Protein-protein interactions mediating hypoxia-inducible factor 1 complex function

The hypoxia-inducible factor 1 (HIF1) complex, comprised of a HIF1α and aryl hydrocarbon receptor translocator (ARNT/HIF1β) heterodimer, regulates the transcription of genes promoting tumour progression under hypoxia. Preliminary data suggests that the retinoblastoma protein (RB) attenuates HIF1-mediated transcription directly through interaction with the co-activator thyroid hormone receptor/retinoblastoma interacting protein 230 (TRIP230) to inhibit invasiveness of MCF7 human breast cancer cells. The objective of this study was to further characterize the invasive phenotype in MCF7 cells following loss of RB. Loss of RB resulted in a hypoxic-dependent increase in expression of HIF1 target genes involved in tumour progression. Protein-protein interaction analysis demonstrated that RB exists in complex with ARNT and TRIP230. Moreover, this complex dissociated in the presence of an ARNT-interacting peptide. Lastly, the C-terminal region of the TRIP230 RB-interaction domain has been identified as the minimal interaction domain. Altogether, these results further establish RB as an attenuator of HIF1-mediated transcription.