Sompallae Ramakrishna, Stavropoulou Vaia, Houde Mathieu, Masucci Maria G
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Gene Regul Syst Bio. 2008 Nov 24;2:253-65. doi: 10.4137/grsb.s882.
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.
三肽基肽酶II（TPPII）是一种在恶性伯基特淋巴瘤细胞（BL）中高度表达的丝氨酸肽酶。我们之前已经表明，TPPII的过表达与染色体不稳定性、中心体和有丝分裂纺锤体异常以及对纺锤体毒物诱导的细胞凋亡的抗性相关。此外，RNAi介导的TPPII敲低与核内复制以及未能完成细胞分裂的多核细胞的积累有关，这表明TPPII在细胞周期中发挥作用。在此，我们应用了一种全局基因表达分析方法，以深入了解TPPII调节这种表型的机制。对照和TPPII敲低的BL细胞的mRNA谱分析鉴定出185个差异表达基因。这些基因的功能分类突出了主要的生理功能，如细胞凋亡、细胞周期进程、细胞骨架重塑、蛋白水解和信号转导。通路和蛋白质相互作用组分析显示，丝裂原活化蛋白激酶（MAPK）信号通路的成分显著富集。这些发现表明，TPPII影响由MAPK调节的广泛信号通路网络，从而对与细胞存活、增殖和基因组不稳定性相关的生物学过程产生多效性作用。
