MYC, Metabolism, Cell Growth, and Tumorigenesis

Abstract

The MYC proto-oncogene, which belongs to the MYC family of genes (MYC, MYCN, MYCL), is downstream from many signal transduction pathways that are responsive to growth factors or the cellular microenvironment, such as cellular engagement with the extracellular matrix and nutrient or growth factor availability (Eilers and Eisenman 2008; Dang 2012b). For example, stimulation of receptor tyrosine kinases triggers activation of MEK-ERK and PI3K pathways, which in turn induces MYC expression. TGF-β can down-regulate MYC expression in a SMAD-dependent manner. The MYC proto-oncogene is, therefore, tightly linked to growth signals, cellular adherence, and the availability of nutrients. In this regard, depletion of MYC is detrimental for embryogenesis. However, the reliance of adult tissues on MYC depends on the tissue type and the role of other MYC family members for the renewal of specific adult tissues.

The inference that overexpressed MYC contributes to the genesis of certain human cancers is compatible with the tumorigenic activity of retroviral v-Myc in naturally occurring chicken tumors (see Connacci-Sorrell 2013). Hence, it is not surprising that ectopic expression of MYC in many transgenic murine tissues results in their oncogenic transformation, often associated with other genetic alterations such as loss of p53 or ARF (Zindy et al. 1998; Eischen et al. 1999). Intriguingly, the context in which MYC is activated could significantly affect tumorigenesis and the tumor type. For example, in a MYC-inducible system restricted to liver cells, activation of MYC in utero results in an aggressive postnatal hepatoblastoma-like diffuse liver cancer that kills the animals within several weeks after birth (Beer et al. 2004). Activation of MYC several weeks after birth resulted in multifocal, less aggressive liver tumors in adult animals.

Deregulated expression of MYC in cancers must be inherently different from regulated MYC expression in normal stem cell compartments. Deregulated MYC expression is surmised to induce a transcriptional response network that is different from the response triggered by endogenous normal MYC, which is fully restrained by feedback loops. In this regard, deregulated MYC expression predisposes cells to growth factor or nutrient deprivation-induced cell death, while deprived normal cells withdraw into the cell-cycle G₁ phase (Askew et al. 1991; Evan et al. 1992; Shim et al. 1998; Yuneva et al. 2007). In addition, the MYC transcriptional program is likely to be different in the background of tumor suppressor mutations versus the program induced with normal cellular checkpoints still intact.

ACKNOWLEDGMENTS

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