MRC National Institute for Medical Research, London
Science for Health
Explaining c-myc regulation
17 August 2010
The proto-oncogene c-myc is a master regulator of cell proliferation, growth and differentiation and is one of a small group of transcription factors whose overexpression has been shown to reprogram somatic cells into stem cells. The Far UpStream Element (FUSE) regulatory system creates a sharp peak in c-Myc concentration during the cell cycle. In FUSE-mediated regulation, an activator (the FUSE Binding Protein or FBP) binds to a single-stranded DNA region upstream of the promoter (the FUSE) increasing productive transcription of c-myc. The FBP activator recruits its own repressor (the FBP Interacting Repressor or FIR), that downregulates c-myc transcription.
Research in the laboratory of Andres Ramos (pictured) in NIMR's Division of Molecular Structure, in collaboration with Steve Martin in the Division of Physical Biochemistry and with the MRC Biomedical NMR Centre, has explained how the interaction between FBP and FIR can control the peak in c-Myc concentration during the cell cycle. An unfolded linker, located between the FIR-interacting region and the DNA-interacting region of FBP, decreases the cooperativity between FIR-FBP and FIR-DNA binding. The low cooperativity delays the recruitment of the repressor to the transcriptionally activated system, allowing a substantial surge in c-Myc concentration.
FIR recruitment to the FUSE-FBP complex
Click image to view at full-size
Left - A 4-turn helix from the c-myc activator FTP (blue) binds a hydrophobic surface (red) on the second RNA Recognition Motif of the repressor FIR. A patch of Alanines occupies the solvent-excluded part of the interface, reducing side-chain inter-digitation between the two proteins engaged in this transient interaction.
Right - A flexible 50-amino acid linker separates the FIR-interacting and DNA-interacting regions of FBP, reducing cooperativity and allowing a surge in c-Myc concentration.
The misfunction of the FUSE regulatory system has been associated with several important cancer pathologies and recent work in a mouse model has asserted the potential of targeting c-myc as an anti-cancer therapy. Our work indicates that a small change in FBP-FIR affinity leads to a significant effect on c-Myc concentration and suggests that compounds that stabilise the Nbox FBP-RRM2 FIR interaction could speed FIR recruitment and reduce productive transcription of c-myc."
Andres Ramos
Original article
The research findings are published in full in:
Molecular basis of FIR-mediated c-myc transcriptional control (2010)
Cyprian D. Cukier, David Hollingworth, Stephen R. Martin, Geoff Kelly, Irene Díaz-Moreno and Andres Ramos
Nature Structural & Molecular Biology Epub ahead of print. Publisher abstract
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