The RB tumour suppressor pathway in oxidative stress responses in the haematopoietic system

In addition to conventional cell cycle regulatory target genes, E2fs have been reported to interact functionally with other transcription factors, such as Foxos, hypoxia-inducible factor 1α (HIF-1α), nuclear factor κB (NFκB), nuclear respiratory factor 1 (NRF1) and peroxisome proliferator-activated receptor γ (PPARγ), to modulate effects on autophagy, metabolism, mitochondrial mass and the redox response of cells. These activities are distinct from its role in regulating pro-apoptotic genes, but may indirectly impinge upon the viability of cells by determining the overall levels of nutrients, ATP, NAD+ and reactive oxygen species (ROS). For example, E2F1 cooperates with HIF to induce BNIP3 expression, which promotes mitochondrial autophagy in response to hypoxia, thereby limiting ROS and necrosis. E2F1 has also been shown to regulate the expression of other autophagy regulators, such as ATG1 and ATG8 (REF. ). E2F1 modulates cellular ROS levels through inhibition of NFκB activity mediated by direct protein–protein interactions between E2F1 and the NFκB subunit RELA (REF. ). Multiple feedback loops operate at the transcriptional level, with NFκB feeding back to induce HIF, and E2Fs regulating Foxo expression, which in turn negatively modulates HIF activity through induction of the transcriptional co-activator CITED2 (REF. ). Upstream of HIF and Foxos, the SIRT1 deacetylase counters the activity of p300 and is dependent on available NAD+ for its ability to activate Foxos, its ability to promote RB turnover and its downstream interaction with and activation of peroxisome proliferator-activated receptor γ, coactivator 1α (PGC-1α),.

Publication

The role of the RB tumour suppressor pathway in oxidative stress responses in the haematopoietic system. () Kay F. Macleod. Nat Rev Cancer. ;8(10):769-781. Figure: F3. All organisms Homo sapiens Mus musculus Drosophila melanogaster

Disease mentions