Disentangling the MYC web

Abstract

That MYC is causally associated with cancer has been apparent for decades. As a retroviral transforming gene or as the target of chromosomal translocations, rearrangements, amplification, mutations, and viral insertions, disturbance of MYC regulation and/or function is one of the most common molecular lesions contributing to multistep carcinogenesis (1–5). Disordered MYC expression alters cell proliferation, cell growth, differentiation, and metabolism. How MYC provokes this panoply of cellular pathology has been debated for years. Whether MYC acts directly on a small number of downstream effectors that elicit many secondary changes or whether MYC itself directly operates on all of these processes has been controversial. The works of Menssen and Hermeking (6) in this issue of PNAS and other recent studies (6–11) point to a complex web of direct MYC targets regulating metabolic flux and information streams through normal and transformed cells. Their work indicates the need for new tools to understand how multiple signals and processes are superimposed and integrated to determine the fate of a cell. The c-myc gene encodes a helix–loop–helix basic leucine zipper protein (HLH-bZIP) that when dimerized with the appropriate partner, binds to the E-box DNA sequence, CACGTG (1–5). E-box-bound MYC interacts with the basal transcription apparatus and with complexes that remodel and modify chromatin. Belying its biological importance, MYC has proven to be only a weak activator or repressor of synthetic reporters and for a few generally accepted natural targets. Because MYC is not a dominating transactivator either in vivo or in vitro, it has been difficult to sift the true MYC targets from the clutter of low-amplitude changes in gene expression caused by secondary effects. A variety of strategies and systems have been used to control MYC expression to enable comparison of target gene expression before and after …