The MYC family of transcription factors has had a prominent role in human cancer for 30 years. MYC family genes are frequently altered by chromosomal abnormalities in cancer cells, either by chromosomal translocations or copy-number variation from gene amplification. MYC is also one of the most important downstream targets of major oncogenic signaling pathways which lead to elevated MYC levels in 70% of all cancers (1). Thus, MYC has been intensely studied as a critical mediator of cancer cell growth and metabolism. However, MYC proteins are localized in the nucleus and lack innate enzymatic function, and hence present a challenge as potential therapeutic targets to combat cancer.

The MYC gene family

There are three distinct MYC family proteins encoded within the human genome, with genes located on separate chromosomes and subject to independent developmental regulation. (Figure 26.1a). The most commonly studied gene is MYC, which resides on chromosomal band 8q24. MYC is expressed throughout development in virtually all dividing cells, but expression is repressed in non-dividing cells, for example in response to terminal differentiation. A second family member is MYCN on chromosome 2p24. MYCN is expressed in most of the early embryo with more prolonged expression in the developing brain and kidneys. MYCN is also expressed at significant levels in embryonic stem cells, as well as primitive hematopoietic cells. The third family member, MYCL1, is on chromosome 1p34 and expressed in the developing brain and primitive neuronal cells. Both MYC and MYCN are essential for mammalian embryogenesis, whereas MYCL1 is dispensable. All three MYC family proteins have sequence-specific DNA-binding activity when dimerized with a common partner protein MAX, which is constitutively expressed in all tissues at all stages of development. MYC/MAX heterodimers bind most avidly to the short DNA sequence CACGTG, although other sequences are also recognized. When bound to chromosomal sites, MYC proteins recruit various nuclear co-factors that enhance the transcription of target genes, including histone acetyltransferase complexes and kinases that directly modify RNA polymerase II (2; Figure 26.1b). MYC can also repress genes through mechanisms that are only partially understood (3). An enormous number of cellular genes have been found to be MYC responsive, spanning all aspects of growth, division, metabolism, signaling, and architecture (1). Critical pathways that may mediate MYC's function in cancer cells will be discussed in more detail below.