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Lookup NU author(s): Professor John LunecORCiD
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The MYC family of proto-oncogenes, which includes MYC, MYCN and MYCL, has strong oncogenic potential. Genetic alterations, including gene amplification, chromosome translocation and overexpression resulting in deregulation of MYC expression have been found in a wide range of tumor types. Amplification of MYCN is associated with rapid tumor progression and poor outcome in human neuroblastoma. Nuclear MYC proteins form heterodimers with MAX protein through their conserved HLHZip domains. The MYC/MAX complexes transactivate a number of MYC-target genes in a sequence-specific manner. MYC-MAX interaction is essential for MYC-induced cell cycle progression, cellular transformation, and transcriptional activation. Inhibition of MYC-MAX dimerization by small-molecule antagonists (IIA6B17) has recently been shown to interfere with MYC-induced transformation of chick embryo fibroblasts (Berg T. et al, PNAS 99:3830-3835, 2002), indicating that functional inhibitors of the MYC family of oncoproteins have potential as therapeutic agents. In the present study, a functional MYC reporter gene assay has been developed and validated, using a luciferase gene construct under control of the ornithine decarboxylase (ODC) gene promoter. This luciferase gene construct has been stably transfected into a number of cell lines including MYCN amplified neuroblastoma cells (NGP) and MYC-overexpressed neuroepithelioma cells (NB/CHP100). As a non-MYC transcriptional activity control, MYC-overexpressed HCT-116 cells were stably transfected with a luciferase gene construct under control of the MDM2 gene promoter. After exposure of the three cell lines to IIA6B17 for 24 hours, a significant reduction of luciferase activity was only observed in NB/CHP100 cells, with IC50 values of approximately 28 + 4 M, indicating that IIA6B17 preferentially inhibits MYC, with little effect on MYCN. Protein levels of MYC and their targets and cellular behavior are currently being examined in these cell lines in response to IIA6B17. This cell-based, MYC reporter gene assay provides a tool to distinguish between MYC, MYCN and pan-MYC inhibitory activity and will aid in the future development of specific therapeutic strategies in tumors in which MYC amplification and overexpression have been implicated. The results also indicated that inhibitors specific for individual member of MYC family could be developed.
Author(s): Xiaohong L, Vogt PK, Boger DL, Lunec J
Publication type: Conference Proceedings (inc. Abstract)
Publication status: Published
Conference Name: American Association For Cancer Research
Year of Conference: 2003
