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The deregulation of proto-oncogene MYC plays a key role in human oncogenesis. Unlike other proto-oncogenes, whose activity is due to mutation or truncation, MYC becomes deregulated due to loss of transcriptional control leading to protein over-expression.
For example, in human Burkitt's lymphoma, translocation of the MYC gene into the immunoglobulin heavy or light chain loci results in c-Myc the over-expression.
Amplification of the MYC gene is also found in a number of human epithelial tumors and large diffuse B-cell lymphomas, where it directly correlates with poor prognosis.
The c-Myc protein is expressed at low levels in proliferating cells with an extremely short half-life of 30 minutes, after when it is degraded via the ubiquitin proteasome pathway.
Upon serum stimulation, Ras mediates the stabilization of c-Myc by promoting its phosphorylation by ERK on Ser 62. This triggers subsequent phosphorylation of Thr 58 by GSK3 resulting in the destabilization of c-Myc.
Once phosphorylated, c-Myc becomes ubiquitinated by the E3-ligases Fbw7 and Skp2 resulting in its proteasomal degradation.
The c-Myc protein contains an unstructured N-terminal transcriptional regulatory domain, which contains the conserved Myc boxes I to IV, and a nuclear targeting sequence. Its C-terminus contains the bHLH-Zip domain which remains partially unstructured until it dimerizes with MAX.
Once c-Myc and MAX heterodimerize they bind DNA through the E-Box motif (5’-CACGTG -3’) and facilitate transcription by bending DNA. The N-terminal domain of c-Myc has been shown to form complexes with transcription factors including TRRAP, GCN5 and TBP.
When bound to DNA, heterodimerized Myc-Max recruit chromatin modifying complexes including histone acetylases.
Myc is also found to be involved in transcriptional inhibition, and in the absence of TGF-β inhibits CDK2NB (p15INK4b) by binding to and displacing Miz-1 cofactors. c-Myc can also inhibit gene expression through the activation of the miRNA cluster miR17-92, which mediates E2F1 attenuation and targets the TGF-β signaling pathway.