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Conditional Knockout ESCs Reveal Cell Survival Role for Gabpa

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Review of “GA-Binding Protein Alpha Is Involved in the Survival of Mouse Embryonic Stem Cells” from STEM CELLS by Stuart P. Atkinson

Tumorigenic cells and pluripotent stem cells (PSCs) share many characteristics, including rapid cell proliferation, the capacity to self-renew, and even transcriptional regulatory pathways. To some, these similarities suggest that tumor-related transcription factors, such as the Ets family [1], might also play a role in the regulation of pluripotency in embryonic stem cells (ESCs). 

Researchers from the laboratories of Tadayuki Akagi and Takashi Yokota (Kanazawa University, Japan) have previously described how the Ets family members Etv4 and Etv5 control ESC proliferation [2], and how the related GA-binding protein alpha (Gabpa) regulates Oct4 expression in ESCs by inhibiting Oct4 repressors [3]. In a new study in STEM CELLS, Ueda et al. have employed conditional knockout mouse ESCs (cKO ESCs) to demonstrate that Gabpa also controls cell survival by regulating the stability of the p53 tumor suppressor [4].

Following the induction of Gabpa inhibition, the authors noted alterations to ESC morphology, followed by a failure to proliferate and cell death by day 2; however, the reintroduction of Gabpa recovered these perturbations. Gene and protein expression profiling indicated that loss of Gabpa deregulated the expression of cell cycle- and growth arrest-related genes. Importantly, a decrease in Gabpa also promoted the accumulation of p53 protein and the activation of Caspase3, which can lead to growth repression and apoptosis. However, artificial inhibition of p53 activity via treatment with pifithrin-α or p53 downregulation via RNA interference partially rescued the phenotype of Gabpa cKO ESCs.

While a previous study demonstrated that targeted disruption of Gabpa in mice results in an early embryonic lethality before implantation [5], the cKO strategy employed has permitted the description of Gabpa as a regulator of p53 stability and mESC survival and proliferation. The team behind this new body of work hopes that this first analysis of Gabpa cKO ESCs will provide valuable information for the maintenance of ESCs, although just how Gabpa regulates p53 stability remains unknown.

For more on Gabpa, p53, pluripotency, and ESCs, stay tuned to the Stem Cells Portal!

References

  1. Wei GH, Badis G, Berger MF, et al., Genome‐wide analysis of ETS‐family DNA‐binding <em>in vitro</em> and <em>in vivo</em>. The EMBO Journal 2010;29:2147-2160.
  2. Akagi T, Kuure S, Uranishi K, et al., ETS-related transcription factors ETV4 and ETV5 are involved in proliferation and induction of differentiation-associated genes in embryonic stem (ES) cells. J Biol Chem 2015;290:22460-73.
  3. Kinoshita K, Ura H, Akagi T, et al., GABPalpha regulates Oct-3/4 expression in mouse embryonic stem cells. Biochem Biophys Res Commun 2007;353:686-91.
  4. Ueda A, Akagi T, and Yokota T, GA-Binding Protein Alpha Is Involved in the Survival of Mouse Embryonic Stem Cells. STEM CELLS 2017;35:2229-2238.
  5. Ristevski S, O'Leary DA, Thornell AP, et al., The ETS transcription factor GABPalpha is essential for early embryogenesis. Mol Cell Biol 2004;24:5844-9.