TPPII promotes genetic instability by allowing the escape from apoptosis of cells with activated mitotic checkpoints.
Overexpression of TPPII correlates with accelerated growth and the appearance of centrosome and chromosome aberrations, suggesting that the activity of this enzyme may be critical for the induction and/or maintenance of genetic instability in malignant cells. We now find that the length of mitosis and of the entire cell cycle is significantly reduced in TPPII overexpressing HEK293 cells compared to untransfected and control transfected cells. Functional TPPII knockdown by shRNA interference caused a significant slowdown in cell growth and the accumulation of cells that delayed or failed to complete mitosis. TPPII overexpressing cells evade mitotic arrest induced by spindle poisons and display high levels of polyploidy despite the constitutively high expression of major components of the spindle checkpoint. TPPII overexpression correlated with upregulation of IAPs and with resistance to mitochondria dependent apoptosis induced by p53 stabilization. Thus, TPPII appears to promote malignant cell growth by allowing exit from mitosis and the survival of cells with severe mitotic spindle damage.
Stavropoulou
Vaia
V
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Vasquez
Vanessa
V
Cereser
Biancastella
B
Freda
Elio
E
Masucci
Maria G
MG
D000626:Aminopeptidases; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D002453:Cell Cycle / Q000235:genetics*; D002460:Cell Line; D002461:Cell Line, Transformed; D002470:Cell Survival; D018385:Centrosome / Q000502:physiology; D043171:Chromosomal Instability; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D016158:Genes, p53; D006801:Humans; D008928:Mitochondria / Q000502:physiology; D008938:Mitosis / Q000235:genetics; D015739:Nocodazole / Q000494:pharmacology; D011123:Polyploidy; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D008941:Spindle Apparatus / Q000235:genetics; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C048001:tripeptidyl-peptidase 2; D012697:Serine Endopeptidases; D015739:Nocodazole