title: Transcriptome analysis of tetraploid cells identifies cyclin D2 as a facilitator of adaptation to genome doubling in the presence of p53.
abstract: Tetraploidization, or genome doubling, is a prominent event in tumorigenesis, primarily because cell division in polyploid cells is error-prone and produces aneuploid cells. This study investigates changes in gene expression evoked in acute and adapted tetraploid cells and their effect on cell-cycle progression. Acute polyploidy was generated by knockdown of the essential regulator of cytokinesis anillin, which resulted in cytokinesis failure and formation of binucleate cells, or by chemical inhibition of Aurora kinases, causing abnormal mitotic exit with formation of single cells with aberrant nuclear morphology. Transcriptome analysis of these acute tetraploid cells revealed common signatures of activation of the tumor-suppressor protein p53. Suppression of proliferation in these cells was dependent on p53 and its transcriptional target, CDK inhibitor p21. Rare proliferating tetraploid cells can emerge from acute polyploid populations. Gene expression analysis of single cell-derived, adapted tetraploid clones showed up-regulation of several p53 target genes and cyclin D2, the activator of CDK4/6/2. Overexpression of cyclin D2 in diploid cells strongly potentiated the ability to proliferate with increased DNA content despite the presence of functional p53. These results indicate that p53-mediated suppression of proliferation of polyploid cells can be averted by increased levels of oncogenes such as cyclin D2, elucidating a possible route for tetraploidy-mediated genomic instability in carcinogenesis.
authors: Stowers Institute for Medical Research, Kansas City, MO 64110 tpo@stowers.org.
authors: Tamara A
authors: TA
authors: Potapova
authors: Stowers Institute for Medical Research, Kansas City, MO 64110.
authors: Christopher W
authors: CW
authors: Seidel
authors: Stowers Institute for Medical Research, Kansas City, MO 64110.
authors: Andrew C
authors: AC
authors: Box
authors: Institute of Medical Biology, Agency for Science, Technology and Research, Singapore 138648, Singapore.
authors: Giulia
authors: G
authors: Rancati
authors: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors: Rong
authors: R
authors: Li
mesh_terms: D002453:Cell Cycle; D002455:Cell Division; D003285:Contractile Proteins / Q000378:metabolism; D056742:Cyclin D2 / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D048749:Cytokinesis / Q000502:physiology; D004261:DNA Replication; D020869:Gene Expression Profiling / Q000379:methods; D016158:Genes, p53; D016678:Genome; D011123:Polyploidy; D057891:Tetraploidy; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D003285:Contractile Proteins; D056742:Cyclin D2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; C095886:anillin