Oncogenes in cell survival and cell death

Abstract

The transforming effects of proto-oncogenes such as MYC that mediate unrestrained cell proliferation are countered by "intrinsic tumor suppressor mechanisms" that most often trigger apoptosis. Therefore, cooperating genetic or epigenetic effects to suppress apoptosis (e.g., overexpression of BCL2) are required to enable the dual transforming processes of unbridled cell proliferation and robust suppression of apoptosis. Certain oncogenes such as BCR-ABL are capable of concomitantly mediating the inhibition of apoptosis and driving cell proliferation and therefore are less reliant on cooperating lesions for transformation. Accordingly, direct targeting of BCR-ABL through agents such as imatinib have profound antitumor effects. Other oncoproteins such as MYC rely on the anti-apoptotic effects of cooperating oncoproteins such as BCL2 to facilitate tumorigenesis. In these circumstances, where the primary oncogenic driver (e.g., MYC) cannot yet be therapeutically targeted, inhibition of the activity of the cooperating antiapoptotic protein (e.g., BCL2) can be exploited for therapeutic benefit.

Figure 1.

Cellular transformation through concomitant stimulation of cell proliferation and inhibition of apoptosis. (A) Oncogenes such as MYC induce cellular proliferation, however, intrinsic “fail-safe” apoptotic mechanisms such as those induced by the ARF/MDM2/P53 pathway counteract the mitotic stimulus mediated by MYC and suppress transformation. (B) Oncogenes such as BCL2 are potent inhibitors of apoptosis but poor inducers of cell proliferation and are, therefore, insufficient to drive tumorigenesis as a single oncogenic event. (C) The cooperative activity of oncogenes such as MYC and BCL2 suppress apoptosis and drive proliferation resulting in cellular transformation. (D) Certain oncogenes such as BCR-ABL can activate signaling pathways that simultaneously induce cell proliferation and suppress apoptosis, thereby leading to transformation.

Figure 2.

The interplay between MYC AND PI3K/MTOR. The MYC-regulated transcriptional network interacts with canonical PI3K/AKT/MTOR signaling at multiple levels with opposing “counter-regulatory effects.” In one example, MYC represses the activity of TSC to activate MTORC-1 and enhance the cell’s capacity to translate MYC-mRNA in what is postulated to represent an oncogenic feed-forward loop (+). The concurrent regulatory “fail-safe” is that TSC is required for full activation of the AKT hydrophobic motif-kinase, MTORC-2. In this way, MYC activates MTORC-1 while dampening MTORC-2/AKT activity (−). Consequently, oncogenic activation of AKT by MTORC-2 independent mechanisms dramatically accelerates MYC-driven oncogenesis.