Disease relevance of Mycn

• Here, we show that conditional deletion of N-Myc (Mycn) in the developing mouse limb leads to uniformly small skeletal elements and profound soft-tissue syndactyly [1].
• To address the role of N-myc in neurogenesis and in nervous system tumors, it was conditionally disrupted in neuronal progenitor cells (NPCs) with a nestin-Cre transgene [2].
• Finally, cyclin D1 and N-myc are overexpressed in murine medulloblastoma [3].
• Id2 is critical for cellular proliferation and is the oncogenic effector of N-myc in human neuroblastoma [4].
• These results demonstrate that the 3' region of the N-myc gene is one of the integration targets for murine leukemia viruses in spontaneous thymic lymphomas [5].

Psychiatry related information on Mycn

• Whereas c-myc/pim-1 animals develop pre-B-cell leukemia prenatally, the mean latency period for N-myc/pim-1 and L-myc/pim-1 mice is 36 and 94 days respectively [6].

High impact information on Mycn

• In all these T cell lymphomas either c-myc or N-myc was activated by proviral insertion, suggesting strong cooperation between pim-1 and myc in lymphomagenesis [7].
• In neuroblastoma, an embryonal tumour derived from the neural crest, Id2 is overexpressed in cells carrying extra copies of the N-myc gene [8].
• Activated N-myc and L-myc expression has been implicated in oncogenesis; for example, although N-myc expression has been found in all neuroblastomas tested, activated (greatly increased) N-myc expression, resulting from gene amplification, is correlated with progression of the tumour [9].
• The L-myc gene is less well characterized, but shows homology to N-myc and c-myc (ref. 6; also see below). c-myc is expressed in most dividing cells, and deregulated expression of this gene has been implicated in the development of many classes of tumours [9].
• The N-myc and c-myc genes have 5'-noncoding exons, strikingly homologous coding regions, and display similar oncogenic potential in an in vitro transformation assay [9].

Chemical compound and disease context of Mycn

• An exceptional mouse plasmacytoma with a new kappa/N-myc [T(6; 12) (C1; B)] translocation expresses N-myc but not c-myc [10].
• Effect of vitamin E succinate and a cAMP-stimulating agent on the expression of c-myc and N-myc and H-ras in murine neuroblastoma cells [11].
• A nude mouse model for human neuroblastoma has been developed to examine possible relationships between amplification/over-expression of the N-myc oncogene and altered regulation of expression of specific integrin subunits during tumor progression [12].
• It is shown in this paper that serum growth factors are required for activation of expression of gene encoding translation initiation factor 4E (eIF-4E) in non-transformed NIH 3T3 and Rat-1 fibroblasts but this requirement is lost in C6 glioblastoma, A431 carcinoma and N-myc transformed Rat-1 cells [13].

Biological context of Mycn

• In particular, we found that in cerebellar granule neuron precursors, the N-myc transcription factor communicates with the cell cycle machinery via cyclins D1 and D2, but not D3, explaining the inability of D3-only mice to up-regulate cyclin D3 in this compartment [14].
• Targeted deletion of N-myc results in severely compromised proliferation as shown by a striking decrease in S phase and mitotic cells as well as in cells expressing the Myc target gene cyclin D2, whereas apoptosis is unaffected [2].
• Previously, we have shown that TGF-beta 1 inhibits branching morphogenesis and N-myc expression in mouse embryonic lung cultures [15].
• For the N-myc and L-myc oncogenes, expression was also highest in prenatal and newborn tissue as compared to the 6-month young adult, but little or no further change was found at older ages [16].
• Taken together, these results indicate that the expression of the proto-oncogenes c-, L- and N-myc is dependent not only on tissue and embryonic development, as previously shown by other workers, but also on age past the young adult stage of life span [16].

