Antagonism of E2F-1 regulated Bnip3 transcription by NF-κB is essential for basal cell survival
Open Access
- 30 December 2008
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 105 (52), 20734-20739
- https://doi.org/10.1073/pnas.0807735105
Abstract
The transcription factor E2F-1 drives proliferation and death, but the mechanisms that differentially regulate these divergent actions are poorly understood. The hypoxia-inducible death factor Bnip3 is an E2F-1 target gene and integral component of the intrinsic mitochondrial death pathway. The mechanisms that govern Bnip3 gene activity remain cryptic. Herein we show that the transcription factor NF-κB provides a molecular switch that determines whether E2F-1 signals proliferation or death under physiological conditions. We show under basal nonapoptotic conditions that NF-κB constitutively occupies and transcriptionally silences Bnip3 gene transcription by competing with E2F-1 for Bnip3 promoter binding. Conversely, in the absence of NF-κB, or during hypoxia when NF-κB abundance is reduced, basal Bnip3 gene transcription is activated by the unrestricted binding of E2F-1 to the Bnip3 promoter. Genetic knock-down of E2F-1 or retinoblastoma gene product over-expression in cardiac and human pancreatic cancer cells deficient for NF-κB signaling abrogated basal and hypoxia-inducible Bnip3 transcription. The survival kinase PI3K/Akt inhibited Bnip3 expression levels in cells in a manner dependent upon NF-κB activation. Hence, by way of example, we show that the transcriptional inhibition of E2F-1-dependent Bnip3 expression by NF-κB highlights a survival pathway that overrides the E2F-1 tumor suppressor program. Our data may explain more fundamentally how cells, by selectively inhibiting E2F-1-dependent death gene transcription, avert apoptosis down-stream of the retinoblastoma/E2F-1 cell cycle pathway.Keywords
This publication has 30 references indexed in Scilit:
- The Cell Cycle Factor E2F-1 Activates Bnip3 and the Intrinsic Death Pathway in Ventricular MyocytesCirculation Research, 2008
- An E2F1-Dependent Gene Expression Program that Determines the Balance between Proliferation and Cell DeathCancer Cell, 2008
- Transcriptional Silencing of the Death Gene BNIP3 by Cooperative Action of NF-κB and Histone Deacetylase 1 in Ventricular MyocytesCirculation Research, 2006
- Degradation of Promoter-bound p65/RelA Is Essential for the Prompt Termination of the Nuclear Factor κB ResponseThe Journal of Experimental Medicine, 2004
- IKKβ Is Required for Bcl-2-mediated NF-κB Activation in Ventricular MyocytesPublished by Elsevier BV ,2002
- Mutant Mouse Models Reveal the Relative Roles of E2F1 and E2F3 In VivoMolecular and Cellular Biology, 2002
- NF-κB at the crossroads of life and deathNature Immunology, 2002
- Akt Stimulates the Transactivation Potential of the RelA/p65 Subunit of NF-κB through Utilization of the IκB Kinase and Activation of the Mitogen-activated Protein Kinase p38Published by Elsevier BV ,2001
- Dynamic Shuttling of Nuclear Factor κB between the Nucleus and Cytoplasm as a Consequence of Inhibitor DissociationPublished by Elsevier BV ,2000
- Mitochondria and ApoptosisScience, 1998