c-MYC: more than just a matter of life and death

Abstract

Summary The proto-oncogene c-MYC encodes a transcription factor that is implicated in various cellular processes ? cell growth, proliferation, loss of differentiation and apoptosis. c-MYC activates a variety of known target genes as part of a heterodimeric complex with the protein MAX. For example, cyclin D2 and CDK2 are essential for cell-cycle progression, and translation initiation factors eIF4 and eIF2 are important in cell growth. MYC?MAX heterodimers regulate gene activation through chromatin remodelling: association with co-activator TRRAP, which contains HAT activity, leads to acetylation of nucleosomal histones. c-MYC inhibits the differentiation of many cell types. Conversely, MAD/MXI1 transcription factors promote differentiation by antagonizing c-MYC function by forming dimers with MAX. MAD?MAX dimers recruit corepressors (such as SIN3) and HDACs to target DNA, leading to histone deacetylation and subsequent repression of MYC target genes. c-MYC sensitizes cells to a wide range of pro-apoptotic stimuli in vitro via cytochrome c release from mitochondria and subsequent formation of the apoptosome with APAF1 and procaspase-9. Oncogenic c-MYC implies constitutive or deregulated expression of c-MYC that is no longer dependent on external signals and is associated with many human cancers. Conditional transgenic mice, which allow regulated activation of c-MYC in distinct tissues (epidermis and pancreatic islets), have highlighted which cellular response attributed to c-MYC alone (proliferation or apoptosis) predominates in intact tissues in vivo. Regulatable c-MYC transgenic mouse models of cancer have highlighted oncogenic properties of c-MYC in vivo when its apoptotic pathway is blocked, which include induction of angiogenesis, loss of cell?cell contacts and local tissue invasion. Conditional mouse transgenic systems have ascertained when cancer-initiating oncogenic mutations (such as c-MYC and RAS) remain essential for maintenance of the established tumour in vivo. These findings are important for the development of candidate drug molecules that are directed against the oncoprotein.