Centrosome overduplication, increased ploidy and transformation in cells expressing endoplasmic reticulum-associated cyclin A2.
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 (Delta152) 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-Delta152 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.
Faivre
Jamila
J
INSERM U370, Institut Pasteur/Necker, Faculté de Médecine Necker, 75015 Paris, France. faivre@necker.fr
Frank-Vaillant
Marie
M
Poulhe
Robert
R
Mouly
Hélène
H
Jessus
Catherine
C
Bréchot
Christian
C
Sobczak-Thépot
Joëlle
J
D000818:Animals; D002453:Cell Cycle; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D018385:Centrosome / Q000648:ultrastructure*; D019925:Cyclin A / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D056751:Cyclin A2; D004721:Endoplasmic Reticulum / Q000737:chemistry*; D011905:Genes, ras; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009374:Neoplasms, Experimental / Q000209:etiology; D015513:Oncogene Proteins / Q000502:physiology; D011123:Polyploidy; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism
C503721:CCNA2 protein, human; C503722:Ccna2 protein, rat; D019925:Cyclin A; D056751:Cyclin A2; D015513:Oncogene Proteins; D011993:Recombinant Fusion Proteins