Two proteins that act independently to arrest the cell cycle can combine to inhibit cell adhesion and drive apoptosis instead, say Herkert et al.

The transcription factor Miz1 arrests damaged cells by inducing the production of cyclin-dependent kinase (Cdk) inhibitors. The tumor suppressor Arf, meanwhile, can either arrest cells or kill them following oncogenic stress, although what determines each of these two outcomes remains unknown. Miz1 and Arf have several interacting proteins in common, but Herkert et al. found that the two proteins also bind each other directly.

Surprisingly, rather than synergizing to block the cell cycle more efficiently, Arf prevented Miz1 from activating Cdk inhibitors. Instead, when combined, Arf and Miz1 assembled into a DNA-binding complex that silenced genes by inducing changes in their histone methylation states. As well as repressing the Cdk inhibitor genes, this complex also switched off many genes associated with cell–cell and cell–matrix adhesions, causing cells expressing Arf and Miz1 to lose their attachments and undergo apoptosis. This pathway could help tissues eliminate cells that have picked up potentially oncogenic mutations, the authors suggest.

Assembly of the repressive complex relied on the interaction of both Arf and Miz1 with the transcription factor Myc, suggesting that Myc levels may be crucial in switching Arf's function from arrest to cell death. In addition, association with Arf and Myc triggered Miz1’s modification by the ubiquitin-like molecule SUMO. Lead author Martin Eilers now plans to investigate how this modification helps the complex repress its target genes.

et al
J. Cell Biol.