The tumor suppressor p53 spurs the destruction of a critical cell cycle regulator to prevent cells from proliferating during an energy shortage, say Mandal et al.
Cell division uses up a lot of energy, so cells ensure they have enough resources to complete the job before committing to it. Drosophila cells with a mutation in their mitochondrial electron transport chain generate less ATP, and stop their DNA from replicating by activating a stress response that eliminates cyclin E, a cell cycle regulator that would otherwise push the cells into S phase. The pathway involves p53, but how this protein lowers cyclin E levels is unknown.
Mandal et al. found that p53 stimulates cyclin E's degradation by increasing the transcription of a protein called archipelago. Archipelago recruits cyclin E to an E3 ubiquitin ligase called SCF, which ubiquitinates the cyclin and targets it to the proteasome. Reducing archipelago levels in Drosophila with dysfunctional mitochondria restored cyclin E expression and allowed cells to reenter S phase, despite their low ATP levels. The researchers showed that archipelago is a direct transcriptional target of p53, driving cyclin E's destruction and cell cycle arrest during unfavorable metabolic conditions.
p53 can initiate cell death in response to stresses such as DNA damage but it doesn't induce proapoptotic genes following disruption of the electron transport chain. This suggests that p53 has thresholds of stress activation, says lead author Sudip Mandal, which would allow cells to resume proliferation if metabolic conditions improve.