Anatomical context of Mycn

• N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation [2].
• In addition, loss of N-myc disrupts neuronal differentiation as evidenced by ectopic staining of the neuron specific marker betaTUBIII in the cerebrum [2].
• For example, during mouse lens maturation, the growth arrest and differentiation of epithelial cells into lens fiber cells is associated with a decrease in L- and c-myc expression and a reciprocal rise in N-myc levels [17].
• Lmyc, but not c-myc and Nmyc, was upregulated in terminally differentiated visceral endoderm cells [18].
• However, substantial tissue-dependent differences in expression were also found, and no expression at all was detected at any age for N-myc in liver and for L-myc in heart, small intestine and liver [16].

Associations of Mycn with chemical compounds

• N-myc transcription is induced in the presence of the protein synthesis inhibitor cycloheximide, so it appears to be a direct target of Shh [3].
• The expression of N-myc was synergistically enhanced by LPS and IFNgamma in microglia [19].
• Tetracycline-based conditional expression of N-myc sensitized microglia to nitric oxide (NO)-induced apoptosis [19].
• The N-myc alleles were disrupted in ES cells, line E14, by means of homologous recombination of targeting vectors that carry neomycin or hygromycin resistant genes [20].
• Previous studies have shown that N-myc expression significantly decreases when the stem cells are subjected to long-term induction for differentiation by retinoic acid (RA) [21].

Physical interactions of Mycn

• We have also found that Tbx2 directly binds to the Nmyc1 promoter in developing heart, and can repress expression of the Nmyc1 promoter in transient transfection studies [22].
• To assess the impact of constitutive N-myc expression on lymphocytes, we generated lines of transgenic mice bearing the murine N-myc oncogene coupled to the immunoglobulin heavy chain enhancer (E mu) [23].

Regulatory relationships of Mycn

• We present a model whereby Tbx2 directly represses Nmyc1 in outflow tract and atrioventricular canal of the developing heart, resulting in relatively low proliferation [22].
• According to this interpretation, constitutive activation of N-myc would suppress the expression of c-myc, but would not interfere with the differentiation of the pro-B cell into a fully mature plasma cell [24].
• We have generated transgenic mouse lines that carry one of three different constructs in which the murine N-myc gene is expressed under the control of the immunoglobulin heavy chain transcriptional enhancer element (E mu-N-myc genes) [25].
• Our data present a paradigm by which T-box proteins regulate regional differences in Nmyc1 expression and proliferation to effect organ morphogenesis [22].
• We report a new common proviral insertion site in murine leukemia virus-induced T cell lymphomas to be N-myc [26].

Other interactions of Mycn

• Transcriptional profiling of the Sonic hedgehog response: a critical role for N-myc in proliferation of neuronal precursors [3].
• pRb is necessary for inhibition of N-myc expression by TGF-beta 1 in embryonic lung organ cultures [15].
• The Ndr1 gene was augmented 20-fold in the mutant embryos at 10.5 days post coitus which is indicative of repression by N-myc [27].
• We studied the loci into which the M-MuLV had inserted, and found that in 73% of animals, either the c-myc or the N-myc genes had been disrupted and deregulated [28].
• Other studies revealed that preimplantation embryos lacking c-myc, N-myc, or L-myc are viable, indicating that these genes are either not essential for preimplantation development or can be substituted for functionally by other myc gene family members [29].

Analytical, diagnostic and therapeutic context of Mycn

• Analysis and quantitation of c-myc and N-myc in dually stained cells was done by flow cytometry [30].
• Development of a two color immunofluorescence stain and immunolocalization method for N-myc and c-myc oncoproteins with a newly generated mouse IgM anti N-myc antibody [30].
• We have explored this possibility by using hybridization in situ to examine the expression of myc and N-myc during gastrulation of mouse embryos [31].
• We have generated a leaky mutation in N-myc by gene targeting in embryonic stem cells [32].
• The synergistic effect of LPS/IFNgamma on the microglial N-myc induction was mediated through Janus kinase (JAK)/STAT1 (signal transducer and activator of transcription 1) pathway [19].

References