MYC Cofactors: Molecular Switches Controlling Diverse Biological Outcomes

Abstract

The transcription factor MYC has fundamental roles in proliferation, apoptosis, tumorigenesis, and stem cell pluripotency. Over the last 30 years extensive information has been gathered on the numerous cofactors that interact with MYC and the target genes that are regulated by MYC as a means of understanding the molecular mechanisms controlling its diverse roles. Despite significant advances and perhaps because the amount of information learned about MYC is overwhelming, there has been little consensus on the molecular functions of MYC that mediate its critical biological roles. In this perspective, the major MYC cofactors that regulate the various transcriptional activities of MYC, including canonical and noncanonical transactivation and transcriptional repression, will be reviewed and a model of how these transcriptional mechanisms control MYC-mediated proliferation, apoptosis, and tumorigenesis will be presented. The basis of the model is that a variety of cofactors form dynamic MYC transcriptional complexes that can switch the molecular and biological functions of MYC to yield a diverse range of outcomes in a cell-type-and context-dependent fashion.

An Overview of MYC and Its Interactome

“…Analysis of target genes indicates that MYC binding results in hyperacetylation of histones, consistent with MYC's recruitment of HATs (Martinato et al 2008). However MYC -MAX interacts with a bewildering variety of other factors with diverse activities (chromatin remodelers, demethylases, antipausing factors, as well as other transcription factors such as MIZ-1 and the estrogen receptor) (see Hann 2014). One implication of this is that MYC's precise molecular function in transcriptional activation and repression may be dependent on the particular factors recruited by MYC, the constellation of other transcription factors proximal to the binding site, and the chromatin context of the target gene (Cheng et al 2006;Guccione et al 2006;Eilers and Eisenman 2008).…”

Therapeutic Strategies to Inhibit MYC

“…MBI possesses a degron targeted by FBW-7 (Welcker et al 2004;Yada et al 2004). MBII recruits a chromatin-modifying complex containing TRRAP, GCN-5, and TIP60 (McMahon et al 1998;Hann 2014). MBIII and MBIV contribute to MYC-specific phenotypes, such as MYC-induced apoptosis, but are not clearly relevant for MYC-induced cell proliferation and survival (Herbst et al 2005;.…”

“…3) (Dang et al 2006;Eilers and Eisenman 2008; also see Hann 2014). Communication of transcriptional impulses is initiated by promoter-and enhancer-bound MYC, which serves to organize histone acetyltransferases (such as TIP60, GCN5, and CBP/P300) and the mediator complex.…”

“…As shown in Figure 4 (and as described in Conacci-Sorrell et al 2014;Hann 2014) the MYC interactome features known critical mediators of transcriptional output, among them protein targets amenable to small-molecule discovery. Through MBII, MYC recruits the TRRAP complex that includes the histone acetyltransferases TIP60 and GCN5.…”

Genome Recognition by MYC

“…MYC interacts with many other transcriptional cofactors that lack sequence specificity (see Hann 2014). One of these is TRRAP (McMahon et al 1998), a subunit of the histone acetyltransferase (HAT) complexes TFTC/ STAGA and NuA4, which contain the HAT subunits GCN5/PCAF and Tip60, respectively (Allard et al 1999;Doyon et al 2004;Nagy and Tora 2007).…”