RGD Reference Report - Antagonism of E2F-1 regulated Bnip3 transcription by NF-kappaB is essential for basal cell survival. - Rat Genome Database

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Antagonism of E2F-1 regulated Bnip3 transcription by NF-kappaB is essential for basal cell survival.

Authors: Shaw, J  Yurkova, N  Zhang, T  Gang, H  Aguilar, F  Weidman, D  Scramstad, C  Weisman, H  Kirshenbaum, LA 
Citation: Shaw J, etal., Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20734-9. Epub 2008 Dec 16.
RGD ID: 2316261
Pubmed: PMID:19088195   (View Abstract at PubMed)
PMCID: PMC2603431   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.0807735105   (Journal Full-text)

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-kappaB provides a molecular switch that determines whether E2F-1 signals proliferation or death under physiological conditions. We show under basal nonapoptotic conditions that NF-kappaB constitutively occupies and transcriptionally silences Bnip3 gene transcription by competing with E2F-1 for Bnip3 promoter binding. Conversely, in the absence of NF-kappaB, or during hypoxia when NF-kappaB 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-kappaB 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-kappaB activation. Hence, by way of example, we show that the transcriptional inhibition of E2F-1-dependent Bnip3 expression by NF-kappaB 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.




Biological Process

  
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Original Reference(s)
E2f1Ratcellular response to hypoxia  IEP  RGD 


Genes (Rattus norvegicus)
E2f1  (E2F transcription factor 1)