A critical role for Mnt in Myc-driven T-cell proliferation and oncogenesis

Abstract

Mnt (Max's next tango) is a Max-interacting transcriptional repressor that can antagonize both the proproliferative and proapoptotic functions of Myc in vitro. To ascertain the physiologically relevant functions of Mnt and to help define the relationship between Mnt and Myc in vivo, we generated a series of mouse strains in which Mnt was deleted in T cells in the absence of endogenous c-Myc or in the presence of ectopic c-Myc. We found that apoptosis caused by loss of Mnt did not require Myc but that ectopic Myc expression dramatically decreased the survival of both Mnt-deficient T cells in vivo and Mnt-deficient MEFs in vitro. Consequently, Myc-driven proliferative expansion of T cells in vitro and thymoma formation in vivo were prevented by the absence of Mnt. Consistent with T-cell models, mouse embryo fibroblasts (MEFs) lacking Mnt were refractory to oncogenic transformation by Myc. Tumor suppression caused by loss of Mnt was linked to increased apoptosis mediated by reactive oxygen species (ROS). Thus, although theoretically and experimentally a Myc antagonist, the dominant physiological role of Mnt appears to be suppression of apoptosis. Our results redefine the physiological relationship between Mnt and Myc and requirements for Myc-driven oncogenesis.cancer | antioxidant | buthionine sulfoximine | Ras | Bcl-2

Functional interactions among members of the MAX and MLX transcriptional network during oncogenesis

“…However, recent reports demonstrate that loss of Mnt inhibits Myc driven tumorigenesis by promoting apoptosis. Therefore MNT may promote or inhibit tumorigenesis depending on the context [144] (see apoptosis section).…”

An Overview of MYC and Its Interactome

“…Therefore, they may not directly oppose MYC activity but rather function along with other differentiation factors to repress growth and proliferation genes that are stimulated by MYC before differentiation. In contrast, constitutive deletion of MNT, which is induced by mitogenic stimuli and coexpressed with MYC, results in early postnatal lethality (Toyo-oka et al 2004;Link et al 2012). Redundancy among MXD paralogs may also contribute to the mild phenotypes of the single-gene MXD1 -4 knockouts.…”

“…Yet that antagonism acts to favor MYCinduced tumorigenesis because the dominant physiological activity of MNT is to oppose the proapoptotic activity elicited by MYC (Link et al 2012). In biological settings where MYC protein levels are elevated, cell survival becomes increasingly dependent on MNT as shown by the fact that even a small increase in MYC abundance compromises cell survival in the absence of MNT.…”

“…In biological settings where MYC protein levels are elevated, cell survival becomes increasingly dependent on MNT as shown by the fact that even a small increase in MYC abundance compromises cell survival in the absence of MNT. The lowered threshold for MYC-induced apoptosis caused by loss of MNT is tied to the aberrant accumulation of reactive oxygen species (ROS) (Link et al 2012). Therefore, as proposed for MYC-induced neoplasia (Vafa et al 2002), tumors generated as a consequence of MNT deletion may arise owing to ROSinduced oxidative damage to DNA and mutations that suppress apoptosis (see Kuzyk and Mai 2014).…”

Control of Vertebrate Development by MYC

“…These findings generally support the idea that MYC may function during development to reinforce transcriptional programs that confer functional cell or lineage identities, including stem and progenitor identities. However, it is notable that forced MYC expression is compatible with differentiation within different lineages, including the Bcell (Habib et al 2007) and T-cell lineages (Link et al 2012), epidermal keratinocytes (Gandarillas and Watt 1997; Waikel et al 2001), and more generally in the hematopoietic system (Wilson et al 2004). Thus, forced MYC expression, or normal regulated induction of endogenous MYC within a specific lineage, does not inherently impede the activity of factors that drive differentiation events, and may even stimulate latent, active, or newly directed differentiation programs.…”