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

ArticleinBlood Cells Molecules and Diseases 27(5):825-9 · September 2001with4 Reads
DOI: 10.1006/bcmd.2001.0452 · Source: PubMed
PBK/TOPK is a recently cloned serine/threonine kinase which is phosphorylated during mitosis. Earlier work indicated that this kinase is upregulated in a Burkitt's lymphoma cell line (GA-10). To determine whether PBK/TOPK is upregulated in other mitotically active neoplastic cell lines and tissues, Northern analysis was performed on a panel of malignant cell lines and on clinical samples from patients with leukemia or lymphoma. While PBK/TOPK mRNA was not detectable in normal peripheral blood cells and was weakly expressed in hyperplastic tonsillar B-cells, significantly higher levels of mRNA were detected in 8 Burkitt's lymphoma cell lines, 10 other neoplastic cell lines, and 2 clinical samples-one derived from a patient with ALL and a second derived from a patient with relapsed myeloma. In addition, Northern analysis of fetal tissues showed upregulated expression of PBK/TOPK in fetal kidney, lung, spleen, brain, and testis. These data suggest that PBK/TOPK expression is increased in highly proliferative malignant cells and during normal fetal development.
    • "Indeed, the regulation of PTEN and the activation of PI3K are important for CE movements in Xenopus [29]. Additionally, pbk has been shown to act as MAPKK-like kinase and is highly expressed in various types of cancer such as lymphoma, leukemia, breast cancer, and colorectal cancers [30][31][32][33][34]. During CE movements, the MAPK mediated Erb signaling is important for cell migration. "
    [Show abstract] [Hide abstract] ABSTRACT: Background A tight regulation of the Wnt-signaling network, activated by 19 Wnt molecules and numerous receptors and co-receptors, is required for the establishment of a complex organism. Different branches of this Wnt-signaling network, including the canonical Wnt/β-catenin and the non-canonical Wnt/PCP, Wnt/Ror2 and Wnt/Ca2+ pathways, are assigned to distinct developmental processes and are triggered by certain ligand/receptor complexes. The Wnt-signaling molecules are closely related and it is still on debate whether the information for activating a specific branch is encoded by specific sequence motifs within a particular Wnt protein. The model organism Xenopus offers tools to distinguish between Wnt-signaling molecules activating distinct branches of the network. Results We created chimeric Wnt8a/Wnt11 molecules and could demonstrate that the C-terminal part (containing the BS2) of Wnt8a is responsible for secondary axis formation. Chimeric Wnt11/Wnt5a molecules revealed that the N-terminus with the elements PS3-1 and PS3-2 defines Wnt11 specificity, while elements PS3-1, PS3-2 and PS3-3 are required for Wnt5a specificity. Furthermore, we used Xenopus dorsal marginal zone explants to identify non-canonical Wnt target genes regulated by the Wnt5a branch and the Wnt11 branch. We found that pbk was specifically regulated by Wnt5a and rab11fip5 by Wnt11. Overexpression of these target genes phenocopied the overexpression of their regulators, confirming the distinct roles of Wnt11 and Wnt5a triggered signaling pathways. Furthermore, knock-down of pbk was able to restore convergent extension movements in Wnt5a morphants. Conclusions The N-terminal part of non-canonical Wnt proteins decides whether the Wnt5a or the Wnt11 branch of the Wnt-signaling network gets activated. The different non-canonical Wnt branches not only regulate cellular behavior, but, surprisingly, also regulate the expression of different target genes. One of these target genes, pbk, seems to be the relevant target gene executing Wnt5a-mediated regulation of convergent extension movements. Electronic supplementary material The online version of this article (doi:10.1186/s12915-016-0278-x) contains supplementary material, which is available to authorized users.
    Full-text · Article · Dec 2016
    • "In addition, we found that activation/phosphorylation of TOPK was increased after renal IRI. Previous studies have demonstrated that TOPK conferred protective effects against IRI in the brains [29,30] and cardiomyocytes [31] via enhancing antioxidant capacity, promoting cell proliferation, and inhibiting cell apoptosis. This provides an explanation that the increase of TOPK activation after renal IRI in our study may work as a compensation response to the renal ischemia, which activates its downstream effectors and increases antioxidant capacity for combating the increase of oxidative stress and the subsequent IRI. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Recent clinical and animal studies suggested that remote limb ischemic postconditioning (RIPostC) can invoke potent cardioprotection or neuroprotection. However, the effect and mechanism of RIPostC against renal ischemia/reperfusion injury (IRI) are poorly understood. T-LAK-cell-originated protein kinase (TOPK) is crucial for the proliferation and migration of tumor cells. However, the function of TOPK and the molecular mechanism underlying renal protection remain unknown. Therefore, this study aimed to evaluate the role of TOPK in renoprotection induced by RIPostC. Materials and methods: The renal IRI model was induced by left renal pedicle clamping for 45min followed by 24h reperfusion and right nephrectomy. All mice were intraperitoneally injected with vehicle, TOPK inhibitor HI-TOPK-032 or Akt inhibitor LY294002. After 24h reperfusion, renal histology, function, and inflammatory cytokines and oxidative stress were assessed. The proteins were measured by Western blotting. Results: The results showed that RIPostC significantly protected the kidneys against IRI. The protective effects were accompanied by the attenuation of renal dysfunction, tubular damage, inflammation and oxidative stress. In addition, RIPostC increased the phosphorylation of TOPK, PTEN, Akt, GSK3β and the nuclear translocation of Nrf2 and decreased the nuclear translocation of NF-κB. However, all of the above renoprotective effects of RIPostC were eliminated either by the inhibition of TOPK or Akt with HI-TOPK-032 or LY294002. Conclusions: The current data reveal that RIPostC protects against renal IRI via activation of TOPK/PTEN/Akt signaling pathway mediated anti-oxidation and anti-inflammation.
    Full-text · Article · Jun 2016
    • "TOPK is highly expressed in a variety of tumors including breast cancer, colorectal cancer (CRC) and melanoma, and involves in regulating several cell functions such as tumor cell cycle progression [3][4][5][6], transformation [7, 8], proliferation [9] and apoptosis [10, 11]. More and more published reports have suggested that elevated levels of TOPK may be associated with the tumorigenesis, metastasis and poor prognosis of cancers [12][13][14][15][16][17]. Colon cancer is one of the most prevalent cancers worldwide, as well as one of the leading causes of cancer death. "
    [Show abstract] [Hide abstract] ABSTRACT: T-LAK cell-originated protein kinase (TOPK), a serine/threonine protein kinase, is highly expressed in a variety of tumors and associated with a poor prognosis of human malignancies. However, the activation mechanism of TOPK is still unrevealed. Herein, first we found that Src directly bound with and phosphorylated TOPK at Y74 and Y272 in vitro. Anti-phospho-TOPK at Y74 was prepared, the endogenous phosphorylation of TOPK at Y74 was detected in colon cancer cells, and the phosphorylation was inhibited in cells expressing low levels of Src. Subsequently, we stably transfected Y74 and Y272 double mutated TOPK (TOPK-FF) into JB6 or SW480 cells, and observed that both the anchorage-independent growth ability and tumorigenesis of TOPK-FF cells were suppressed compared with those of wild type TOPK (TOPK-WT) ex vivo and in vivo. The phosphorylation level of TOPK substrate, Histone H3 at Ser10 also decreased dramatically ex vivo or in vivo. Moreover, we showed that Src could inhibit the ubiquitination of TOPK. Transiently expressed TOPK-WT was more stable than TOPK-FF in pause and chase experiment. Endogenous TOPK was more stable in Src wild type (Src+/+) MEFs than in Src knockout (Src-/-). Taken together, our results indicate that Src is a novel upstream kinase of TOPK. The phosphorylation of TOPK at Y74 and Y272 by Src increases the stability and activity of TOPK, and promotes the tumorigenesis of colon cancer. It may provide opportunities for TOPK based prognosis and targeted therapy for colon cancer patients.
    Full-text · Article · Mar 2016
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