Abstract
Cyclin A2 is predominantly, but not exclusively, localized in the nucleus from G1/S transition onwards. It is degraded when cells enter mitosis after nuclear envelope breakdown. We previously showed that a fusion protein (S2A) between the hepatitis B virus (HBV) surface antigen protein and a non-degradable fragment of human cyclin A2 (Δ152) resides in the endoplasmic reticulum membranes, escapes degradation and transforms normal rat fibroblasts. The present study investigates whether cytoplasmic cyclin A2 may play a role in oncogenesis. We show that the sequestration of non-degradable cyclin A2-Δ152 by a cellular ER targeting domain (PRL-A2) leads to cell transformation when coexpressed with activated Ha-ras. REF52 cells constitutively expressing PRL-A2 are found to have a high incidence of multinucleate giant cells, polyploidy and abnormal centrosome numbers, giving rise to the nucleation of multipolar spindles. Injection of these cells into athymic nude mice causes tumors, even in the absence of a cooperating Ha-ras oncogene. These results demonstrate that, independently of any viral context, an intracellular redistribution of non-degradable cyclin A2 is capable of deregulating the normal cell cycle to the point where it promotes aneuploidy and cancer.
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Acknowledgements
We would like to thank all the members of our two laboratories for helpful discussions. We thank C Garcia-Cordier and G Pivert for their technical assistance. We are grateful to Dr P Denoulet for GT335 antibody and to Dr VR Lingappa for pSP Sp+1L.ST.gG. This research was supported by grants from INSERM, CNRS, INRA, University Paris VI, ARC (no. 5899 to C Jessus, no. 9169 to J Sobczak-Thépot and C Bréchot), LNCC.
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Faivre, J., Frank-Vaillant, M., Poulhe, R. et al. Centrosome overduplication, increased ploidy and transformation in cells expressing endoplasmic reticulum-associated cyclin A2. Oncogene 21, 1493–1500 (2002). https://doi.org/10.1038/sj.onc.1205215
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DOI: https://doi.org/10.1038/sj.onc.1205215
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