title: Tumor suppressor roles of CENP-E and Nsl1 in Drosophila epithelial tissues.
abstract: Depletion of spindle assembly checkpoint (SAC) genes in Drosophila epithelial tissues leads to JNK-dependent programmed cell death and additional blockade of the apoptotic program drives tumorigenesis. A recent report proposes that chromosomal instability (CIN) is not the driving force in the tumorigenic response of the SAC-deficient tissue, and that checkpoint proteins exert a SAC-independent tumor suppressor role. This notion is based on observations that the depletion of CENP-E levels or prevention of Bub3 from binding to the kinetochore in Drosophila tissues unable to activate the apoptotic program induces CIN but does not cause hyperproliferation. Here we re-examined this proposal. In contrast to the previous report, we observed that depletion of CENP-E or Nsl1-the latter mediating kinetochore targeting of Bub3-in epithelial tissues unable to activate the apoptotic program induces significant levels of aneuploidy and drives tumor-like growth. The induction of the JNK transcriptional targets Wingless, a mitogenic molecule, and MMP1, a matrix metaloproteinase 1 involved in basement membrane degradation was also observed in these tumors. An identical response of the tissue was previously detected upon depletion of several SAC genes or genes involved in spindle assembly, chromatin condensation, and cytokinesis, all of which have been described to cause CIN. All together, these results reinforce the role of CIN in driving tumorigenesis in Drosophila epithelial tissues and question the proposed SAC-independent roles of checkpoint proteins in suppressing tumorigenesis. Differences in aneuploidy rates might explain the discrepancy between the previous report and our results.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona); Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Clemente-Ruiz
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona); Barcelona, Spain.
authors.forename: Mariana
authors.initials: M
authors.lastname: Muzzopappa
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona); Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA); Barcelona, Spain.
authors.forename: Marco
authors.initials: M
authors.lastname: Milán
mesh_terms: D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004330:Drosophila / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D009687:Nuclear Proteins; D008941:Spindle Apparatus / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D033921:Vesicular Transport Proteins; D051155:Wnt1 Protein / Q000378:metabolism
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D029721:Drosophila Proteins; C553663:NSL1 protein, Drosophila; D009687:Nuclear Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D033921:Vesicular Transport Proteins; D051155:Wnt1 Protein; C068688:centromere protein E; C074622:wg protein, Drosophila; D020781:Matrix Metalloproteinase 1
keywords: CIN; JNK; mitotic checkpoint; tumorigenesis