Crosstalk between MYCN and MDM2-p53 signal pathways regulates tumor cell growth and apoptosis in neuroblastoma

He, Jing; Gu, Liqun; Zhang, Hailong; Zhou, Mi

doi:10.4161/cc.10.17.17118

Cited by 35 publications

(39 citation statements)

References 22 publications

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“…Subsequent inhibition of MDM2 via siRNA in these cells removed the p53 inhibition and resulted in decreased growth and induction of apoptosis due to the unrestricted p53 stimulation by MYCN itself. 93 Similar findings have been demonstrated in vivo . Utilizing murine models of human neuroblastoma xenografts, MDM2 knockdown with siRNA in cell lines expressing wild-type p53 resulted in decreased tumor growth and increased animal survival.…”

Section: Neuroblastoma and Transcription Factorssupporting

confidence: 72%

Cell Survival Signaling in Neuroblastoma

Megison¹,

Gillory²,

Beierle³

2013

ACAMC

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Neuroblastoma is the most common extracranial solid tumor of childhood and is responsible for over 15% of pediatric cancer deaths. Neuroblastoma tumorigenesis and malignant transformation is driven by overexpression and dominance of cell survival pathways and a lack of normal cellular senescence or apoptosis. Therefore, manipulation of cell survival pathways may decrease the malignant potential of these tumors and provide avenues for the development of novel therapeutics. This review focuses on several facets of cell survival pathways including protein kinases (PI3K, AKT, ALK, and FAK), transcription factors (NF-κB, MYCN and p53), and growth factors (IGF, EGF, PDGF, and VEGF). Modulation of each of these factors decreases the growth or otherwise hinders the malignant potential of neuroblastoma, and many therapeutics targeting these pathways are already in the clinical trial phase of development. Continued research and discovery of effective modulators of these pathways will revolutionize the treatment of neuroblastoma.

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Section: Neuroblastoma and Transcription Factorssupporting

confidence: 72%

Cell Survival Signaling in Neuroblastoma

Megison¹,

Gillory²,

Beierle³

2013

ACAMC

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“…All 12 cancer cell lines were established from pediatric ALL or NB patients and were well-characterized for their expression of MDM2 and p53-status (Table S1), as reported previously (Gu et al, 2012; He et al, 2011; Zhou et al, 1995). The 293T cell line was used for gene transfection and in vivo ubiquitination assays.…”

Section: Methodsmentioning

confidence: 99%

Discovery of Dual Inhibitors of MDM2 and XIAP for Cancer Treatment

Zhang

Liu

et al. 2016

Cancer Cell

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SUMMARY MDM2 and XIAP are mutually regulated: Binding of MDM2 RING protein to the IRES region on XIAP mRNA results in MDM2 protein stabilization and enhanced XIAP translation. In this study, we developed a protein-RNA fluorescence polarization (FP) assay for high-throughput screening (HTS) of chemical libraries. Our FP-HTS identified eight inhibitors that blocked the MDM2 protein-XIAP RNA interaction, leading to MDM2 degradation. The compound-induced MDM2 downregulation resulted not only in inhibition of XIAP expression, but also in activation of p53, which contributed to cancer cell apoptosis in vitro and inhibition of cancer cell proliferation in vivo. Importantly, one of the MDM2/XIAP inhibitors, MX69, showed minimal inhibitory effect on normal human hematopoiesis in vitro and was very well tolerated in animal models.

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“…MYCN has been shown to bind to the p53 promoter and positively regulate its expression [46], but whether a significant change in cellular phenotypes result is questionable. For instance, He and colleagues have demonstrated that silencing Mdm2 in MYCN positive cell lines inhibited cell growth in a p53-independent manner, whereas silencing Mdm2 in non- MYCN cell lines triggered p53-dependent apoptosis [47], suggesting the role for other cell survival proteins in the MYCN positive cells with relation to p53. Additionally, Tweddle, in 2001, published that neuroblastoma cell lines without MYCN amplification, but not those that were MYCN amplified, entered G1 arrest following induction of p53 activity with irradiation.…”

Section: Discussionmentioning

confidence: 99%

Focal adhesion kinase and p53 synergistically decrease neuroblastoma cell survival

Gillory

Stewart

Megison

et al. 2015

Journal of Surgical Research

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Neuroblastoma is the most common extracranial solid tumor of childhood and is responsible for over 15% of pediatric cancer deaths. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is important in many facets of neuroblastoma tumor development and progression. The p53 oncogene, although wild type in most neuroblastomas, lacks significant function as a tumor suppressor in these tumors. Recent reports have found that FAK and p53 interact in some tumor types. We have hypothesized FAK and p53 coordinately control each other’s expression and also interact in neuroblastoma. In the current study, we showed that not only do FAK and p53 interact but each one controls the expression of the other. In addition, we also examined the effects of FAK inhibition combined with p53 activation in neuroblastoma and showed that these two, in combination, had a synergistic effect upon neuroblastoma cell survival. The findings from this current study help to further our understanding of the regulation of neuroblastoma tumorigenesis, and may provide novel therapeutic strategies and targets for neuroblastoma and other pediatric solid tumors.

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Crosstalk between MYCN and MDM2-p53 signal pathways regulates tumor cell growth and apoptosis in neuroblastoma

Cited by 35 publications

References 22 publications

Cell Survival Signaling in Neuroblastoma

Cell Survival Signaling in Neuroblastoma

Discovery of Dual Inhibitors of MDM2 and XIAP for Cancer Treatment

Focal adhesion kinase and p53 synergistically decrease neuroblastoma cell survival

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