Downregulation of human polo-like kinase activity by antisense oligonucleotides induces growth inhibition in cancer cells

Spänkuch-Schmitt, Birgit; Wolf, Georg; Solbach, Christine; Loibl, Sibylle; Knecht, Rainald; Stegmüller, M.; Minckwitz, Gϋnter von; Kaufmann, M.; Strebhardt, Klaus

doi:10.1038/sj.onc.1205412

Cited by 156 publications

(124 citation statements)

References 37 publications

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“…Indeed, enforced expression of Plk1 in mouse fibroblasts causes oncogenic focus formation and promotes tumor growth in nude mice (22), suggesting that Plk1 has an oncogenic potential. In support with this notion, knockdown of the endogenous Plk1 induces G 2 /M cell cycle arrest and/or apoptosis in various cell lines (23)(24)(25). Furthermore, it has been shown that Plk1 is inhibited in response to DNA damage in a mutated in ataxia telangiectasia (ATM) and ATM related kinase-dependent manner (26,27), indicating that Plk1 is one of targets of DNA damage response.…”

mentioning

confidence: 57%

Inhibitory Role of Plk1 in the Regulation of p73-dependent Apoptosis through Physical Interaction and Phosphorylation

Koida

Ozaki

Yamamoto

et al. 2008

Journal of Biological Chemistry

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In response to DNA damage, p73 plays a critical role in cell fate determination. In this study, we have found that Plk1 (pololike kinase 1) associates with p73, phosphorylates p73 at Thr-27, and thereby inhibits its pro-apoptotic activity. During cisplatinmediated apoptosis in COS7 cells in which the endogenous p53 is inactivated by SV40 large T antigen, p73 was induced to accumulate in association with a significant down-regulation of Plk1. Consistent with these observations, Plk1 reduced the stability of the endogenous p73. Immunoprecipitation and in vitro pulldown assay demonstrated that p73 binds to the kinase domain of Plk1 through its NH 2 -terminal region. Luciferase reporter assay and reverse transcription-PCR analysis revealed that Plk1 is able to block the p73-mediated transcriptional activation. Of note, kinase-deficient Plk1 mutant (Plk1(K82M)) retained an ability to interact with p73; however, it failed to inactivate the p73-mediated transcriptional activation, suggesting that kinase activity of Plk1 is required for the inhibition of p73. Indeed, in vitro kinase assay indicated that p73 is phosphorylated at Thr-27 by Plk1. Furthermore, small interference RNA-mediated knockdown of the endogenous Plk1 in p53-deficient H1299 cells resulted in a significant increase in the number of cells with sub-G 1 DNA content accompanied by the upregulation of p73 and pro-apoptotic p53 AIP1 as well as the proteolytic cleavage of poly(ADP-ribose) polymerase. Thus, our present results suggest that Plk1-mediated dysfunction of p73 is one of the novel molecular mechanisms to inhibit the p53-independent apoptosis, and the inhibition of Plk1 might provide an attractive therapeutic strategy for cancer treatment.p73 is one of newly identified p53 tumor suppressor gene family members (p53, p73, and p63) that encodes a nuclear transcription factor (1-3). Like the other p53 family members, p73 encodes multiple isoforms, including TA (transactivating), with distinct COOH-terminal extensions arising from alternative splicing events and ⌬N (nontransactivating) variants generated by alternative promoter usage (2-4). ⌬Np73 has an oncogenic potential (5) and displays a dominant-negative behavior toward TAp73 as well as wild-type p53 (6). TAp73 transactivates overlapping set of p53-target genes implicated in the induction of cell cycle arrest and/or apoptosis, and plays an important role in the regulation of DNA damage response, which is closely linked to its DNA binding activity. The initial studies demonstrated that TAp73 does not induce enough to accumulate in response to DNA damage arising from UV exposure or actinomycin D treatment (1); however, it has been shown that, in response to certain subset of DNA-damaging agents, TAp73 accumulates in the cell nucleus and exerts its pro-apoptotic function (7).Accumulating evidence suggests that TAp73 is regulated by post-translational modifications such as phosphorylation and acetylation. For example, TAp73 is stabilized in response to DNA damage such as cisplatin (CDDP) 2 treatment or e...

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mentioning

confidence: 57%

Inhibitory Role of Plk1 in the Regulation of p73-dependent Apoptosis through Physical Interaction and Phosphorylation

Koida

Ozaki

Yamamoto

et al. 2008

Journal of Biological Chemistry

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“…Reagents-Control (scrambled) siRNA and siRNA to PLK1 (nucleotides 1416 -1438 (31) were synthesized by Dharmacon Research, Inc. (Lafayette, CO). Normal mouse IgG, anti-c-Myc (9E10), and anti-PLK1 (F-8) monoclonal antibodies (mAbs) were from Santa Cruz Biotechnology.…”

Section: Methodsmentioning

confidence: 99%

Polo-like Kinase 1 (PLK1) Regulates Interferon (IFN) Induction by MAVS

Vitour

Dabo

Pour

et al. 2009

Journal of Biological Chemistry

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“…Constitutive expression of Plk1 in NIH 3T3 cells causes malignant transformation and induces tumor growth in nude mice (Smith et al, 1997). Importantly, antisense oligonucleotides that downregulate Plk1 cause decreased cell proliferation in MDA-MB-435 breast cancer cells and A549 non-small-cell lung cancer cells in vitro and in tumor regression when these cells were xenografted onto nude mice (Spankuch-Schmitt et al, 2002;Elez et al, 2003). Interestingly, the viability of nontransformed cells such as amniocytes, mesangial cells, and skin fibroblasts was unaffected by these types of Plk1 downregulation (Elez et al, 2003).…”

Section: Prospects For Structure-based Drug Designmentioning

confidence: 99%

Structure and function of Polo-like kinases

2005

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Polo-like kinases play critical roles during multiple stages of cell cycle progression. All Polo-like kinases contain an N-terminal Ser/Thr kinase catalytic domain and a Cterminal region that contains one or two Polo-boxes. For Polo-like kinase 1, 2, and 3, and their homologs, the entire C-terminal region, including both Polo-boxes, functions as a single modular phosphoserine/threonine-binding domain known as the Polo-box domain (PBD). In the absence of a bound substrate, the PBD inhibits the basal activity of the kinase domain. Phosphorylation-dependent binding of the PBD to its ligands releases the kinase domain, while simultaneously localizing Polo-like kinases to specific subcellular structures. These observations suggest two different models for how the PBD integrates signals arising from other mitotic kinases to target the activated kinase towards distinct substrates. The recent X-ray crystal structures of the PBD provide insights into the structural basis for PBD function and kinase regulation. Molecular modelling of the structure of the isolated kinase domain reveals a potential basis for motif-dependent substrate specificity.

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Downregulation of human polo-like kinase activity by antisense oligonucleotides induces growth inhibition in cancer cells

Cited by 156 publications

References 37 publications

Inhibitory Role of Plk1 in the Regulation of p73-dependent Apoptosis through Physical Interaction and Phosphorylation

Inhibitory Role of Plk1 in the Regulation of p73-dependent Apoptosis through Physical Interaction and Phosphorylation

Polo-like Kinase 1 (PLK1) Regulates Interferon (IFN) Induction by MAVS

Structure and function of Polo-like kinases

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