Bcl-2 is a key regulator for the retinoic acid-induced apoptotic cell death in neuroblastoma

Niizuma, Hidetaka; Nakamura, Yohko; Ozaki, Toshinori; Nakanishi, Hiroyuki; Ohira, Miki; Isogai, Emiko; Kageyama, Hajime; Imaizumi, Masue; Nakagawara, Akira

doi:10.1038/sj.onc.1209515

Cited by 70 publications

(44 citation statements)

References 44 publications

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“…Of note, the expression levels of pro-apoptotic p53 AIP1 , which is one o the p53/p73 target genes, were significantly induced in Plk1-knocked down cells. Immunoblot analysis clearly demonstrated that the proteolytic cleavage of PARP, which is one of the substrates of the activated caspase-3 (30), is observed in Plk1-knocked down cells in association with a significant induction of pro-apoptotic p73␣ (Fig. 1B).…”

Section: Sirna-mediated Knockdown Of Plk1 Results In a Massivementioning

confidence: 99%

“…In accordance with this notion, our in vitro kinase reactions demonstrated that GST-p73␣-(1-130) is phosphorylated by Plk1. During the extensive search for putative phosphorylation site(s) within the NH 2 -terminal portion of p73␣, we found out two canonical phosphorylation sites targeted by Plk1, including ( 25 DSTYFD 30 ) and ( 46 DSSMDV 51 ). Thr-27 substituted to Ala GST or the indicated GST-p73␣ deletion mutants bound to glutathione-Sepharose beads were washed with washing buffer and resuspended in 90 l of kinase reaction buffer.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Sirna-mediated Knockdown Of Plk1 Results In a Massivementioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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“…Together with previous reports demonstrating the importance of the Notch pathway for neuronal commitment, 12,48 this study helps to characterize critical genes that might contribute to the setting up of neuronal lineages. In addition, Bcl2 gene, known as an RA-induced gene, 49,50 could be one of the direct effectors of neuronal differentiation in RA-based differentiation procedures classically used in the ES cell system.…”

Section: Discussionmentioning

confidence: 99%

Bcl2, a transcriptional target of p38α, is critical for neuronal commitment of mouse embryonic stem cells

et al. 2008

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Mouse embryonic stem (ES) cells remain pluripotent in vitro when grown in the presence of leukemia inhibitory factor (LIF) cytokine. LIF starvation leads to cell commitment, and part of the ES-derived differentiated cells die by apoptosis together with caspase3-cleavage and p38a activation. Inhibition of p38 activity by chemical compounds (PD169316 and SB203580), along with LIF withdrawal, leads to different outcomes on cell apoptosis, giving the opportunity to study the influence of apoptosis on cell differentiation. By gene profiling studies on ES-derived differentiated cells treated or not with these inhibitors, we have characterized the common and specific set of genes modulated by each inhibitor. We have also identified key genes that might account for their different survival effects. In addition, we have demonstrated that some genes, similarly regulated by both inhibitors (upregulated as Bcl2, Id2, Cd24a or downregulated as Nodal), are bona fide p38a targets involved in neurogenesis and found a correlation with their expression profiles and the onset of neuronal differentiation triggered upon retinoic acid treatment. We also showed, in an embryoid body differentiation protocol, that overexpression of EGFP (enhanced green fluorescent protein)-BCL2 fusion protein and repression of p38a are essential to increase formation of TUJ1-positive neuronal cell networks along with an increase in Map2-expressing cells.

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“…SMS-KCNR cells (human neuroblastoma) were provided by Dr J. Maris (CHOP, Philadelphia, PA) and TCL-1 cells (immortalized retroviral large T-antigen transfected trophoblasts) by Dr S. Sharma (Woman & Infants Hospital, Providence, RI). All cells were seeded at 5x10 5 /T75 flask (Corning, New York, NY) and cultured to ~80% confluency according to the suppliers recommendations at 37˚C, 5% CO 2 in a humidified incubator.…”

Section: Isolation Of Oligomeric Proanthocyanidines (Pac)mentioning

confidence: 99%

“…Eradication of refractory disease remains one of the most significant challenges in the treatment of high-risk NB. The etiology of NB reveals various potential targets for new drugs such as aberrant Bcl-2-family gene expression (5), MYCN amplification and expression (6) or growth factor pathways (7). The tumor necrosis factor (TNF) signaling pathway is a key player in aggressive NB (8) in which caspase-8, component of the apoptotic death receptor pathway is inactive (9).…”

Section: Introductionmentioning

confidence: 99%

Purified cranberry proanthocyanidines (PAC-1A) cause pro-apoptotic signaling, ROS generation, cyclophosphamide retention and cytotoxicity in high-risk neuroblastoma cells

Vorsa

2011

Int J Oncol

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Abstract. Optimized purification of oligomeric proanthocyanidines (PAC) from cranberry generated PAC-1A which selectively affected the viability of various neuroblastoma (NB) cell lines representing a spectrum of high-risk NB features. PAC-1A caused a loss of mitochondrial transmembrane depolarization potential (∆Ψm) and increased generation of reactive oxygen species (ROS) which was directly correlated to the modulation of apoptotic marker proteins in SMS-KCNR cells. PAC-1A reduced the expression of pro-survival (Bcl-2, MCL-1, Bcl-xL) and increased levels of pro-apoptotic (Bax, Bad, Bid) Bcl family proteins, upregulated the activity of SAPK/JNK MAPK and downregulated expression or activity of PI3K/AKT/mTOR pathway components. PAC-1A increased the cellular uptake/ retention of cyclophosphamide (CP). PAC-1A and CP synergistically increased cytotoxicity and expression of pro-apoptotic markers, reduced cellular glutathione (GSH) and superoxide dismutase (SOD) levels. Additional features of PAC-1A as an anticancer drug as shown in SMS-KCNR NB cells include delay of cell cycle progression and induction of cell death via TNF-family death receptor activity, thus, targeting both the extrinsic and intrinsic pathway of apoptosis. PAC-1A partially blocked the cell cycle in G2/M phase which correlated with a decrease of the G0/G1 subpopulation, upregulation of cyclin D1 and downregulation of CDK6 and p27 expression. In summary, PAC-1A has demonstrated chemotherapeutic potential to treat a broad spectrum of NBs including highly malignant tumors that show resistance to standard chemotherapeutics and apoptotic stimuli.

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Bcl-2 is a key regulator for the retinoic acid-induced apoptotic cell death in neuroblastoma

Cited by 70 publications

References 44 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

Bcl2, a transcriptional target of p38α, is critical for neuronal commitment of mouse embryonic stem cells

Purified cranberry proanthocyanidines (PAC-1A) cause pro-apoptotic signaling, ROS generation, cyclophosphamide retention and cytotoxicity in high-risk neuroblastoma cells

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