Mitotic Infidelity and Centrosome Duplication Errors in Cells Overexpressing Tripeptidyl-Peptidase II

Stavropoulou, Vaia; Xie, Jianjun; Henriksson, Marie Arsenian; Tomkinson, Birgitta; Imreh, Stefan; Masucci, Maria G.

doi:10.1158/0008-5472.can-04-2085

Cited by 46 publications

(39 citation statements)

References 36 publications

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“…However, other roles of TPPII may also exist, which may be unrelated to protein turnover. TPPII regulates transduction of apoptotic signals as well as centrosome homeostasis by unclear mechanisms (21,(27)(28)(29). We here found that the expression of TPPII is controlled by mTOR and that TPPII is rapidly translocated into the nucleus in response to g-irradiation.…”

Section: Introductionmentioning

confidence: 65%

Tripeptidyl-peptidase II Controls DNA Damage Responses and In vivo γ-Irradiation Resistance of Tumors

Lü

Künert

et al. 2007

Cancer Research

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Cellular responses to ;-irradiation exposure are controlled by phosphatidylinositol 3-kinase-related kinases (PIKK) in the nucleus, and in addition, cytosolic PIKKs may have a role in such responses. Here, we show that the expression of tripeptidyl-peptidase II (TPPII), a high molecular weight cytosolic peptidase, required PIKK signaling and that TPPII was rapidly translocated into the nucleus of ;-irradiated cells. These events were dependent on mammalian target of rapamycin, a cytosolic/mitochondrial PIKK that is activated by ;-irradiation. Lymphoma cells with inhibited expression of TPPII failed to efficiently stabilize p53 and had reduced ability to arrest proliferation in response to ;-irradiation. We observed that TPPII contains a BRCA COOH-terminal-like motif, contained within sequences of several proteins involved in DNA damage signaling pathways, and this motif was important for nuclear translocation of TPPII and stabilization of p53. Novel tripeptide-based inhibitors of TPPII caused complete in vivo tumor regression in mice in response to relatively low doses of ;-irradiation (3-4 Gy/wk). This was observed with established mouse and human tumors of diverse tissue backgrounds, with no tumor regrowth after cancellation of treatment. These TPPII inhibitors had minor effects on tumor growth as single agent and had low cellular toxicity. Our data indicated that TPPII connects signaling by cytosolic/mitochondrial and nuclear PIKK-dependent pathways and that TPPII can be targeted for inhibition of tumor therapy resistance. [Cancer Res 2007; 67(15):7165-74]

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Section: Introductionmentioning

confidence: 65%

Tripeptidyl-peptidase II Controls DNA Damage Responses and In vivo γ-Irradiation Resistance of Tumors

Lü

Künert

et al. 2007

Cancer Research

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“…Due to low endogenous TPPII expression and high transfection efficiencies, the human embryonic kidney cell line (HEK293) was chosen. Transient rather than stable overexpression of TPPII was performed because TPPII has been reported to disturb mitotic fidelity [20]. Because of restriction element incompatibility, the HEK293 cells were stably transfected with an expression construct encoding the H-2D b restriction element (named HEK-D b ) (Fig.…”

Section: Tppii Overexpression Does Not Increase the Presentation Of Lmentioning

confidence: 99%

No essential role for tripeptidyl peptidase II for the processing of LCMV‐derived T cell epitopes

Basler

Groettrup

2007

Eur J Immunol

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The proteasome is critically involved in the production of MHC class I-restricted T cell epitopes. Approximately 20% of all peptides generated by the proteasome are too large for direct presentation by MHC class I molecules. Reits et al. (Immunity 2004. 20: 495-506) suggested that a major portion of proteasomal products are larger than 15 amino acids and require further degradation by the tripeptidyl peptidase II (TPPII) before becoming ligands of MHC class I molecules. Using the well-characterized lymphocytic choriomeningitis virus (LCMV) model, the role of TPPII in the processing of several LCMV-derived T cell epitopes was investigated. In contrast to Reits' proposal, TPPII inhibition and TPPII overexpression experiments revealed that five out of six LCMV-derived CD8 + T cell epitopes were not affected by inhibition of TPPII, while one epitope (GP276) was slightly reduced upon TPPII overexpression. Additionally, we demonstrated that the processing of two epitopes derived from ovalbumin and murine cytomegalovirus were not altered by TPPII inhibition. We propose that TPPII is not generally required for the production of MHC class I peptides, but the presentation of some peptides can be negatively affected by TPPII.

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“…The human papillomavirus type 16 E7 oncoprotein (HPV16 E7) induces centrosome duplication errors in primary human diploid epithelial cells (Duensing et al, 2000) through a CDK2-dependent mechanism . Similarly, the c-Myc oncogene has been linked to induction of centrosome abnormalities (Duensing et al, 2003;Stavropoulou et al, 2005). U2OS-C cells were transiently transfected with expression vectors encoding HA-tagged HPV16 E7 or c-Myc.…”

Section: S5a Expression Does Not Affect Induction Of Centrosome Abnormentioning

confidence: 99%

Interference of the dominant negative helix–loop–helix protein ID1 with the proteasomal subunit S5A causes centrosomal abnormalities

2007

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The inhibitor of DNA-binding (ID) proteins are dominantnegative inhibitors of basic helix-loop-helix transcription factors that have multiple functions during development and cellular differentiation. High-level expression of some ID family members has been observed in human malignancies, and in some cases was correlated with poor clinical prognosis. Ectopic ID1 expression extends the life span of primary human epithelial cells, inhibits cellular differentiation and induces centrosome duplication errors, thus suggesting that ID1 may have oncogenic activities. ID1 can bind to the proteasomal subunit S5A/Rpn10, but the biological consequences of the interaction have not been studied in detail. Here, we show that ID1's ability to induce supernumerary centrosomes correlates with S5A binding. Similar to ID1, a fraction of the S5A protein localizes to centrosomal structures. Furthermore, partial depletion of S5A by RNA interference causes accumulation of cells with supernumerary centrosomes. These results are consistent with the model that ID1 dysregulates centrosome homeostasis at least in part by interfering with S5A activities at the centrosome.

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Mitotic Infidelity and Centrosome Duplication Errors in Cells Overexpressing Tripeptidyl-Peptidase II

Cited by 46 publications

References 36 publications

Tripeptidyl-peptidase II Controls DNA Damage Responses and In vivo γ-Irradiation Resistance of Tumors

Tripeptidyl-peptidase II Controls DNA Damage Responses and In vivo γ-Irradiation Resistance of Tumors

No essential role for tripeptidyl peptidase II for the processing of LCMV‐derived T cell epitopes

Interference of the dominant negative helix–loop–helix protein ID1 with the proteasomal subunit S5A causes centrosomal abnormalities

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