E2F1 pathways to apoptosis

Abstract

The E2F family of transcription factors plays a pivotal role in the regulation of cell proliferation and their activity is often deregulated in human tumors. Recent studies demonstrate that E2F1 can induce both proliferation and apoptosis. E2F1-induced apoptosis occurs via multiple pathways, some of which induce stabilization and activation of the tumor suppressor p53. The pro-apoptotic activity of E2F1 suggests that its deregulation constitutes an oncogenic stress that may target pre-malignant cells to undergo apoptosis, thus preventing tumor development. ß 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.

Apoptosis-stimulating protein of p53-2 (ASPP2/53BP2L) is an E2F target gene

“…Nevertheless, the paradigm that both transcriptional and posttranscriptional mechanisms can play cell context-dependent roles in controlling proapoptotic gene products has been described, such as is the case for E2F-1. 4,29,[55][56][57] To what extent cell context influences E2F regulation of ASPP2/ 53BP2L remains to be determined. Intriguingly, as described in the accompanying report, ASPP1 is also regulated by E2F.…”

“…2 Additionally, deregulation of the Rb/E2F pathway also occurs in a majority of human tumors, resulting in both unrestrained proliferation as well as promotion of apoptosis via p53-dependent and p53-independent mechanisms. [3][4][5] Thus, understanding the molecular linkage between cellular proliferation and sensitivity to apoptotic inputs in cancer cells is one of the most fundamental, yet incompletely understood, issues in oncology today.…”

“…The 'activating' E2Fs (E2F-1, E2F-2, E2F-3) are important for controlling gene expression in late G1/early Sphase in addition to promoting apoptosis -particularly in the case of E2F-1. 3,4,[26][27][28][29] Entry into the cell cycle is therefore accompanied by sensitization to apoptotic inputs. In tumors that have not completely disabled the apoptotic pathway, this apoptosis sensitization may provide the 'therapeutic window' that allows chemotherapy to selectively kill cancer cells.…”

pVHL acts as a downstream target of E2F1 to suppress E2F1 activity

“…Meanwhile, apoptotic induction of E2F1 separates it from other E2F family members [17]. In response to various DNA-damage conditions, including ionizing radiation, UV radiation and chemotherapeutic drugs, E2F1 is induced and activated, resulting in expression of its downstream genes for induction of cell apoptosis [18,19].…”

E2F1 deficiency impairs murine spermatogenesis and augments testicular degeneration in SCP3-nullizygous mice

“…1 Both depletion and overexpression of E2F1 in mice result in testicular atrophy at 36 or 6 weeks of age, respectively. 2,3 Whereas testicular atrophy in mice overexpressing E2F1 results from p53-independent apoptosis, 3 the cause of testicular atrophy in mice deficient in E2F1 remains unclear.…”