Suppression of Myc-Induced Apoptosis in β Cells Exposes Multiple Oncogenic Properties of Myc and Triggers Carcinogenic Progression

Abstract

To explore the role of c-Myc in carcinogenesis, we have developed a reversible transgenic model of pancreatic beta cell oncogenesis using a switchable form of the c-Myc protein. Activation of c-Myc in adult, mature beta cells induces uniform beta cell proliferation but is accompanied by overwhelming apoptosis that rapidly erodes beta cell mass. Thus, the oncogenic potential of c-Myc in beta cells is masked by apoptosis. Upon suppression of c-Myc-induced beta cell apoptosis by coexpression of Bcl-x(L), c-Myc triggers rapid and uniform progression into angiogenic, invasive tumors. Subsequent c-Myc deactivation induces rapid regression associated with vascular degeneration and beta cell apoptosis. Our data indicate that highly complex neoplastic lesions can be both induced and maintained in vivo by a simple combination of two interlocking molecular lesions.

Deregulated expression of a novel component of TFTC/STAGA histone acetyltransferase complexes, rat SGF29, in hepatocellular carcinoma: possible implication for the oncogenic potential of c-Myc

“…This result was further confirmed by the data that downregulation of rSGF29 in K2 cells lowered the rMTA1 and rODC gene expressions, and antisense ODNs against both genes inhibited the colony formation of K2 cells. Recent study has shown that the elevated expression of c-Myc could promote metastasis (Pelengaris et al, 2002). In this study, we demonstrated that downregulation of rSGF29 could reduce tumorigenicity and lung metastasis.…”

Hepatocyte-specific Bid depletion reduces tumor development by suppressing inflammation-related compensatory proliferation

“…26,27 On the other hand, overexpression of Bcl-2 and Bcl-XL proteins with known antiapoptotic functions, promotes tumor development in pancreatic beta-cells, in lymphoid cells and in myeloid cells. [28][29][30] In the present study, we addressed the tissue/cell-specific effects of BID in HCC development. We found a profound decrease in HCC development induced by DEN administration, and as early as 48 h after high-dose DEN injection we found a marked decrease in hepatocyte proliferation markers.…”

Omomyc expression in skin prevents Myc-induced papillomatosis

“…Indeed, in some tissues, such as pancreatic b cells, activation of Myc triggers rapid apoptotic involution of the entire tissue and suppression of Myc-induced apoptosis is sufficient to foster rapid cell expansion and malignant progression. 23 In other tissues, such as skin epidermis, activation of Myc (and, by implication other oncoproteins) implements a transcriptional program for apoptosis but execution of cell death is then suppressed by endogenous survival factors. 11 In all instances, however, restoration or reinforcement of Myc-induced apoptosis offers the potential of a powerful therapeutic strategy that would, moreover, be tumor specific since it relies on the presence of the underlying tumorigenic Myc lesion.…”