CONICET | Buscador de Institutos y Recursos Humanos

Embryonic stem (ES) cells have the ability to differentiate into all the adult cell lineages and are an invaluable resource due to its regenerative-medicine potential in the clinic. Stress mitigation in stem cells is critical both attributable to their essential role in development and the risk for malignant transformation. In these cells, redox status regulates the balance between self-renewal and differentiation, making crucial oxidative stress control. Heme Oxygenase 1 (HO-1) is a highly relevant component of the antioxidant system. Besides its cytoprotective function, HO-1 is involved in embryo development and in ES cells differentiation. At the same time, p53 controls cellular response to multiple types of harmful stimulus, including oxidative stress. Particularly, the primary role of p53 in ES cells is to promote differentiation in response to DNA damage or developmental signals. Despite the role of both proteins has been extensively studied, little is known about their relationship. The aim of this work is to explore the HO-1 - p53 interplay in ES cells. We found that p53 knockout (KO) ES cells have higher HO-1 levels but similar HO-1 mRNA levels than the wild type (WT) ES cell line. Furthermore, evaluation of NRF2, the main HO-1 transcription factor, showed no significant differences in both its total levels and its active form with phosphorylation at Ser40 between p53 KO and WT cells. Cycloheximide treatment revealed increased HO-1 abundance in p53 KO cells suggesting that p53 modulates HO-1 protein stability. Notoriously, despite higher HO-1 basal levels in KO cells, both hemin treatment and differentiation induced HO-1 expression. Finally, H2O2 treatment did not increase HO-1 levels in p53 KO ES cells evidencing an altered response to oxidative stress. Our findings demonstrate the existence of a connection between p53 and HO-1 in ES cells highlighting the relationship between these stress defense pathways in the stem cells context.