasms, Glandular and Epithelial / genetics* Neoplasms, Glandular and Epithelial / pathology Nuclear Proteins / genetics* Nuclear Proteins / metabolism Oncogene Protein p65(gag-jun) / genetics Oncogene Protein p65(gag-jun) / metabolism Protein-Serine-Threonine Kinases / genetics Protein-Serine-Threonine Kinases / metabolism Transcription Factors / genetics Transcription Factors / metabolism Tumor Suppressor Proteins / genetics Tumor Suppressor Proteins / metabolism
IF 5.224
Times Cited 21
WOS Category GENETICS & HEREDITY
Resource
Drosophila 12072R-1 GS lines