Mediation of c-Myc-Induced Apoptosis by p53

Abstract

The cellular proto-oncogene c-myc is involved in cell proliferation and transformation but is also implicated in the induction of programmed cell death (apoptosis). The same characteristics have been described for the tumor suppressor gene p53, the most commonly mutated gene in human cancer. In quiescent mouse fibroblasts expressing wild-type p53 protein, activation of c-Myc was found to induce apoptosis and cell cycle reentry, preceded by stabilization of p53. In contrast, in quiescent p53-null fibroblasts, activation of c-Myc induced cell cycle reentry but not apoptosis. These results suggest that p53 mediates apoptosis as a safeguard mechanism to prevent cell proliferation induced by oncogene activation.

Chimeric oncoprotein E2a-Pbx1 induces apoptosis of hematopoietic cells by a p53-independent mechanism that is suppressed by Bcl-2

“…E2a-Hlf, like E2a-Pbx1, is a chimeric transcriptional protein resulting from chromosomal translocations in B cell precursor leukemias, however E2a-Hlf contains a basic DNA-binding region and leucine zipper dimerization motif in contrast to the homeodomain contained by E2a-Pbx1. As a consequence, E2a-Hlf binds and activates transcription through DNA sites di erent from those recognized by E2a-Pbx1 or wild type E2a proteins (Hunger et al, 1994;Inaba et al, 1994). Recent studies have shown that forced expression of E2a-Hlf prevents precursor B cells of the BaF3 cell line from undergoing apoptosis in response to IL3 withdrawal (Inaba et al, 1996).…”

“…Both were una ected over the 60 h period during which A2 cells were undergoing E2a-Pbx1-induced apoptosis (Figure 4). We also quantitated the levels of tumor suppressor gene product p53 given its previously reported role in programmed cell death induced by nuclear oncoproteins adenovirus E1a and Myc (Debbas and White, 1993;Hermeking and Eick, 1994). The levels of p53 protein were found to increase dramatically in A2 cells undergoing E2a-Pbx1-induced apoptosis, however, a comparable increase of p53 was observed in MT1 cells (Figure 4) which lack E2a-Pbx1 and do not undergo apoptosis suggesting that p53 levels were responding to the zinc treatment alone although no apparent e ects on the cycling activity of MT1 cells were observed (data not shown).…”

“…E1A, Myc and E2F) by inducing cell cycle progression (Debbas and White, 1993;Hermeking and Eick, 1994;Shan and Lee, 1994), we investigated whether E2a-Pbx1 may share similar properties. These studies were conducted in Rat-1 ®broblasts since Reh cells did not tolerate arrest and concurrent treatment with ZnSO 4 Rat-1 ®broblasts, unlike Reh, support constitutive expression of E2a-Pbx1 without undergoing apoptosis (Figure 7).…”

“…Overexpression of the proto-oncogene c-myc has been shown to modulate apoptotic cell death in rat ®broblasts under low serum conditions or drug-induced cell cycle arrest (Evan et al, 1992). Myc-induced apoptosis is dependent on p53 induction (Hermeking and Eick, 1994) and may represent a cell-suicide response to inappropriate cell cycle progression. Likewise the adenoviral oncoprotein E1A induces cell cycle advancement and concomitant p53-mediated apoptosis in primary rodent cells but coexpressed E1B inhibits p53 with resultant suppression of apoptosis (Debbas and White, 1993).…”

Pim-1 kinase stimulates c-Myc-mediated death signaling upstream of caspase-3 (CPP32)-like protease activation

“…It has been reported that wild-type p53 is required for c-Myc-mediated apoptosis (Hermeking and Eick, 1994;Wagner et al, 1994), during which p53 protein is stabilized by c-Myc expression (Hermeking and Eick, 1994). We therefore examined the expression level of p53 protein in Rat-1 cells expressing c-myc and/or pim-1.…”