Gene Dosage Imbalance Contributes to Chromosomal Instability-Induced Tumorigenesis
| Autor: | Marta Clemente-Ruiz, Lidia Pérez, Juan Manuel Murillo-Maldonado, Lara Barrio, Gonzalo Quiroga, Najate Benhra, Marco Milán, Angel R. Nebreda |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Programmed cell death DNA Repair DNA damage Cell Gene Dosage Aneuploidy Apoptosis Biology medicine.disease_cause Gene dosage General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Chromosome instability Chromosomal Instability medicine Animals aneuploidy Molecular Biology Dosage compensation ROS Cell Biology medicine.disease Molecular biology female genital diseases and pregnancy complications Cell biology 030104 developmental biology medicine.anatomical_structure Cell Transformation Neoplastic Drosophila melanogaster dosage compensation Carcinogenesis Reactive Oxygen Species Developmental Biology |
| Zdroj: | Developmental Cell. 36(3):290-302 |
| ISSN: | 1534-5807 |
| DOI: | 10.1016/j.devcel.2016.01.008 |
| Popis: | SummaryChromosomal 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. |
| Databáze: | OpenAIRE |
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