Reciprocal Regulation of Akt and Oct4 Promotes the Self-Renewal and Survival of Embryonal Carcinoma Cells

College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Molecular cell (Impact Factor: 14.02). 10/2012; 17(4). DOI: 10.1016/j.molcel.2012.08.030
Source: PubMed


Signaling via the Akt serine/threonine protein kinase plays critical roles in the self-renewal of embryonic stem cells and their malignant counterpart, embryonal carcinoma cells (ECCs). Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG. Furthermore, in ECCs, unphosphorylated Oct4 bound to the AKT1 promoter and repressed its transcription. Phosphorylation of Oct4 by Akt resulted in dissociation of Oct4 from the AKT1 promoter, which activated AKT1 transcription and promoted cell survival. Therefore, a site-specific, posttranslational modification of the Oct4 protein orchestrates the regulation of its stability, subcellular localization, and transcriptional activities, which collectively promotes the survival and tumorigenicity of ECCs.

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Available from: Ying Yang, Oct 28, 2015
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    • "Immunoblotting and immunoprecipitation was conducted as described previously [10] "
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    • "Typically, expression of these markers is lost 24–36 h following removal of LIF. Reciprocal roles for PKB and Oct-3/4 in positively regulating each other in embryonal carcinoma cells (ECCs), the malignant equivalent of ES cells, has also emerged (Lin et al., 2012). PKB was shown to phosphorylate and positively regulate the protein stability, nuclear localization, and transcriptional activity of Oct-3/4. "
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    • "In addition, translation of OCT3/4 is mediated by micro-RNAs, specifically miR-145 [238] [239] and miR- 34a [240]. Also, post-translational modification of OCT3/4, i.e. phosphorylation by AKT has been shown to change its affinity/specificity for DNA binding sites, potentially changing the functional impact of this transcription factor [241]. Like OCT3/4 and in line with their pluripotent phenotype, the homeodomain NANOG is only detectable in the TGCC stem cell components SE and EC and in CIS and not in differentiated NS derivatives [18] [242] (Fig. 1). "
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