Disease relevance of MYCN

• In summary, iNKTs migrate toward neuroblastoma cells in a CCL2-dependent manner, preferentially infiltrating MYCN nonamplified tumors that express CCL2 [1].
• MYCN transgene amplification was present at low levels in perinatal neuroblast hyperplasia from both homo- and hemizygote TH-MYCN mice [2].
• Recently, we have shown that the novel DDX1 gene containing a DEAD box motif maps to the same chromosome band as MYCN at 2p24 and is co-amplified with MYCN in retinoblastoma cell lines [3].
• Mapping of chromosomal imbalances in gastric adenocarcinoma revealed amplified protooncogenes MYCN, MET, WNT2, and ERBB2 [4].
• Of these four presumably activated oncogenes, two, MYCN and WNT2, were previously not assumed to play a pathogenic role in stomach cancer [4].
• MYCN knockdown in MYCN-amplified neuroblastoma cell lines restored CCL2 production and NKT cell chemoattraction [5].
• 2. These data indicate that, besides MYCN, other genes proximal and distal to MYCN are highly expressed in neuroblastoma [6].

Psychiatry related information on MYCN

• The status of the MYCN gene has become an important factor in clinical decision making and therapy stratification [7].
• Increase in Bcl-2 and N-myc occurred in Purkinje cells in CJD and OPCA [8].

High impact information on MYCN

• All mutations are predicted to disrupt both the full-length protein and a new shortened MYCN isoform, suggesting that multiple aspects of early embryogenesis and postnatal brain growth in humans are tightly regulated by MYCN dosage [9].
• This gain has been associated with advanced disease, patients who are > or =1 year old, deletion of chromosome arm 1p, and amplification of the N-myc oncogene, all of which predict an adverse outcome [10].
• Clinical and survival information were collected, along with data on 1p, N-myc, and ploidy [10].
• The findings suggest that expression of this multidrug-resistance gene accounts for the association between N-myc amplification and reduced survival [11].
• The expression of MRP by neuroblastoma cells correlates with N-myc oncogene amplification, a well-established prognostic indicator in patients with neuroblastoma [11].

Chemical compound and disease context of MYCN

• However, in a neuroblastoma cell line that does not express MYCN, overexpression of E2F-1 was not sufficient to activate the MYCN promoter even in the presence of trichostatin A and 5-aza-cytidine [12].
• Expression of trkB in human neuroblastoma in relation to MYCN expression and retinoic acid treatment [13].
• This shows that MYCN overexpression per se is not sufficient to induce trkB expression. trkB expression and BDNF responsiveness in neuroblastoma cells can be induced by all-trans-retinoic acid (RA) [13].
• The MYCN protein of human neuroblastoma cells is phosphorylated by casein kinase II in the central region and at serine 367 [14].
• Induction of senescence in MYCN amplified neuroblastoma cell lines by hydroxyurea [15].

Biological context of MYCN

• The MYCN oncogene is the major negative prognostic marker in neuroblastoma with important roles in both the pathogenesis and clinical behavior of this aggressive malignancy [16].
• To identify novel transcriptional targets mediating the MYCN-dependent phenotype, we screened a MYCN-amplified neuroblastoma cell line by using chromatin immunoprecipitation (ChIP) cloning [16].
• Targeted inhibition of MYCN in a MYCN-amplified neuroblastoma cell line resulted in decreased MDM2 expression levels with concomitant stabilization of p53 and induction of apoptosis [16].
• Oligonucleotide pull-down assays further established the capacity of MYCN to bind to this promoter region, confirming the ChIP results [16].
• PURPOSE: Amplification of the MYCN oncogene at chromosome 2p24-25 identifies an aggressive subtype of human neuroblastoma with a poor clinical outcome [17].

Anatomical context of MYCN

• Furthermore, the MYCN gene is also present in multiple copies in these two cell lines, suggesting coamplification of the two genes [18].
• These data suggest that inappropriate perinatal MycN expression in paravertebral ganglia cells from TH-MYCN mice initiated tumorigenesis by altering the physiologic process of neural crest cell deletion [2].
• Paravertebral neuronal cells cultured from perinatal TH-MYCN mice exhibited 3- to 10-fold resistance to nerve growth factor (NGF) withdrawal, compared with normal mice [2].
• Finally, we show a significant correlation between centrosome amplification and MYCN amplification in primary neuroblastoma tumors [19].
• Caspase-9 and Apaf-1 are expressed and functionally active in human neuroblastoma tumor cell lines with 1p36 LOH and amplified MYCN [20].

