The MYCN Protein in Health and Disease

Abstract

MYCN is a member of the MYC family of proto-oncogenes. It encodes a transcription factor, MYCN, involved in the control of fundamental processes during embryonal development. The MYCN protein is situated downstream of several signaling pathways promoting cell growth, proliferation and metabolism of progenitor cells in different developing organs and tissues. Conversely, deregulated MYCN signaling supports the development of several different tumors, mainly with a childhood onset, including neuroblastoma, medulloblastoma, rhabdomyosarcoma and Wilms' tumor, but it is also associated with some cancers occurring during adulthood such as prostate and lung cancer. In neuroblastoma, MYCN-amplification is the most consistent genetic aberration associated with poor prognosis and treatment failure. Targeting MYCN has been proposed as a therapeutic strategy for the treatment of these tumors and great efforts have allowed the development of direct and indirect MYCN inhibitors with potential clinical use.

Keywords: MYCN; childhood tumors; embryonal development; neuroblastoma; targeted therapy.

Figure 1

The MAX/MLX protein networks with domain organization of the members. The organization of the MAX and MLX network proteins with colored boxes indicating the functional domains. Each network reciprocal heterodimerization partner is indicated with its binding site. MAX: MYC associated factor X; MLX: MAX-like protein X; MGA: MAX gene-associated; MNT: MAX network transcription repressor; MXD: MAX dimerization protein; TAD: transcriptional activation domain; NLS: nuclear localization signal; b: basic region; HLH: helix loop helix; LZ: leucine zipper; SID: SID3-interacting domain; MCR: Mondo conserved region which contains six conserved regions creating a glucose sensing domain; DCD: dimerization and cytoplasmic localization domain; E-box: enhancer-box; ChoRE: carbohydrate response element. *MXD1, MXD4 and MNT bind to MLX while MXD2 and MXD3 do not.

Figure 2

Strategies for direct and indirect targeting of MYCN. Different approaches have been developed to hinder MYCN activity, including inhibition of MYCN gene transcription, disruption of the dimerization with its transcriptional partner MAX, induction of MYCN protein destabilization, inhibition of MYCN-promoted cellular processes as well as immunotherapy. Specific inhibitors are highlighted in red. Solid lines indicate direct activity. Dashed lines indicate different protein status (inactive monomeric, active dimeric and degradation-targeted phosphorylated MYCN). PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; GSK3ß: glycogen synthase kinase 3 beta; mTOR, mammalian target of rapamycin; BRD, bromodomain; BET, bromodomain and extra terminal domain; Ub: ubiquitin.