Control of Drosophila MYC transcription, cell growth and developmental patterning by the single stranded DNA binding protein Psi
- The John Curtin School of Medical Research, ANU, Canberra, Australia.
- The University of Melbourne, Parkville, Australia.
- Menzies Institute for Medical Research, Hobart, Australia.
- Peter MacCallum Cancer Centre, Melbourne, Australia.
- National Cancer Institute, NIH, Bethesda, Maryland, USA.
The transcription factor MYC is upregulated in 70% of cancers and elevated MYC potently drives growth and proliferation. Thus, the capacity of the MYC promoter to integrate developmental signals is essential for correct growth patterning in all multicellular animals. Studies of the MYC promoter identified Far Upstream Binding Protein 1 (FUBP 1), a single stranded DNA binding protein, which acts to activate MYC expression. Consistently with this function, FUBP1 is upregulated in many cancers, including breast, liver, bladder, kidney and lung. Moreover, our recent Drosophila studies revealed that the FUBP1 ortholog (Psi) interacts with the transcriptional Mediator (MED) complex to integrate developmental signals, activate MYC and promote cell and tissue growth in the wing epithelium. Paradoxically, our recent unpublished data demonstrate expansion of the neuroblast stem cell lineage in the Drosophila brain after Psi depletion. In line with tissue-specific functions, FUBP1 knockout mice exhibit hypoproliferation in the embryonic blood lineage, while overgrowth occurs in the brain. Furthermore, in contrast to other tumour types, FUBP1 loss-of-function ranks in the top 10% of predicted driver mutations in oligodendroglioma, the second most common primary brain cancer in adults. The mechanisms behind these striking context-specific roles is unknown; therefore our current studies in Drosophilamodels focus on identification of key Psi transcriptional targets in both wing epithelium and neural stem cells.