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Review
. 2010 May 13;53(9):3439-53.
doi: 10.1021/jm901361d.

Small molecules and stem cells. Potency and lineage commitment: the new quest for the fountain of youth

Agnès I Lukaszewicz  1 , Michael K McMillan, Michael Kahn
Affiliations
Review

Small molecules and stem cells. Potency and lineage commitment: the new quest for the fountain of youth

Agnès I Lukaszewicz et al. J Med Chem. .
No abstract available

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Figures

FIGURE 1
FIGURE 1
structures and described modes of action of small molecules that have been shown to regulate stem cell biology and are potentially useful for regenerative medicine.
FIGURE 2
FIGURE 2
templated library approach (reverse turn /helix template and extended strand template) and published examples therof
FIGURE 3
FIGURE 3
Wnt signaling is a complex pathway, believed to be involved in the regulation of divergent processes, including the maintenance of pluripotency and commitment to differentiation. To resolve these divergent responses to activation of Wnt/β-catenin signaling, we have developed a model in which β-catenin/CBP-mediated transcription is critical for the maintenance of potency, whereas a switch to β-catenin/p300-mediated transcription is the first critical step to initiate differentiation. Hence the balance between CBP and p300-mediated β-catenin transcription regulates the balance between maintenance of potency and the initiation of commitment to differentiate. The interaction of β-catenin with either CBP or p300 can be modulated by two small molecules, respectively ICG-001 and IQ-1, identified in our laboratory. As a consequence, these small molecules regulate Wnt signaling pathway outcomes.
FIGURE 4
FIGURE 4
a negative feedback normally turns off the CBP/β-catenin arm of the pathway and initiates differentiation via the p300/β-catenin arm.
FIGURE 5
FIGURE 5
the ultimate decision for a cell to retain potency or initiate differentiation is dependent upon numerous inputs some of which are presented here: e.g. concentration of different growth factors, cytokines and hormones and the subsequent activation of different signal transduction complexes and kinase cascades, ionic concentrations (e.g. Ca++), nutrient levels, oxygen levels, genetic mutations, adhesion to substratum. In the end those multiple pathways must be integrated and funneled down into a simple decision point, i.e. a yes/no binary decision. We believe that Wnt signaling and the equilibrium between CBP-mediated and p300-mediated transcription play a central role in integrating these signals.
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