PBK/TOPK Is a Novel Mitotic Kinase Which Is Upregulated in Burkitt's Lymphoma and Other Highly Proliferative Malignant Cells

Simons-Evelyn, Michelle; Bailey-Dell, Kim; Toretsky, Jeffrey A.; Ross, Douglas D.; Fenton, R. G.; Kalvakolanu, Dhan V.; Rapoport, Aaron P.

doi:10.1006/bcmd.2001.0452

Cited by 105 publications

(86 citation statements)

References 9 publications

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“…Furthermore, based on its restricted pattern of expression to tumor cells, testis, embryonic tissues and adult progenitor cells (Simons-Evelyn et al, 2001;Dougherty et al, 2005;Park et al, 2006), PBK may be considered a novel cancer/testis antigen that may also have a role in maintenance of tumor stem cells. Future studies are warranted to identify small molecular inhibitors of PBK and test them for the ability to sensitize tumor cells to chemotherapy-induced apoptosis and growth suppression.…”

Section: Hct116-rs Hct116-shpbk1mentioning

confidence: 99%

“…PBK/TOPK was also identified as a differentially expressed sequence tag in Burkitt's lymphoma cells (Simons-Evelyn et al, 2001). The murine homologue was cloned as an IL-6-stimulated gene from murine myeloma cells (Cote et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…The murine homologue was cloned as an IL-6-stimulated gene from murine myeloma cells (Cote et al, 2002). PBK/TOPK mRNA is expressed in various tumor cell lines and in normal testicular and embryonic tissues (Simons-Evelyn et al, 2001). PBK/TOPK protein is also highly expressed in primary clinical samples from patients with aggressive hematopoietic neoplasms (Nandi et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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PBK/TOPK interacts with the DBD domain of tumor suppressor p53 and modulates expression of transcriptional targets including p21

et al. 2010

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Section: Hct116-rs Hct116-shpbk1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PBK/TOPK interacts with the DBD domain of tumor suppressor p53 and modulates expression of transcriptional targets including p21

et al. 2010

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“…TOPK is a 322 amino-acid MAPKK-like serine/threonine kinase and is highly expressed in various types of cancer, such as lymphoma, leukemia, breast cancer, melanoma and colorectal cancers, but is undetectable in normal tissues except the germ cells of testis and several fetal tissues (Abe et al, 2000;Simons-Evelyn et al, 2001;Nandi et al, 2004;Park et al, 2006;Zykova et al, 2006;Zhu et al, 2007). In cultured cells, the expression of TOPK is upregulated during mitosis, when it is thought to be phosphorylated on Thr 9 and activated by cyclin B1/cdk1 (Matsumoto et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

TOPK/PBK promotes cell migration via modulation of the PI3K/PTEN/AKT pathway and is associated with poor prognosis in lung cancer

et al. 2011

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We integrated four gene expression profile data sets, namely two different pair-matched stage I lung adenocarcinoma data sets, secondary metastatic tumors vs benign tumors and lung tumor metastasizes to the brain, and we identified one kinase, T-LAK Cell-Originated Protein Kinase (TOPK), as a putative gene that promotes metastasis. To delineate the role of TOPK in lung cancer, we showed that overexpression of TOPK, but not a catalytically inactive form of TOPK, can enhance the migration and invasion of lung fibroblasts or cells with low TOPK expression. In addition, TOPK-induced cell migration was shown to be a PI3K/AKT-dependent event. TOPK concurrently promoted AKT phosphorylation at Ser 473 and decreased the phosphatase and tensin homolog (PTEN) levels, whereas TOPK knockdown had the reverse effects. LY294002, a PI3K inhibitor, did not inhibit the TOPK-induced decrease in PTEN, and coexpression of PTEN significantly reduced TOPK-induced AKT phosphorylation in a dose-dependent manner; these results indicate that the TOPK-mediated PTEN decrease has an upstream role in regulating PI3K/AKT-stimulated migration. Using immunohistochemical analysis of lung cancer tissue samples, we showed that a high TOPK expression level correlates strongly with reduced overall and disease-free survivals. Moreover, an inverse correlation between TOPK and PTEN expression was present and is consistent with the biochemical findings. Finally, a combination of high TOPK and low PTEN expression was inversely correlated with overall and disease-free survivals, independent of other pathologic staging factors. Our results suggest that TOPK is a potential therapeutic target in lung cancer that promotes cell migration by modulating a PI3K/PTEN/AKT-dependent signaling pathway; they also suggest that high TOPK expression, either alone or in combination with a low level of PTEN, may serve as a prognostic marker for lung cancer.

