Polo-Like Kinase 1: Target and Regulator of Transcriptional Control

Martin, Bernd; Strebhardt, Klaus

doi:10.4161/cc.5.24.3538

Cited by 60 publications

(50 citation statements)

References 37 publications

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“…Polo-like kinases (Plks) are known regulators of cell cycle progression (39). In addition, Plks have a role in the protection against cellular stress through the transcription factor HSF1 (40).…”

Section: Discussionmentioning

confidence: 99%

RNAi screening for kinases and phosphatases identifies FoxO regulators

Mattila

Kallijärvi

Puig

2008

Proc. Natl. Acad. Sci. U.S.A.

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Forkhead box class O (FoxO) transcription factors are key regulators of growth, metabolism, life span, and stress resistance. FoxOs integrate signals from different pathways and guide the cellular response to varying energy and stress conditions. FoxOs are modulated by several signaling pathways, e.g., the insulin-TOR signaling pathway and the stress induced JNK signaling pathway. Here, we report a genome wide RNAi screen of kinases and phosphatases aiming to find regulators of dFoxO activity in Drosophila S2 cells. By using a combination of transcriptional activity and localization assays we identified several enzymes that modulate dFoxO transcriptional activity, intracellular localization and/or protein stability. Importantly, several currently known dFoxO regulators were found in the screening, confirming the validity of our approach. In addition, several interesting new regulators were identified, including protein kinase C and glycogen synthase kinase 3␤, two proteins with important roles in insulin signaling. Furthermore, several mammalian orthologs of the proteins identified in Drosophila also regulate FOXO activity in mammalian cells. Our results contribute to a comprehensive understanding of FoxO regulatory processes.dFoxO ͉ insulin signaling ͉ PKC F orkhead box class O (FoxO) transcription factors are members of the forkhead box transcription factor superfamily, with orthologs in various species such as mammals (1, 2), C.elegans (3), Zebrafish (4) and Drosophila (5, 6). FoxO proteins possess a wide range of cellular functions ranging from the induction of apoptosis and cell cycle control, to the oxidative stress response and lifespan determination. In addition, FoxOs are well defined targets downstream of the conserved insulin/TOR and JNK signaling networks having an important role in the regulation of processes as diverse as cellular growth, stress resistance, and energy homeostasis (7,8). Consequently, FoxOs have several characterized bona fide target genes involved in metabolism and growth, such as g6pase (9), pepck (10), 4e-bp (5, 6), insulin receptor (6, 11), and myc (12).To date, several proteins are known to interact with FoxO transcription factors, regulating their intracellular localization and/or activity, and the number of newly identified regulators is rapidly increasing (13). One of the best documented is the AKT/ PKB -kinase, which phosphorylates FoxO in three conserved Ser/Thr residues, leading to FoxO cytoplasmic retention and transcriptional inactivation (14-17). In the cytoplasm, FoxO is ubiquitinylated and targeted for degradation (18,19). Upon growth factor depletion, FoxO is predominantly nuclear. Interestingly, FoxO transcriptional activity can also be modulated in the nucleus (20,21). Furthermore, some subpopulations of growing cells possess nuclear inactive FoxO, implying that additional layers of control exist in the nucleus (22). Given the variety of cellular functions where FoxOs are implicated, and the observation that FoxOs act as a converging point for many different signa...

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Section: Discussionmentioning

confidence: 99%

RNAi screening for kinases and phosphatases identifies FoxO regulators

Mattila

Kallijärvi

Puig

2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Overexpression of Plk1 has been shown to result in the formation of abnormal centrosomes and mitotic spindle poles, which have been correlated with aneuploidy and chromosomal instability leading to tumor development. 11,12 High Plk1 levels have been seen in some cancers and implicated as a prognostic marker. [13][14][15][16][17] Studies have suggested that drugs that target the mitotic spindle assembly may be useful in the management of a variety of neoplasms because they lead to chronic mitotic arrest, cytokinesis errors and possibly apoptosis from sustained activation of the mitotic checkpoint.…”

Section: Introductionmentioning

confidence: 99%

Polo-like kinase 1 (Plk1) is expressed by cutaneous T-cell lymphomas (CTCLs), and its downregulation promotes cell cycle arrest and apoptosis

Nihal¹,

Stutz²,

Schmit³

et al. 2011

Cell Cycle

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“…Plk1 can physically bind to p53 and negatively regulate its stability and function (46). Conversely, p53 can negatively regulate Plk1 expression (56), and is a key player in the precise restriction of Plk1 gene expression during the G2/M phase (57). siRNA studies against Plk1 have also shown that knocking down Plk1 preferentially reduced survival of cells with mutant TP53 (30, 58).…”

Section: Introductionmentioning

confidence: 99%

Targeting Polo-like Kinase in Cancer Therapy

Degenhardt

Lampkin

2010

Clinical Cancer Research

231

184

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Polo-like kinases (Plk) function in mitosis and maintaining DNA integrity. There are four family members, of which Plk1 represents a target for anticancer therapy. Plk1 is only expressed in dividing cells with peak expression during G2/M. Plk1 functions in multiple steps of mitosis, and is overexpressed in many tumor types. Mitotic arrest and inhibition of proliferation, apoptosis, and tumor growth inhibition have been observed in preclinical studies using small interfering RNAs (siRNA) or small molecules that inhibit Plk1. Preclinical studies also show that Plk1 inhibitors may be active against tumors with RAS mutations and that tumor cells with mutations in TP53 are more sensitive to inhibition of Plk1. Several Plk inhibitors are in phase I or II clinical studies. As expected, hematologic toxicity is the primary dose-limiting toxicity. Some patients have achieved clinical response, although in some studies only at doses above the maximum tolerated dose defined in the study. Further evaluation is necessary to discern the clinical utility of Plk1 inhibitors.

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Polo-Like Kinase 1: Target and Regulator of Transcriptional Control

Cited by 60 publications

References 37 publications

RNAi screening for kinases and phosphatases identifies FoxO regulators

RNAi screening for kinases and phosphatases identifies FoxO regulators

Polo-like kinase 1 (Plk1) is expressed by cutaneous T-cell lymphomas (CTCLs), and its downregulation promotes cell cycle arrest and apoptosis

Targeting Polo-like Kinase in Cancer Therapy

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