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Understanding the Intricacies of ESC Signaling

Review of “Functional Compensation between Myc and PI3K Signaling Supports Self‐Renewal of Embryonic Stem Cells” from Stem Cells by Stuart P. Atkinson

Almost innumerable studies have attempted to define signaling pathways which regulate embryonic stem cell (ESC) growth and differentiation. Nonetheless, we still have a long way to go to fully understand cross-talk and redundancy between said pathways. Myc and PI3K signaling are both linked to the maintenance of ESC pluripotency, and evidence suggests that they may converge to negatively regulate the MAPK pathway, although interactions/redundancies remain largely unstudied [1-3]. Now, enterprising researchers from the groups of Juan Carlos Izpisua Belmonte and Akihiko Okuda, have stepped forward to fill this knowledge gap, and report in Stem Cells on their new findings [4].

Hishida et al began their study by interrupting Myc and PI3K signaling to uncover potential redundancies or compensatory mechanisms. Disruption of Myc signaling in ESCs led to loss of cell viability, but forced expression of Myr‐p110α, a constitutively active myristoylated form of the p110α catalytic subunit of PI3K, and Nrf2 reversed this loss. However, while Myr‐p110α ESCs maintained their pluripotent nature and did not exhibit an increase in apoptosis, Nrf2 cells quickly lost their ESC-like characteristics. Reduced PI3K signaling through treatment of ESCs with LY294002 inhibitor inhibited certain pluripotent characteristics, but also led to the upregulation of c‐Myc and N‐Myc expression, while overexpression of Myc rescued any loss of pluripotent characteristics. This novel link suggests that Myc and PI3K cooperatively but independently regulate ESC status and both pathways may converge in a common signaling node.

Previous studies highlight a potentially important role for MAPK signaling in pluripotency [5, 6], and so the authors studied this pathway as the common convergence point of both PI3K and Myc signaling. Disruption of MAPK signaling through ESC-treatment with Mek and GSK3 inhibitors (2i conditions which promote ESC pluripotency) in the presence of LY294002 did not alter pluripotent characteristics. This finding was further confirmed through the use of specific genetic approaches, and suggests that PI3K signaling is redundant when MAPK signaling is also inhibited. Additional studies also found Myc signaling to be redundant under 2i conditions, reinforcing MAPK as a common pathway.

Lastly the groups assessed the transcriptional consequences of PI3K signaling on ESCs, finding a strong link between PI3K signaling and the expression of genes/processes involved in tumor formation and/or maintenance, and that this may be due to the alteration of Myc expression rather other effects of PI3K signaling. This highlighted that PI3K and Myc affect the transcription of different sets of genes, although there are likely to common targets, such as Nanog.

Overall, the authors suggest that PI3K and Myc signaling may act together to negatively regulate MAPK pathway to support the undifferentiated state of mouse ESCs, a novel finding (See the adjoining figure for a graphical overview of these findings). Importantly, they also highlight that PI3K activity and Myc expression are not required for ESC self‐renewal and pluripotency under conditions of MAPK inhibition; any may indeed inhibit tumorigenic characteristics. This may be important information towards the safe therapeutic use of ESCs in the clinic, if such information holds for human pluripotent stem cells.

References

  1. Liu P, Cheng H, Santiago S, et al. Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms. Nature medicine 2011;17:1116-1120.
  2. Sander S, Calado DP, Srinivasan L, et al. Synergy between PI3K signaling and MYC in Burkitt lymphomagenesis. Cancer Cell 2012;22:167-179.
  3. Schmitz R, Young RM, Ceribelli M, et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature 2012;490:116-120.
  4. Hishida T, Nakachi Y, Mizuno Y, et al. Functional Compensation Between Myc and PI3K Signaling Supports Self-Renewal of Embryonic Stem Cells. Stem Cells 2015;33:713-725.
  5. Hishida T, Nozaki Y, Nakachi Y, et al. Indefinite self-renewal of ESCs through Myc/Max transcriptional complex-independent mechanisms. Cell Stem Cell 2011;9:37-49.
  6. Storm MP, Bone HK, Beck CG, et al. Regulation of Nanog expression by phosphoinositide 3-kinase-dependent signaling in murine embryonic stem cells. The Journal of biological chemistry 2007;282:6265-6273.