THE KINASE AKT/PKB INDUCES THE EXPRESSION OF THE PLURIPOTENCY TRANSCRIPTION FACTOR NANOG IN A SUMOYLATION-DEPENDENT MANNER IN MOUSE EMBRYONIC STEM CELLS.

MARCOS FRANCIA; CAMILA VAZQUEZ ECHEGARAY; STORTZ, MARTIN; OSES, CAMILA; VERNERI, PAULA; PETRONE, MARÍA VICTORIA; AYELEN TORO; CANDELARIA DIAZ; LEVI, VALERIA; ALEJANDRA GUBERMAN

Simposio; The 2nd Crick Beddington Developmental Biology Symposium; 2022

Akt/PKB is a kinase involved in the regulation of a plethora of cell processes. A wide variety of post-translational modifications are known to modulate its activity, including conjugation to the small ubiquitin-related modifier (SUMO). In embryonic stem (ES) cells, Akt is crucial for the maintenance of pluripotency, and it is known to promote the expression of Nanog, a central pluripotency transcription factor (TF). Due to the relevance of this kinase in ES cells, we explored the impact of its SUMOylation by analyzing the effect of Akt1 variants with differential SUMOylation susceptibility on Nanog gene regulation. Our results demonstrate that both, the Akt1 SUMOylatability, and a functional SUMO conjugase activity are required to induce Nanog gene expression in ES cells. Interestingly, we found that the hyperactive oncogenic Akt1 mutant E17K increased Nanog expression also in a SUMOylation-dependent manner. Remarkably, these effects take place in ES cells but not in non-pluripotent heterologous cells, suggesting the presence of a crucial factor for this induction present in the context of pluripotency. Surprisingly, two major candidate factors to mediate this induction, GSK3-β and Tbx3, are non-essential players of this effect, as well as p53, Oct4, Sox2 and Nanog itself, suggesting either a yet elusive mediator, a complex mechanism involving non-canonical pathways, or both. Overall, our results highlight the impact of SUMO conjugation in the function of Akt on the regulation of the expression of a key pluripotency TF and provide new insights of the molecular mechanisms underlying cell pluripotency, thus possibly, embryo development.