Associations of MYCN with chemical compounds

• In addition, MYCN constitutive expression abolishes HMGA1 repression by RA [21].
• In addition, we provide evidence that E2F proteins are involved in the negative regulation of MYCN by TGF-beta and retinoic acid [22].
• Therefore, we analysed the mechanism of action of DFMO and/or SAM486A in two established MYCN-amplified human NB cell lines [23].
• A nutlin-3 response was observed regardless of MYCN amplification status [24].
• In Tet21N cells, which conditionally express MYCN, greatly enhanced (nearly 6-fold) sensitivity to WP744 killing was seen when this oncogene was induced, while enhanced sensitivity to Dox was more modest (2-fold) under MYCN-induced conditions [25].

Physical interactions of MYCN

• Expression of a MYCN-interacting isoform of the tumor suppressor BIN1 is reduced in neuroblastomas with unfavorable biological features [26].
• Finally, DNA cross-linking experiments show that nestin binds DNA in N-myc-amplified N-type cell lines [27].
• However, the ability of the CD44 receptor to bind immobilized hyaluronan was restricted to CD44H+ cell lines without NMYC amplification (SH-EP and ACN) [28].
• The high-mobility group transcription factor Sox10 interacts with the N-myc-interacting protein Nmi [29].
• The alteration in the N-myc level was well correlated with the formation of complexes with the E2F motif in the N-myc promoter region, and no complex was formed with cell extracts prepared from cells treated with HMBA for 12-24 h [30].

Enzymatic interactions of MYCN

• These results suggest that two serine residues of the acidic central region of the N-myc protein are phosphorylated by CKII in vivo as well as in vitro [31].

Regulatory relationships of MYCN

• MYCN cotransfection activated a promoter/luciferase reporter containing a 1,600 bp region surrounding the first three transcription start sites of the human HMGA1 and eight imperfect E-boxes [21].
• E2F proteins regulate MYCN expression in neuroblastomas [22].
• Further research into the MYCN/MDM2 regulated pathways will provide insight into the pathogenesis of MYCN-driven tumors and provide targets for novel therapeutic interventions [32].
• These findings indicate that by interacting with E-box elements within the promoter, MYCN can upregulate MRP1 expression and modulate drug resistance in NB [33].
• BIN1 inhibits colony formation and induces apoptosis in neuroblastoma cell lines with MYCN amplification [34].

Other interactions of MYCN

• Coamplification of DDX1 correlates with an improved survival probability in children with MYCN-amplified human neuroblastoma [17].
• These data support the hypothesis that elevated MDM2 levels contribute to MYCN-induced genomic instability through altered regulation of centrosome replication in neuroblastoma [19].
• Either 5' or 3' deletion variants of the 1,600 bp promoter/luciferase reporter strongly decreased luciferase activity, suggesting that, more than a single site, the cooperative function of multiple cis-acting elements mediates direct HMGA1 transactivation by MYCN [21].
• Additionally, overexpression of the proto-oncogenes CCND2 and MYCN were confirmed from the literature [35].
• Using an MDR1 promoter-CAT construct, we have shown that the MycN protein activates MDR1 transcription both in exogenous transient MYCN-transfected SK-N-SH cells and in endogenous BM metastatic neuroblasts with an increase in the MYCN transcript level [36].

Analytical, diagnostic and therapeutic context of MYCN

• Real-time quantitative PCR and Western blot analysis demonstrated a rapid increase in endogenous MDM2 mRNA and MDM2 protein upon induction of MYCN [16].
• Fluorescence in situ hybridization analysis confirmed an amplicon on chromosome 18 as the site of TH-MYCN transgene integration [37].
• In addition, ID2 mRNA expression was not associated with MYCN gene amplification status (P = 0.15) or MYCN expression (r = 0.22) in 131 separate diagnostic primary neuroblastoma samples analyzed by real-time quantitative RT-PCR [38].
• Microarray analysis of RNA from neuroblastoma primary cell cultures revealed 10-fold higher MCM7 expression in MYCN-amplified versus nonamplified tumors [39].
• In order to elucidate the mechanism mediating the effects of BL1521 on neuroblastoma cells, we investigated the gene expression profile of an MYCN single copy (SKNAS) and an MYCN amplified (IMR32) neuroblastoma cell line after treatment with BL1521 using the Affymetrix oligonucleotide array U133A [40].

References