Polo-like kinase 1 phosphorylates and regulates Bcl-xL during pironetin-induced apoptosis

Tamura, Yuki; Simizu, Siro; Muroi, Makoto; Takagi, Satoshi; Kawatani, Masahito; Watanabe, Nobumoto; Osada, Hiroyuki

doi:10.1038/onc.2008.368

Cited by 36 publications

(28 citation statements)

References 39 publications

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“…These include, for example, the MT-destabilizing proteins Op18/ Stahmin1 (44) and TCTP (45), and the MT-depolymerizing Kif2A (46). Although we could not find a direct link between ASAP phosphorylation on Ser-289 and MT nucleation (data not shown), again we cannot exclude that the phenotype observed is only partial and would require the cumulative effect of several mutations to be complete and therefore stronger as is often described in the literature (16,47). ASAP phosphorylation by Plk1 on Ser-289 may be required to maintain PCM integrity directly or indirectly via the regulation of other proteins involved in this process as proposed in Fig.…”

Section: Discussioncontrasting

confidence: 44%

Plk1 Regulates Both ASAP Localization and Its Role in Spindle Pole Integrity

Éot-Houllier¹,

Venoux²,

Vidal-Eychenié

et al. 2010

Journal of Biological Chemistry

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Bipolar spindle formation is essential for faithful chromosome segregation at mitosis. Because centrosomes define spindle poles, abnormal number and structural organization of centrosomes can lead to loss of spindle bipolarity and genetic integrity. ASAP (aster-associated protein or MAP9) is a centrosome-and spindle-associated protein, the deregulation of which induces severe mitotic defects. Its phosphorylation by Aurora A is required for spindle assembly and mitosis progression. Here, we show that ASAP is localized to the spindle poles by Polo-like kinase 1 (Plk1) (a mitotic kinase that plays an essential role in centrosome regulation and mitotic spindle assembly) through the ␥-TuRC-dependent pathway. We also demonstrate that ASAP is a novel substrate of Plk1 phosphorylation and have identified serine 289 as the major phosphorylation site by Plk1 in vivo. ASAP phosphorylated on serine 289 is localized to centrosomes during mitosis, but this phosphorylation is not required for its Plk1-dependent localization at the spindle poles. We show that phosphorylated ASAP on serine 289 contributes to spindle pole stability in a microtubule-dependent manner. These data reveal a novel function of ASAP in centrosome integrity. Our results highlight dual ASAP regulation by Plk1 and further confirm the importance of ASAP for spindle pole organization, bipolar spindle assembly, and mitosis.

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Section: Discussioncontrasting

confidence: 44%

Plk1 Regulates Both ASAP Localization and Its Role in Spindle Pole Integrity

Éot-Houllier¹,

Venoux²,

Vidal-Eychenié

et al. 2010

Journal of Biological Chemistry

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“…Bcl-xL phosphorylation at Ser62 is well-documented and generally associated with microtubule poisoning [41][42][43][44][45][46][47][48][49]. Phospho-Bcl-xL(Ser62) functions have remained elusive until recently.…”

Section: Discussionmentioning

confidence: 99%

“…Bcl-xL also fulfills functions during the cell cycle [38][39][40]. Bcl-xL phosphorylation at Ser62, within the unstructured loop domain of the protein, has been detected most often in cells treated with microtubule poisons, including nocodazole, paclitaxel, vinblastine, vincristine, colchicine and pironetin [41][42][43][44][45][46][47][48][49], and coupled, more recently, with specific G2 and mitotic events (Wang et al, 2011; manuscripts submitted). Similarly, Bcl-xL phosphorylation at Thr47 and Thr115 has been documented in response to genotoxic stress induced by ionizing radiation [50].…”

Section: Introductionmentioning

confidence: 99%

Bcl-xL phosphorylation at Ser49 by polo kinase 3 during cell cycle progression and checkpoints

Wang

Beauchemin

Bertrand

2011

Cellular Signalling

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Functional analysis of a Bcl-xL phosphorylation mutant series has revealed that cells expressing Bcl-xL(Ser49Ala) mutant are less stable at G2 checkpoint after DNA damage and enter cytokinesis more slowly after microtubule poisoning, than cells expressing wild-type Bcl-xL. These effects of Bcl-xL(Ser49Ala) mutant seem to be separable from Bcl-xL function in apoptosis. Bcl-xL(Ser49) phosphorylation is cell cycle-dependent. In synchronized cells, phosphoBcl-xL(Ser49) appears during the S phase and G2, whereas it disappears rapidly in early mitosis during prometaphase, metaphase and early anaphase, and re-appears during telophase and cytokinesis. During DNA damage-induced G2 arrest, an important pool of phospho-Bcl-xL(Ser49) accumulates in centrosomes which act as essential decision centers for progression from G2 to mitosis. During telophase/cytokinesis, phospho-Bcl-xL (Ser49) is found with dynein motor protein. In a series of in vitro kinase assays, specific small interfering RNA and pharmacological inhibition experiments, polo kinase 3 (PLK3) was implicated in Bcl-xL(Ser49) phosphorylation. These data indicate that, during G2 checkpoint, phospho-Bcl-xL(Ser49) is another downstream target of PLK3, acting to stabilize G2 arrest. Bcl-xL phosphorylation at Ser49 also correlates with essential PLK3 activity and function, enabling cytokinesis and mitotic exit.

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“…23 CI values o1 indicate synergy, a CI ¼ 1 indicates an additive effect, and a CI 41 indicates antagonism between the two agents.…”

Section: Discussionmentioning

confidence: 99%

A novel treatment strategy targeting polo-like kinase 1 in hematological malignancies

et al. 2009

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Polo-like kinase1 (PLK1) belongs to the family of serine/ threonine kinases and plays an important role in centrosome maturation, bipolar spindle formation, and cytokinesis during mitosis. We found in this study that PLK1 was aberrantly highly expressed in a variety of human leukemia cell lines (n ¼ 20), as well as, freshly isolated leukemia cells from individuals with acute myelogenous leukemia (n ¼ 50) and acute lymphoblastic leukemia (n ¼ 15) compared with bone marrow mononuclear cells from healthy volunteers (n ¼ 13) (acute myelogenous leukemia, P ¼ 0.016; acute lymphoblastic leukemia, P ¼ 0.008), as measured by real-time RT-PCR. Downregulation of PLK1 by a small interfering RNA in NB4 acute myelogenous leukemia cells inhibited their proliferation. GW843682X is a novel selective PLK1 inhibitor. The compound-induced growth inhibition, caused accumulation of cells in the G2/M phase of the cell cycle and mediated apoptosis of human leukemia cells. Pre-treatment of cells with the caspase inhibitor Z-VAD-FMK attenuated the action of GW843682X in leukemia cells, indicating the involvement of the caspase pathway in the PLK1 inhibitor-mediated apoptosis. Furthermore, we found that the PLK1 inhibitor synergistically potentiated the growth inhibition and apoptosis of leukemia cells when combined with tubulindepolymerizing agent vincristine. Taken together, targeting PLK1 may be a promising treatment strategy for individuals with leukemia.

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Polo-like kinase 1 phosphorylates and regulates Bcl-xL during pironetin-induced apoptosis

Cited by 36 publications

References 39 publications

Plk1 Regulates Both ASAP Localization and Its Role in Spindle Pole Integrity

Plk1 Regulates Both ASAP Localization and Its Role in Spindle Pole Integrity

Bcl-xL phosphorylation at Ser49 by polo kinase 3 during cell cycle progression and checkpoints

A novel treatment strategy targeting polo-like kinase 1 in hematological malignancies

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