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Open Access Highly Accessed Research article

Upregulation of meiosis-specific genes in lymphoma cell lines following genotoxic insult and induction of mitotic catastrophe

Martins Kalejs1*, Andrey Ivanov12, Gregory Plakhins1, Mark S Cragg34, Dzintars Emzinsh5, Timothy M Illidge2 and Jekaterina Erenpreisa1

  • * Corresponding author: Martins Kalejs m.kalejs@no.lv

  • † Equal contributors

Author Affiliations

1 Biomedical Research and Study Centre, Latvian University, Ratsupites 1, Riga, LV-1067, Latvia

2 Paterson Institute Cancer Research, Christie Hospital, Cancer Sciences Division University of Manchester, Manchester, Wilmslow Road, M20 4BX, UK

3 Tenovus Research Laboratory, Cancer Sciences Division, School of Medicine, Southampton University Hospital, Southampton SO16 6YD, UK

4 Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia

5 Oncology Center of Latvia, Hipokrata 4, Riga, LV-1079, Latvia

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BMC Cancer 2006, 6:6  doi:10.1186/1471-2407-6-6

Published: 9 January 2006

Abstract

Background

We have previously reported that p53 mutated radioresistant lymphoma cell lines undergo mitotic catastrophe after irradiation, resulting in metaphase arrest and the generation of endopolyploid cells. A proportion of these endopolyploid cells then undergo a process of de-polyploidisation, stages of which are partially reminiscent of meiotic prophase. Furthermore, expression of meiosis-specific proteins of the cancer/testis antigens group of genes has previously been reported in tumours. We therefore investigated whether expression of meiosis-specific genes was associated with the polyploidy response in our tumour model.

Methods

Three lymphoma cell lines, Namalwa, WI-L2-NS and TK6, of varying p53 status were exposed to a single 10 Gy dose of gamma radiation and their responses assessed over an extended time course. DNA flow cytometry and mitotic counts were used to assess the kinetics and extent of polyploidisation and mitotic progression. Expression of meiotic genes was analysed using RT-PCR and western blotting. In addition, localisation of the meiotic cohesin REC8 and its relation to centromeres was analysed by immunofluorescence.

Results

The principal meiotic regulator MOS was found to be significantly post-transcriptionally up-regulated after irradiation in p53 mutated but not p53 wild-type lymphoma cells. The maximum expression of MOS coincided with the maximal fraction of metaphase arrested cells and was directly proportional to both the extent of the arrest and the number of endopolyploid cells that subsequently emerged. The meiotic cohesin REC8 was also found to be up-regulated after irradiation, linking sister chromatid centromeres in the metaphase-arrested and subsequent giant cells. Finally, RT-PCR revealed expression of the meiosis-prophase genes, DMC1, STAG3, SYCP3 and SYCP1.

Conclusion

We conclude that multiple meiotic genes are aberrantly activated during mitotic catastrophe in p53 mutated lymphoma cells after irradiation. Furthermore, we suggest that the coordinated expression of MOS and REC8 regulate the extent of arrested mitoses and polyploidy.