Induction of DNA synthesis and apoptosis are separable functions of E2F-1.

Abstract

The family of E2F transcription factors have an essential role in mediating cell cycle progression, and recently, one of the E2F protein family, E2F-1, has been shown to participate in the induction of apoptosis. Cooperation between E2F and the p53 tumor suppressor protein in this apoptotic response had led to the suggestion that cell cycle progression induced by E2F-1 expression provides an apoptotic signal when placed in conflict with an arrest to cell cycle progression, such as provided by p53. We show here that although apoptosis is clearly enhanced by p53, E2F-1 can induce significant apoptosis in the absence of p53. Furthermore, this apoptotic function of E2F-1 is separable from the ability to accelerate entry into DNA synthesis. Analysis of E2F-I mutants indicates that although DNA-binding is required, transcriptional transactivation is not necessary for the induction of apoptosis by E2F-1, suggesting that it may be mediated through alleviation of E2F-dependent transcriptional repression. These results indicate that E2F.1 can show independent cell cycle progression and apoptotic functions, consistent with its putative role as a tumor suppressor.

MIF loss impairs Myc-induced lymphomagenesis

“…Consistent with this view, DNA binding is required for E2F1-responsive apoptosis, whereas transactivation is largely dispensable. 65,66 Strikingly, this does not seem to be the case in MIF deficiency, as our data with DbE2F1 clearly indicate that the growth-and apoptosis-promoting E2F1 activity in MIF null cells depends on the presence of its C-terminal Rb-binding/ transactivation domain. Because Rb and its family proteins are largely inactive in Myc-or E2F-overexpressing cells, 49,50,56 we speculate that an Rb-independent inhibitor of E2F1 is lost in MIF-deficient cells, explaining why ectopic E2F1 has more effect in MIF-KO than WT fibroblasts.…”

“…25,36,62 Moreover, Myc-induced p53-dependent apoptosis is increased in the epithelium of mice lacking E2F1, 63 while the role of E2F1 in mediating tumorigenesis can be explained by its ability to suppress rather than induce apoptosis. [64][65][66] Collectively, these data imply that E2Fs play complex roles in gene regulation and that apoptotic target genes of E2F1, such as p73, Apaf-1, and procaspases, may be downregulated (rather than upregulated) by E2F1 in vivo, while p53 acts to relieve this expression block. Consistent with this view, DNA binding is required for E2F1-responsive apoptosis, whereas transactivation is largely dispensable.…”

Apoptosis induced by the myelodysplastic syndrome-associated NPM-MLF1 chimeric protein

“…Other apoptotic inducers such as c-Myc and E2F-1 also promote S phase entry (Evan et al, 1992;Askew et al, 1991;Wu and Levine, 1994;Qin et al, 1994;Shan and Lee, 1994), but accelerated initiation of DNA replication itself does not trigger apoptotic pathways (Hsieh et al, 1997;Phillips et al, 1997). For example, other E2F family members (E2F-2 and -3) induce S phase entry of serum-starved ®broblasts without evoking apoptosis (DeGregori et al, 1997).…”

Life and death decisions by E2F-1

“…This model, however, does not completely hold true for E2F-1 as mutants of E2F-1 have been described, which while unable to promote cell cycle progression, retain the ability to induce programmed cell death. 43,44 As a result, interest in the apoptotic function of E2F-1 has resurged and numerous recent studies have provided insights into its deathpromoting activities. Figure 1 pRb binds to an E2F-DP complex in cells in the G0/G1 stage of the cell cycle.…”