Myc or no Myc, that is the question

Abstract

The transcription factor c-MYC functions as the master transcription factor for establishing highly active metabolic states in proliferating cells. c-Myc is essential for rapid proliferation of normal cells and has causal relationship with many cancers, including leukemia and lymphoma. While the expression of c-MYC can be aberrantly driven by genetic abnormalities, such as chromosomal translocations directly involving the MYC locus or mutations of its upstream regulators, how c-MYC expression is induced and amplified in normal lymphocytes in response to antigen stimulation remains elusive. In this issue of The EMBO Journal, Preston et al (2015) report how c-MYC is selectively induced and amplified in the antigen‐specific T cells that undergo massive clonal expansion for host protection against pathogen infection.

Figure 1

Two modes of c-MYC regulation in activated T cells (A) Digital c-MYC induction by TCR signaling. T cells that receive a strong enough signal via TCR are able to express c-MYC. Above this threshold of stimuli, c-MYC level per cell stays constant regardless of strength of antigen stimulation. TCR signaling exerts its effect on c-MYC expression primarily through the activation of Myc transcription. (B) Fine-tuning of c-MYC by cytokines. The pro-inflammatory cytokine IL-2 sustains c-MYC levels in a dose-dependent manner. Mechanistically, signals through the IL-2R complex increase c-MYC protein synthesis via induction of the amino acid transporter SLC7A5. Consequently, the elevated rate of translation overcomes constitutive degradation of c-MYC mediated by GSK3 and the ubiquitin–proteasome pathway, allowing its accumulation.