Author/Authors :
Gogolin، نويسنده , , Sina and Batra، نويسنده , , Richa and Harder، نويسنده , , Nathalie and Ehemann، نويسنده , , Volker and Paffhausen، نويسنده , , Tobias and Diessl، نويسنده , , Nicolle and Sagulenko، نويسنده , , Vitaliya and Benner، نويسنده , , Axel and Gade، نويسنده , , Stephan and Nolte، نويسنده , , Ingo and Rohr، نويسنده , , Karl and Kِnig، نويسنده , , Rainer and Westermann، نويسنده , , Frank، نويسنده ,
Abstract :
High-risk neuroblastomas often harbor structural chromosomal alterations, including amplified MYCN, and usually have a near-di/tetraploid DNA index, but the mechanisms creating tetraploidy remain unclear. Gene-expression analyses revealed that certain MYCN/MYC and p53/pRB-E2F target genes, especially regulating mitotic processes, are strongly expressed in near-di/tetraploid neuroblastomas. Using a functional RNAi screening approach and live-cell imaging, we identified a group of genes, including MAD2L1, which after knockdown induced mitotic-linked cell death in MYCN-amplified and TP53-mutated neuroblastoma cells. We found that MYCN/MYC-mediated overactivation of the metaphase–anaphase checkpoint synergizes with loss of p53-p21 function to prevent arrest or apoptosis of tetraploid neuroblastoma cells.
Keywords :
Genomic instability , Aneuploidy specific lethality genes , p53 , pRb , Mitotic catastrophe
