Mitochondrial cytochrome c liberates the nucleophosmin-sequestered ARF tumor suppressor in the nucleolus
Gonzalez-Arzola, K.; Diaz-Quintana, A.; Bernardo-Garcia, N.; Casado-Combreras, M. A.; Elena-Real, C. A.; Velazquez-Cruz, A.; Gil-Caballero, S.; Velazquez-Campoy, A.; Szulc, E.; Ayala, I.; Arranz, R.; Salvatella, X.; Valpuesta, J. M.; Hermoso, J. A.; De la Rosa, M. A.; Diaz-Moreno, I.
Show abstract
The alternative reading frame (ARF) protein is crucial in the cellular response to oncogenic stress, being likewise the second most frequently inactivated gene in a wide spectrum of human cancers. ARF is usually sequestered in the nucleolus by the well-known oncogenic nucleophosmin (NPM) protein and is liberated in response to cell damage to exhibit its tumor-suppressor ability. However, the mechanism underlying ARF activation is unknown. Here we show that mitochondria-to-nucleus translocation of cytochrome c upon DNA damage leads to the break-off of the NPM-ARF ensemble and subsequent release of ARF from the nucleoli. Our structural and subcellular data support a molecular model in which the hemeprotein triggers the extended-to-compact conformation of NPM and competes with ARF for binding to NPM.
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