Although the transcription factors that control embryonic stem cell (ESC) self-renewal and pluripotency are well characterized, less is known about the upstream signalling pathways. Schaniel, Lemischka and colleagues now identify the mitotic kinase Aurka (Aurora A) to be necessary for ESC maintenance through suppression of p53 (Cell Stem Cell 11, 179–194, 2012 ).

An shRNA screen of 104 protein kinases and phosphatases revealed that depletion of Aurka decreased mouse ESC renewal and expression of pluripotency markers, while promoting mesodermal and ectodermal differentiation. Further, high Aurka expression correlates with the undifferentiated state. The authors observed no major cell cycle or apoptotic defects in Aurka-depleted ESCs, suggesting that residual Aurka activity was sufficient for its normal proliferative and viability functions. Gene profiling of Aurka knockdown cells and subsequent gene set enrichment analysis indicated that Aurka negatively regulates p53 activity. Indeed, two Aurka phosphorylation sites were identified in p53, and a p53 mutant mimicking phosphorylation at one of these sites showed reduced reporter activity in ESCs. Aurka depletion increased known p53 targets associated with developmental processes, and expression of a phospho-mimic p53 mutant shifted gene expression from pluripotency- to differentiation-associated markers. Thus, Aurka maintains pluripotency through suppression of a p53-driven differentiation program.

Interestingly, the authors found that Aurka is also upregulated during reprogramming of mouse embryonic stem cells into induced pluripotent stem cells (iPSC), and that Aurka depletion impairs iPSC generation in a p53-dependent manner.