Abstract
Molecular hardwiring of the cell cycle to the apoptotic machinery is a critical tumor suppressor mechanism for eliminating hyperproliferative cells. Deregulation of the Rb-E2F repressor complex by genetic deletion or functional inhibition of Rb triggers apoptosis through both the intrinsic (caspase-9 mediated) and extrinsic (caspase-8 mediated) death pathways. Induction of the intrinsic pathway has been studied extensively and involves release of free E2F and direct transcriptional activation of E2F-responsive apoptotic genes such as ARF, APAF1, and CASP9. In contrast, the mechanisms leading to activation of the extrinsic pathway are less well understood. There is growing evidence that Rb-E2F perturbation induces the extrinsic pathway, at least in part, through derepression (as opposed to transactivation) of apoptotic genes. Here, we explore this possibility using cells in which Rb-E2F complexes are displaced from promoters without stimulating E2F transactivation. This derepression of Rb-E2F-regulated genes leads to apoptosis through inactivation of focal adhesion kinase and activation of caspase-8. These findings reveal a new mechanistic link between Rb-E2F and the extrinsic (caspase 8-mediated) apoptotic pathway.
Original language | English (US) |
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Pages (from-to) | 10484-10490 |
Number of pages | 7 |
Journal | Journal of Biological Chemistry |
Volume | 280 |
Issue number | 11 |
DOIs | |
State | Published - Mar 18 2005 |
Externally published | Yes |
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology