RRC ID 35957
著者 Clemente-Ruiz M, Murillo-Maldonado JM, Benhra N, Barrio L, Pérez L, Quiroga G, Nebreda AR, Milán M.
タイトル Gene Dosage Imbalance Contributes to Chromosomal Instability-Induced Tumorigenesis.
ジャーナル Dev Cell
Abstract Chromosomal instability (CIN) is thought to be a source of mutability in cancer. However, CIN often results in aneuploidy, which compromises cell fitness. Here, we used the dosage compensation mechanism (DCM) of Drosophila to demonstrate that chromosome-wide gene dosage imbalance contributes to the deleterious effects of CIN-induced aneuploidy and its pro-tumorigenic action. We present evidence that resetting of the DCM counterbalances the damaging effects caused by CIN-induced changes in X chromosome number. Importantly, interfering with the DCM suffices to mimic the cellular effects of aneuploidy in terms of reactive oxygen species (ROS) production, JNK-dependent cell death, and tumorigenesis upon apoptosis inhibition. We unveil a role of ROS in JNK activation and a variety of cellular and tissue-wide mechanisms that buffer the deleterious effects of CIN, including DNA-damage repair, activation of the p38 pathway, and cytokine induction to promote compensatory proliferation. Our data reveal the existence of robust compensatory mechanisms that counteract CIN-induced cell death and tumorigenesis.
巻・号 36(3)
ページ 290-302
公開日 2016-2-8
DOI 10.1016/j.devcel.2016.01.008
PII S1534-5807(16)00042-3
PMID 26859353
MeSH Aneuploidy Animals Apoptosis / genetics Cell Transformation, Neoplastic / genetics* Chromosomal Instability / genetics* DNA Repair / genetics Drosophila melanogaster Gene Dosage / genetics Reactive Oxygen Species / metabolism
IF 10.092
引用数 22
WOS 分野 DEVELOPMENTAL BIOLOGY CELL BIOLOGY
リソース情報
ショウジョウバエ 7393R-3 3749R-2