MYC is required for the interaction between the E2F1 transcription factor and its target gene promoters, which promotes activation of the E2F network and leads to cell proliferation.
How does the oncogenic transcription factor MYC promote cell proliferation? Although MYC binds to at least 11% of promoters in the human genome and this binding contributes to (but is not always sufficient for) gene expression to promote cell growth, the mechanism and key targets that mediate MYC-dependent proliferation have remained elusive. Joseph Nevins and colleagues show that MYC is required for E2F1 interaction with the promoters of target genes, which promotes activation of the E2F network, leading to cell proliferation.
It was previously shown that MYC regulates the expression of the E2F transcription factors, which are essential regulators of the transition from G0 to G1 phase and G1 to S phase of the cell cycle. E2F genes (E2F1, E2F2 and E2F3) all contain E2F binding sites (they can induce the expression of each other) and E boxes, which are bound by MYC. Consistently, the overexpression of MYC can increase E2F1 and E2F3 mRNA levels. The authors found that as cells entered the cell cycle after serum starvation (which induces quiescence) MYC was bound to all three E2F promoters prior to E2F1 binding them. This indicates that MYC facilitates E2F1 binding to E2F promoters and the authors confirmed this was the case using a luciferase reporter gene that was under the control of the E2F2 promoter with or without the E boxes or E2F binding sites. How might MYC facilitate E2F1 binding to E2F promoters? The authors could not find a direct interaction between E2F1 and MYC, indicating that cooperative protein–protein binding is not required, but results from chromatin immunoprecipitation experiments revealed that histone H4 was acetylated surrounding the E2F binding sites and this was dependent on MYC expression.
Therefore, MYC-mediated chromatin remodelling might facilitate the transactivation of genes by priming promoters so they are ready for transactivation by other factors, thereby acting as a 'permissive factor'. Such a mechanism could contribute to the complexity and enormity of the MYC transcriptional network. Moreover, MYC-mediated regulation of the E2F genes in particular might help explain how MYC mediates the entry of quiescent cells into the cell cycle.
Gemma K. Alderton
References
Leung, J. Y., Ehmann, G. L., Giangrande, P.H. & Nevins, J. R. A role for MYC in facilitating transcription activation by E2F1. Oncogene published online 17 March 2008 | Article | PubMed |
