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Review
. 2014 Jun 17;4(9):a014399.
doi: 10.1101/cshperspect.a014399.

MYC cofactors: molecular switches controlling diverse biological outcomes

Stephen R Hann  1
Affiliations
Review

MYC cofactors: molecular switches controlling diverse biological outcomes

Stephen R Hann. Cold Spring Harb Perspect Med. .

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.

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Figures

Figure 1.
Figure 1.
Proliferation pathways mediated by MYC and MYC cofactors. MYC drives proliferation through stimulating cell growth (biomass accumulation) and cell-cycle entry from quiescence while inhibiting cell-cycle inhibitors for cell-cycle progression. Cofactors (in red) control the indicated proliferative pathways that can be opposed by other factors, such as TGF-β and MXD/MAX. Repression of cell-cycle inhibitors by MYC, which appears to be sufficient to drive cell-cycle progression, may be mediated by several possible mechanisms, including the recruitment of repressive complexes containing MIZ-1 or SP1 and/or indirect repression caused by EZH2 induction.
Figure 2.
Figure 2.
Apoptosis pathways mediated by MYC and MYC cofactors. Overexpressed or deregulated MYC (oncogenic MYC) induces ARF protein levels. ARF can then bind to inactivate MDM2, causing p53 induction, or bind to MYC to induce EGR1 through noncanonical transactivation while inhibiting canonical transactivation or bind to MIZ-1 and MYC to cause repression of BCL2. ARF-independent apoptosis can occur through DNA damage. The relative binding and regulation of ARF to its many partners is unknown. These pathways have primarily been investigated in fibroblasts. ARF and MIZ-1 are shown in red as MYC cofactors.
Figure 3.
Figure 3.
Tumorigenesis pathways mediated by MYC and MYC cofactors. MYC-mediated tumorigenesis is primarily driven by enhanced canonical transactivation caused by overexpressed regulatory cofactors such as NPM, SKP2, and CIP2A and oncogenic MYC repression/silencing of tumor suppressors through cofactor complexes MIZ-1 and/or SP1 with HDACs, DNMTs, and EZH2. Loss of ARF and/or p53 and inhibition of RAS-induced senescence through CDK2 phosphorylation of MYC contributes to MYC-driven tumorigenesis. MYC cofactors are shown in red.
Figure 4.
Figure 4.
Cofactor switch model. A summary of pathways mediated by MYC and MYC cofactors (in red) illustrating how the differential interaction of the various cofactors, which control different transcriptional mechanisms and MYC target genes, mediate distinct biological outcomes. Several pathways can cooperate to achieve optimal outcomes. Cell type and cellular context, as well as the levels of MYC, differentially regulate the expression and activity of the MYC cofactors.
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