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“…T-cell-originated protein kinase was described as a MAPKK-like protein involved in p38MAPK and JNK signalling, possibly in a cell-type-dependent manner, and was more recently found to be involved in the ERK/MAPK pathway (Matsumoto et al, 2004;Nandi et al, 2004;Ayllon and O'Connor, 2007;Oh et al, 2007). T-cell-originated protein kinase is overexpressed in highly proliferating normal tissues, foetal tissues and in a wide variety of tumours in vitro, whereas the inhibition of TOPK is shown to lead to apoptosis in breast and melanoma cell lines (Simons-Evelyn et al, 2001;Zhao et al, 2001;Matsumoto et al, 2004;Nandi et al, 2004;Dougherty et al, 2005;Park et al, 2006;Zykova et al, 2006). Most recently, Herrero-Martin et al (2009) evaluated TOPK expression in Ewing sarcoma cell lines and found that the inhibition of TOPK led to a decrease in the proliferation rate and an important change in cell growth, indicating that TOPK could have a significant role in Ewing sarcoma biology.…”

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confidence: 99%

Prognostic and predictive value of TOPK stratified by KRAS and BRAF gene alterations in sporadic, hereditary and metastatic colorectal cancer patients

et al. 2009

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BACKGROUND: Our aim was to investigate the prognostic and predictive value of the oncogenic MAPKK-like protein T-cell-originated protein kinase (TOPK) stratified by KRAS and BRAF mutations in patients with sporadic, hereditary and metastatic colorectal cancer (CRC) treated with anti-EGFR therapy. METHODS: Immunohistochemistry (IHC) for TOPK was performed on four study groups. Group 1 included two subgroups of 543 and 501 sporadic CRC patients used to test the reliability of TOPK expression by IHC. In Group 2, representing an additional 222 sporadic CRCs, the prognostic effect of TOPK stratified by KRAS and BRAF was assessed. The prognostic effect of TOPK was further analysed in Group 3, representing 71 hereditary Lynch syndrome-associated CRC patients. In Group 4, the predictive and prognostic value of TOPK was analysed on 45 metastatic patients treated with cetuximab or panitumumab stratified by KRAS and BRAF gene status. RESULTS: In both sporadic CRC subgroups (Group 1), associations of diffuse TOPK expression with clinicopathological features were reproducible. Molecular analysis of sporadic CRCs in Group 2 showed that diffuse TOPK expression was associated with KRAS and BRAF mutations (po0.001) and with poor outcome in patients with either mutation in univariate and multivariate analysis (P ¼ 0.017). In hereditary patients (Group 3), diffuse TOPK was linked to advanced pT stage. In metastatic patients treated with anti-EGFR therapy (Group 4), diffuse TOPK expression was linked to dismal outcome despite objective response to treatment (P ¼ 0.01). CONCLUSION: TOPK expression is an unfavourable prognostic indicator in sporadic patients with KRAS or BRAF mutations and also in patients with metastatic disease experiencing a response to anti-EGFR therapies. The inhibition of TOPK, which could benefit 30 -40% of CRC patients, may represent a new avenue of investigation for targeted therapy.

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PBK/TOPK Is a Novel Mitotic Kinase Which Is Upregulated in Burkitt's Lymphoma and Other Highly Proliferative Malignant Cells

Cited by 105 publications

References 9 publications

PBK/TOPK interacts with the DBD domain of tumor suppressor p53 and modulates expression of transcriptional targets including p21

PBK/TOPK interacts with the DBD domain of tumor suppressor p53 and modulates expression of transcriptional targets including p21

TOPK/PBK promotes cell migration via modulation of the PI3K/PTEN/AKT pathway and is associated with poor prognosis in lung cancer

Prognostic and predictive value of TOPK stratified by KRAS and BRAF gene alterations in sporadic, hereditary and metastatic colorectal cancer patients

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