Distinct regulatory mechanisms of tumor supressor protein p16/INK4A in self-renewing human pluripotent and neural stem cells


FEDOROVÁ Veronika BARÁK Martin ELREFAE Lina Mohamed Bahaael PETRÁŠOVÁ Martina BOHAČIAKOVÁ Dáša

Year of publication 2019
Type Conference abstract
MU Faculty or unit

Faculty of Medicine

Description Human pluripotent stem cells (hPSCs) have the ability to differentiate and to unlimitedly self-renew. This is partially ensured by rapid cell division and specific cell cycle regulatory mechanisms. Importantly, length of G1 phase, and activity of specific cell cycle regulators determine the cell fate decision and differentiation. Here we aimed to study the cell cycle inhibitor p16/INK4A (p16), an important regulator of G1 phase transition that has been associated with cellular senescence and is frequently deregulated in human glioblasto-ma. Initially, we noticed that expression of p16 in hPSCs is low in early passages ( < 40) and increases with high number of passages (>60). Surprisingly, the elevated level of p16 in cells of high passage does not affect their proliferation. We analysed the cellular localisation of p16 in hPSCs expressing p16 and found that, in addition to nucleus, p16 also localizes to cytoplasm, a phenotype previously found in numerous tumours.. We fur-ther studied possible regulations of p16 expression in hPSCs and in hPSC-derived neu-ral stem cells (NSCs) and our functional experiments suggest that regulations of p16 change upon differentiation of hPSCs into NSCs. While p16 protein level increased in hPSCs after inhibition of miRNA biogenesis, suggesting regulation by miRNA, in NSCs p16 level is modulated by proteasomal degradation. Finally, we also investigated the rela-tionship between p16 and its known regulators Ets1, p53, and Bmi1. In undifferentiated hPSCs, our results point to an interesting regulatory loop between p16 and p53. Ets1, although elevated in high passages of hPSCs does not seem to directly regulate p16. Upon differentiation, in NSCs, the expression of p16 is partly inhibited by polycomb pro-tein Bmi1, oncogene necessary for self-renewal. Altogether, our results reveal novel ex-pression patterns of protein p16 during early human development in vitro and point to several molecular pathways by which its expression is being regulated.

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