Disease relevance of Polyploidy

• A novel protein kinase, polyploidy-associated protein kinase (PAPK), was isolated using a subtraction cDNA library approach from a mouse erythroleukemia cell line that had been induced to polyploidy after serum withdrawal [1].
• The ability of propranolol to inhibit the development of polyploidy in aortic vascular smooth muscle cells associated with hypertension was studied in deoxycorticosterone (DOC)-salt treated rats [2].
• In the pharmacological study, treatment with losartan alone, perindopril alone, or perindopril in combination with N(G)-nitro-L-arginine methyl ester prevented the development of smooth muscle polyploidy and cardiac hypertrophy [3].
• Ang II infusion induced cardiac hypertrophy and medial hypertrophy both in the aorta and in first-order mesenteric arterioles, accompanied by induction of smooth muscle polyploidy [4].
• Actively growing mouse or rat embryo cells suffered structural chromosome damage, mitotic anomalies, and polyploidy after infection by human adenovirus type 5 [5].

High impact information on Polyploidy

• Fertilized eggs from plu or png mutant mothers also have a mutant phenotype; DNA replication is uncoupled from nuclear division, resulting in giant, polyploid nuclei [6].
• Here we show that these hepatic nodules contain more mutant than wild-type Fah alleles, and that their hepatocytes express both donor and host genes, consistent with polyploid genome formation by fusion of host and donor cells [7].
• By screening for sterile mutants that show increased ploidy, we have identified a new gene, pop1+, in mutants that become polyploid [8].
• Our experiments support the view that oscillating levels of CycE control the polyploid S phase [9].
• In some esg mutants, the abdominal histoblasts become polyploid [10].

Chemical compound and disease context of Polyploidy

• When the development of hypertension was inhibited by treatment with enalapril, the incidence of polyploid cells remained low compared with untreated age-matched SHR [11].
• A hyperpolarizing response of 10-30 s duration was produced when bradykinin was iontophoretically applied onto polyploid rat glioma cells (clone C6-4-2) [12].
• Extracellular application of bradykinin and injection of inositol-1,4,5-trisphosphate (Ins-P3) induced a hyperpolarization in polyploid rat glioma cells [13].
• The relA gene product, ATP: GTP 3'-pyrophosphotransferase (stringent factor) has been isolated in homogeneous form from an Escherichia coli strain polyploid for this gene at a yield of 1 mg/100 g cells and at a specific activity in a ribosome-activated assay at 37 degrees C of 120 mumol guanosine pentaphosphate formed min-1 mg protein-1 [14].
• Segregation pattern of kanamycin resistance marker in Azotobacter vinelandii did not show the constraints expected in a polyploid bacterium [15].

Biological context of Polyploidy

• In larvae, esg protein expressed by the heat shock promoter can rescue the polyploid phenotype of abdominal histoblasts, demonstrating that the phenotype is attributable to a loss of esg function. esg must be expressed continuously during the larval period for efficient rescue [10].
• If cytokinesis is blocked, replication continues, forming a giant nucleus with polyploid chromosomes [16].
• Strikingly, Bik1 is not required for viability in haploid cells, but becomes essential in polyploids [17].
• We show that mammalian cells lacking survivin are unable to align their chromosomes, fail to recruit Aurora B to kinetochores and become polyploid at a very high frequency [18].
• Although erythroid cells and megakaryocytes arise from a common progenitor, their terminal maturation follows very different paths; erythroid cells undergo cell-cycle exit and enucleation, whereas megakaryocytes continue to progress through the cell cycle but skip late stages of mitosis to become polyploid cells [19].

Anatomical context of Polyploidy

• As Aurora kinases are overexpressed in a large number of cancers, and ectopic expression of Aurora generates polyploid cells containing multiple centrosomes, it has been tempting to suggest that Aurora overexpression provokes genetic instability underlying the tumorigenesis [20].
• Fertilization of Fmn2(-/-) oocytes results in polyploid embryo formation, recurrent pregnancy loss and sub-fertility in Fmn2(-/-) females [21].
• Enforced expression of SCL at high levels did not provoke differentiation, but GATA-1 induced the appearance of megakaryocytes as assessed by morphology, the presence of acetylcholinesterase and a polyploid DNA content [22].
• Coculture of ES cells for 8-12 days with OP9 stromal cells in the presence of thrombopoietin, IL-6, and IL-11 resulted in the development of large, polyploid megakaryocytes that produced proplatelets [23].
• In this report, it is demonstrated that SDF-1 induces the expression and release of gelatinase B (MMP-9) by purified mature polyploid human MKs and an adeno-CXCR4-infected megakaryocytic cell line [24].

Associations of Polyploidy with chemical compounds

• Multiple origins of polyploids in the Glycine tabacina complex inferred from chloroplast DNA polymorphism [25].
• The mechanism of the p53-dependent arrest in nocodazole-treated adapted cells requires the cyclin-dependent kinase inhibitor p21, as p21-/- fibroblasts fail to arrest in response to nocodazole treatment and become polyploid [26].
• These cells could not resume cell growth and expressed GP IIb/IIIa antigen; some of them showed multinuclear form and DNA polyploidy even after removal of TPA from the culture medium [27].
• It is noteworthy that association of 5-azacytidine to cytochalasin B dramatically induced the production of polyploid MK cells [28].
• Benzo(a)pyrene hydroxylase, ethoxyresorufin O-deethylase, and methoxycoumarin O-demethylase activities were approximately 15-40% lower in the diploid hepatocyte fraction than in the polyploid cell fraction [29].

Gene context of Polyploidy

• Electron microscopy of the cells that transmigrated through the BMEC monolayers in response to SDF-1 demonstrated the presence of intact polyploid MKs as well as MKs in the process of platelet formation [30].
• Polyploidy induced by survivin antagonists is accentuated in p21-deficient cells, and corrected by exogenous expression of p21 [31].
• In addition, p21 and p27 were coexpressed in the majority of mature polyploid megakaryocytes [32].
• PD98059 and GF109203X, inhibitors of ERK1/ERK2 pathway and PKC, respectively, blocked PPF, while adhesion, spreading, and polyploidy were normal [33].
• Here we show that enforced expression in 416B cells of either the GATA-2 or GATA-3 gene also induces megakaryocytic differentiation, as assessed by cellular morphology, acetylcholinesterase activity, polyploid DNA content, and loss of Mac-1 expression [34].

Analytical, diagnostic and therapeutic context of Polyploidy

• Hepatocytes stimulated to proliferate in vivo by hepatectomy also become unusually large and polyploid in the absence of Separase but are able to regenerate functional livers [35].
• Using quantitative reverse transcriptase polymerase chain reaction (RT-PCR), we analyzed the h-nuc mRNA expression on treated K562 cells.Mature megakaryocyte-like polyploid cells were detected at day 5-7 of treatment with nocodazole [36].
• For each donor the incidence of micronuclei, polyploidy and malsegregation (non-disjunction and loss) of chromosomes X and 8 was determined using fluorescence in situ hybridization with chromosome-specific centromeric probes [37].
• MK expansion and polyploidy and platelet production were monitored by flow cytometry analysis using specific surface markers (CD41 and CD42b) and propidium iodide labeling [38].
• The zonae of fertilised eggs (polyploid embryos) showed long solubilisation times (IVF: 45.3+/-3.4 min, n = 18; ICSI: 48.9+/-2.7 min, n = 19) [39].

References