Deconstructing myc.

Eisenman, R N (2001) Deconstructing myc. Genes & development, 15 (16). pp. 2023-2030. ISSN 0890-9369

Abstract

This extract was created in the absence of an abstract. Background Although myc was among the very earliest oncogenes identified and the subject of intense study, it has nonetheless proven to be an enduring enigma. To a large extent the problem derives from the apparent gap between Myc's biological role and what is surmised to be its molecular function. Myc family proteins (comprising c-, N-, and L-Myc) promote proliferation, growth, and apoptosis; inhibit terminal differentiation; and, when deregulated, are profoundly involved in the genesis of an extraordinarily wide range of cancers (for recent review, see Grandori et al. 2000). Alongside this veritable mountain of biological effects, the molecular characterization of Myc—as a relatively weak transcriptional regulator of uncertain target genes—looks like a molehill. Indeed some have wondered whether the transcriptional activities of Myc might be more apparent than real. The notion that Myc proteins might function in transcription arose over a decade ago, after Myc was shown to be a nuclear protein. An N-terminal fragment of Myc stimulated transcription when fused to a heterologous DNA binding domain, and the C-terminal basic-helix-loop-helix-zipper (bHLHZ) of Myc resembled those found in certain families of transcription factors. But full-length Myc did not dimerize or bind DNA and therefore could not be demonstrated to behave as a transcription factor. This picture changed with the discovery of Max, another bHLHZ protein which heterodimerizes with Myc to form a sequence-specific DNA binding complex. Myc–Max heterodimers recognize the E-box sequence CACGTG (as well as related non-canonical sites) and activate transcription from synthetic reporter genes containing multimerized binding sites in mammalian cells as well as yeast (Blackwood and Eisenman 1991; Amati et al. 1992; Kretzner et al. 1992). The effects of Myc on cell proliferation and apoptosis are negated by mutations in the Myc transactivation region, or in the bHLHZ domain required for association with Max and DNA,

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