The N-myc Oncogene: Maximizing its Targets, Regulation, and Therapeutic Potential

Beltran, Himisha

doi:10.1158/1541-7786.mcr-13-0536

Cited by 124 publications

(121 citation statements)

References 90 publications

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“…However, unlike c-myc (Myc -Mouse Genome Informatics), information on targets of N-myc remains scarce (Beltran, 2014). Our microarray-based screening has identified Otx2 as one of the genes for which expression depends on N-myc during inner ear development.…”

Section: Discussionmentioning

confidence: 99%

Otx2 is a target of N-myc and acts as a suppressor of sensory development in the mammalian cochlea

et al. 2015

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Transcriptional regulatory networks are essential during the formation and differentiation of organs. The transcription factor N-myc is required for proper morphogenesis of the cochlea and to control correct patterning of the organ of Corti. We show here that the Otx2 gene, a mammalian ortholog of the Drosophila orthodenticle homeobox gene, is a crucial target of N-myc during inner ear development. Otx2 expression is lost in N-myc mouse mutants, and N-myc misexpression in the chick inner ear leads to ectopic expression of Otx2. Furthermore, Otx2 enhancer activity is increased by N-myc misexpression, indicating that N-myc may directly regulate Otx2. Inactivation of Otx2 in the mouse inner ear leads to ectopic expression of prosensory markers in non-sensory regions of the cochlear duct. Upon further differentiation, these domains give rise to an ectopic organ of Corti, together with the respecification of non-sensory areas into sensory epithelia, and the loss of Reissner's membrane. Therefore, the Otx2-positive domain of the cochlear duct shows a striking competence to develop into a mirrorimage copy of the organ of Corti. Taken together, these data show that Otx2 acts downstream of N-myc and is essential for patterning and spatial restriction of the sensory domain of the mammalian cochlea.

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Section: Discussionmentioning

confidence: 99%

Otx2 is a target of N-myc and acts as a suppressor of sensory development in the mammalian cochlea

et al. 2015

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“…So far, small molecules directly inhibiting MYCN have not yet been found, thus non-small molecules and indirect inhibitors are sought for therapy [7,16]. Peptidic analogs able to induce a sustainable decrease in MYCN expression would be of interest not only for therapy of NB but also for other tumors such as neuroendocrine prostate cancer for which 40% present a MYCN amplification [50]. AKT analysis was performed as described in Figure 5 B.…”

Section: Mycn-amplifiedmentioning

confidence: 99%

VIP and PACAP analogs regulate therapeutic targets in high-risk neuroblastoma cells

et al. 2016

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“…It accounts for approximately 15% of all childhood cancer-related death despite the use of combination chemotherapy, radiotherapy, and bone marrow transplantation (1, 3). Amplification of the MYCN oncogene strongly correlates with an aggressive tumor behavior and is currently used as an indicator for poor patient prognosis (1, 3,4).…”

Section: Introductionmentioning

confidence: 99%

WDR5 Supports an N-Myc Transcriptional Complex That Drives a Protumorigenic Gene Expression Signature in Neuroblastoma

et al. 2015

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MYCN gene amplification in neuroblastoma drives a gene expression program that correlates strongly with aggressive disease. Mechanistically, trimethylation of histone H3 lysine 4 (H3K4) at target gene promoters is a strict prerequisite for this transcriptional program to be enacted. WDR5 is a histone H3K4 presenter that has been found to have an essential role in H3K4 trimethylation. For this reason, in this study, we investigated the relationship between WDR5-mediated H3K4 trimethylation and N-Myc transcriptional programs in neuroblastoma cells. N-Myc upregulated WDR5 expression in neuroblastoma cells. Gene expression analysis revealed that WDR5 target genes included those with MYC-binding elements at promoters such as MDM2. We showed that WDR5 could form a protein complex at the MDM2 promoter with N-Myc, but not p53, leading to histone H3K4 trimethylation and activation of MDM2 transcription. RNAi-mediated attenuation of WDR5 upregulated expression of wild-type but not mutant p53, an effect associated with growth inhibition and apoptosis. Similarly, a small-molecule antagonist of WDR5 reduced N-Myc/WDR5 complex formation, N-Myc target gene expression, and cell growth in neuroblastoma cells. In MYCN-transgenic mice, WDR5 was overexpressed in precancerous ganglion and neuroblastoma cells compared with normal ganglion cells. Clinically, elevated levels of WDR5 in neuroblastoma specimens were an independent predictor of poor overall survival. Overall, our results identify WDR5 as a key cofactor for N-Myc-regulated transcriptional activation and tumorigenesis and as a novel therapeutic target for MYCN-amplified neuroblastomas. Cancer Res; 75(23); 5143-54. Ó2015 AACR.

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The N-myc Oncogene: Maximizing its Targets, Regulation, and Therapeutic Potential

Cited by 124 publications

References 90 publications

Otx2 is a target of N-myc and acts as a suppressor of sensory development in the mammalian cochlea

Otx2 is a target of N-myc and acts as a suppressor of sensory development in the mammalian cochlea

VIP and PACAP analogs regulate therapeutic targets in high-risk neuroblastoma cells

WDR5 Supports an N-Myc Transcriptional Complex That Drives a Protumorigenic Gene Expression Signature in Neuroblastoma

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