Polo-like kinase1, a New Target for Antisense Tumor Therapy

Elez, Robert; Piiper, Albrecht; Giannini, Claudio; Brendel, Martin; Zeuzem, Stefan

doi:10.1006/bbrc.2000.2291

Cited by 36 publications

(22 citation statements)

References 25 publications

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“…In some experiments, approximately 50% of cells transiently treated with small interfering RNA (siRNA) for Plk1 were arrested at G2/M, with 4N DNA content in FACS profiles, and showed a dumbbell-like DNA organization that suggested incomplete separation of sister chromatids Erikson, 2002, 2003). Inactivation of Plk1 by a variety of methods has caused cell-cycle arrest at mitosis and/or apoptosis in cancer cells of several types (Lane and Nigg, 1996;Mundt et al, 1997;Elez et al, 2000;Erikson, 2002, 2003;Spankuch-Schmitt et al, 2002), suggesting that inhibition of Plk1 function might be a promising approach to cancer therapy (Gumireddy et al, 2005). As RGC32 binds to and is phosphorylated by Plk1 in vitro, it is possible that RGC32 may negatively regulate cell cycle through interaction with Plk1.…”

Section: Discussionmentioning

confidence: 99%

RGC32, a novel p53-inducible gene, is located on centrosomes during mitosis and results in G2/M arrest

et al. 2006

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To identify target genes for the hemizygous deletions of chromosome 13 that are recurrently observed in malignant gliomas, we performed genome-wide DNA copy-number analysis using array-based comparative genomic hybridization and gene expression analysis using an oligonucleotide-array. The response gene to complement 32 (RGC32) at 13q14.11 was identified as a deletion target, and its expression was frequently silenced in glioma cell lines compared with normal brain. Levels of RGC32 mRNA tended to decrease toward higher grades of primary astrocytomas, especially in tumors with mutations of p53. Expression of RGC32 mRNA was dramatically increased by exogenous p53 in a p53-mutant glioma cell line, and also by endogenous p53 in response to DNA damage in p53 +/+ colon-cancer cells, but not in isogenic p53 À/À cells. Chromatin immunoprecipitation and reporter assays demonstrated binding of endogenous p53 protein to the promoter region of the RGC32 gene, implying p53-dependent transcriptional activity. Transiently and stably overexpressed RGC32 suppressed the growth of glioma cells, probably owing to induction of G2/M arrest. Immunocytochemical analysis revealed a concentration of RGC32 protein at the centrosome during mitosis. RGC32 formed a protein complex with polo-like kinase 1 and was phosphorylated in vitro. These observations implied a novel mechanism by which p53 might negatively regulate cell-cycle progression by way of this newly identified transcriptional target. Our results provide the first evidence that RGC32 might be a possible tumorsuppressor for glioma, that it is directly induced by p53, and that it mediates the arrest of mitotic progression.

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Section: Discussionmentioning

confidence: 99%

RGC32, a novel p53-inducible gene, is located on centrosomes during mitosis and results in G2/M arrest

et al. 2006

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“…Antisense oligodeoxynucleotides (ODNs) to Plk1 have also been shown to be effective for inhibition of its expression in tumor cell lines, leading to loss of cell viability and even demonstrating an antitumor activity in A549 xenografts (Elez et al, 2000). Results from transient expression of dominantnegative Plk1 differed from previous antibody microinjection experiments in that most of the mitotic HeLa cells were bipolar and cytokinesis seemed to be disrupted (Mundt et al, 1997).…”

Section: Inhibition Of Plk1mentioning

confidence: 96%

Polo-like kinases (Plks) and cancer

et al. 2005

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“…We used 19-mer oligonucleotides (ODNs) that corresponded to the middle region of the human gene for PLK1, as reported previously by Elez et al (2000). The sequences of the ODNs were as follows: PLK1 antisense, 5 0 -CCTGACCAGCC-CACGCTCC-3 0 ; and PLK1 sense, 5 0 -GGAGCGTGGGCTG GTCAGG-3 0 .…”

Section: Treatment Of Human Leukemia K562 Cells With Antisense Oligonmentioning

confidence: 99%

β-Hydroxyisovalerylshikonin induces apoptosis in human leukemia cells by inhibiting the activity of a polo-like kinase 1 (PLK1)

et al. 2003

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b-Hydroxyisovalerylshikonin (b-HIVS), which was isolated from the plant, Lithospermum radix, induces apoptosis in various lines of human tumor cells. To identify genes involved in b-HIVS-induced apoptotic process, we performed cDNA array analysis and found that b-HIVS suppresses the expression of the gene for a polo-like kinase 1 (PLK1) that is involved in control of the cell cycle. When U937 and HL60 cells were treated with 10 À6 m b-HIVS for 0.5 h, both the amount of PLK1 itself and the kinase activity of this enzyme were decreased. By contrast, Bcr-Abl-positive K562 cells were resistant to the induction of apoptosis by b-HIVS and this compound did not suppress the kinase activity of PLK1 in these cells. However, simultaneous treatment of K562 cells with both b-HIVS and STI571, which selectively inhibits the protein tyrosine kinase (PTK) activity of Bcr-Abl, strongly induced apoptosis. Moreover, b-HIVS increased the inhibitory effect of STI571 on PTK activity. Treatment of K562 cells with antisense oligodeoxynucleotides (ODNs) specific for PLK1 sensitized these cells to the b-HIVS-induced fragmentation of DNA. These results suggest that suppression of the activity of PLK1 via inhibition of tyrosine kinase activity by b-HIVS might play a critical role in the induction of apoptosis.

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Polo-like kinase1, a New Target for Antisense Tumor Therapy

Cited by 36 publications

References 25 publications

RGC32, a novel p53-inducible gene, is located on centrosomes during mitosis and results in G2/M arrest

RGC32, a novel p53-inducible gene, is located on centrosomes during mitosis and results in G2/M arrest

Polo-like kinases (Plks) and cancer

β-Hydroxyisovalerylshikonin induces apoptosis in human leukemia cells by inhibiting the activity of a polo-like kinase 1 (PLK1)

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