Abstract
Tripeptidyl-peptidase II (TPPII) is a serine peptidase highly expressed in malignant Burkitt's lymphoma cells (BL). We have previously shown that overexpression of TPPII correlates with chromosomal instability, centrosomal and mitotic spindle abnormalities and resistance to apoptosis induced by spindle poisons. Furthermore, TPPII knockdown by RNAi was associated with endoreplication and the accumulation of polynucleated cells that failed to complete cell division, indicating a role of TPPII in the cell cycle. Here we have applied a global approach of gene expression analysis to gain insights on the mechanism by which TPPII regulates this phenotype. mRNA profiling of control and TPPII knockdown BL cells identified one hundred and eighty five differentially expressed genes. Functional categorization of these genes highlighted major physiological functions such as apoptosis, cell cycle progression, cytoskeleton remodeling, proteolysis, and signal transduction. Pathways and protein interactome analysis revealed a significant enrichment in components of MAP kinases signaling. These findings suggest that TPPII influences a wide network of signaling pathways that are regulated by MAPKs and exerts thereby a pleiotropic effect on biological processes associated with cell survival, proliferation and genomic instability.
Highlights
Tripeptidyl-peptidase II (TPPII) is a 138-kDa serine peptidase found in both cytoplasmic and membrane associated oligomeric complexes of more than 1000 kDa (Balow et al 1983; Balow et al 1986; Geier et al 1999; Rose et al 1996)
We have previously demonstrated that overexpression of TPPII in Burkitt’s lymphoma or transfected HEK293 cells correlates with accelerated proliferation and with the accumulation of centrosome and chromosome aberrations, whereas functional knockdown of TPPII by shRNA results in growth retardation and the accumulation of polynucleated cells that fail to complete cell division (Stavropoulou et al 2005)
This was accompanied by up-regulation of inhibitors of apoptosis (IAPs) and resistance to p53-induced apoptosis, suggesting that TPPII may allow the transit through mitosis and the survival of cells with severe mitotic spindle damage
Summary
TPPII is a 138-kDa serine peptidase found in both cytoplasmic and membrane associated oligomeric complexes of more than 1000 kDa (Balow et al 1983; Balow et al 1986; Geier et al 1999; Rose et al 1996). We have shown that 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 checkpoints (Stavropoulou et al 2006) This was accompanied by up-regulation of inhibitors of apoptosis (IAPs) and resistance to p53-induced apoptosis, suggesting that TPPII may allow the transit through mitosis and the survival of cells with severe mitotic spindle damage.
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