The centrosomal FOP protein is required for cell cycle progression and survival.
FOP is a centrosomal protein originally discovered as a fusion partner of FGFR1 in patients with a rare stem cell myeloproliferative disorder. In DT40 chicken lymphocytes, we show that the normal FOP protein localizes at the centrosome throughout the cell cycle and preferentially accumulates at the distal end of the mother centriole. We used homologous recombination in DT40 cells to generate an inducible null mutant for FOP. Loss of FOP induces apoptosis in the G(1) phase of the cell cycle with accumulation of a 32 kDa P53 tumor suppressor isoform and NOXA and FAS transcripts. However, centrosome integrity and microtubule organization are conserved without FOP and mitotic division and cytokinesis are as efficient as in control cells. Our results suggest that FOP is involved in G(1) to S signaling and thus in proliferation/death fate. Several reports show that centrosome alteration can lead to an arrest in G(1) and, possibly, to senescence in a fraction of cells. The phenotype we observed is more severe in FOP null cells. This could be dependent on the cell context or on the efficiency of a knock out that allows the complete disappearance of the target protein and prevents any de novo synthesis. This is an important observation in regard to the current discussion of what consequence centrosome perturbation could have on a cell and shows that a centrosomal protein can be necessary for cell cycle progression and survival.
Acquaviva
Claire
C
INSERM UMR891, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Université de la Méditerranée, 27 Boulevard Leï Roure, Marseille, France.
Chevrier
Véronique
V
Chauvin
Jean-Paul
JP
Fournier
Gaëlle
G
Birnbaum
Daniel
D
Rosnet
Olivier
O
D000818:Animals; D030161:Avian Proteins / Q000378:metabolism*; D002453:Cell Cycle; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D002502:Centrioles / Q000378:metabolism / Q000648:ultrastructure; D018385:Centrosome / Q000378:metabolism* / Q000648:ultrastructure; D002645:Chickens; D016193:G1 Phase; D055786:Gene Knockout Techniques; D008938:Mitosis; D009154:Mutation / Q000235:genetics; D021381:Protein Transport; D011995:Recombination, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D030161:Avian Proteins; D016159:Tumor Suppressor Protein p53