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    • Embryonic stem cells ESCs display two important

    2018-10-20

    Embryonic stem DIG-11-dUTP (ESCs) display two important characteristics: self-renewal, which allows them to be indefinitely expanded while maintaining the undifferentiated state, and pluripotency, which allows them to differentiate into almost all cell types. ESCs are able to differentiate into all derivatives of the three primary germ layers (ectoderm, endoderm, and mesoderm). Pluripotency distinguishes ESCs from the stem cells (SCs) in an adult organism, thus adult SCs are multipotent and differentiate into a limited number of cell types. Furthermore, ESCs in culture can differentiate spontaneously and give rise to cell types that derive from different primary germ cell layers (Hmadcha et al., 2009). ESC differentiation requires the repression of transcription factors involved in maintaining pluripotency and the activation of developmental genes (Horrillo et al., 2013). Little is known about the relationship between CREB/CBP and SCs. A previous study showed that leukemia inhibitory factor (LIF) in mouse ESCs produces LIF-dependent phosphorylation of CREB. This process is partially under the control of the RSK2 kinase and as a consequence CREB regulates pluripotency and survival genes in mouse ESCs (Boeuf et al., 2001). CREB is also involved in differentiation and survival process of neural SCs in the evolutionary scale (Dworkin and Heath, 2007; Dworkin et al., 2009). Dworkin et al. (2009) have shown a specific role for CREB in mammalian embryonic neurogenesis. Another study associated CREB with early neurogenesis (Peltier et al., 2007) but presented only indirect evidence of PI3K/Akt stimulation activating both CREB and neurogenesis. Phosphorylation of CREB at serine 133 (Ser133) is a required step for inducing the transcription of multiple genes through the cAMP response element (CRE). Several kinases possess the capability of phosphorylating CREB at this site, including protein kinases A and C (Manier et al., 2001), MAP kinase activated protein kinase-2 (Xing et al., 1998), and Akt (Peltier et al., 2007; Caravatta et al., 2008). In particular, the kinase Akt and its activator PI3K play a significant role in multiple cellular functions, such as cell survival, proliferation, and cytoskeletal rearrangements (Cantley, 2002; Engelman et al., 2006; Xue and Hemmings, 2013). While the role of the PI3K/Akt signaling pathway in the function of adult neural stem or progenitor cells is still unclear, its role during development has been widely demonstrated. For instance, Akt is implicated in maintaining self-renewal of embryonic cortical progenitors (Sinor and Lillien, 2004) and ESC lines (Paling et al., 2004; Watanabe et al., 2006). Furthermore, the PI3K antagonist phosphatase and tensin homolog (PTEN) has been shown to negatively regulate proliferation of embryonic neural SCs (Groszer et al., 2006). The activation of the PI3K/Akt signaling pathway is also associated with neurogenesis in progenitor cells derived from the subventricular zone and in olfactory SCs (Vojtek et al., 2003). In line with these reports, Akt3-deficient mice showed reduced brain size and weight (Tschopp et al., 2005), revealing that Akt is crucial for the correct brain development. All the above demonstrate a mechanistic link between PI3K/Akt, CREB, and neurogenesis. ESCs and cancer cells share self-renewal capacity, which allows them to be indefinitely expanded. Moreover, the recent recognition that CREB may have oncogenic properties leads us to hypothesize that over-activation of CREB could contribute to the development of some types of tumors (Ghosh et al., 2007; Abramovitch et al., 2004; Linnerth et al., 2005; Shankar et al., 2005). This suggests that CREB could have a role in regulating genes related to self-renewal. At a mechanistic level, CREB is perhaps one of the best-understood phosphorylation-dependent transcription factors. In principle, phosphorylation of CREB at Ser133 seems to be sufficient to promote target gene activation through recruitment of CBP14. On the other hand, unphosphorylated CREB interacts with DREAM to abolish the CREB–CBP interaction in a Ca-dependent manner (Ledo et al., 2002; Fontan-Lozano et al., 2009).