Wnt/beta-catenin/CBP signaling maintains long-term murine embryonic stem cell pluripotency.
Embryonic stem cells (ESCs) represent an important research tool and a potential resource for regenerative medicine. Generally, ESCs are cocultured with a supportive feeder cell layer of murine embryonic fibroblasts, which maintain the ESCs' capacity for self-renewal and block spontaneous differentiation. These cumbersome conditions, as well as the risk of xenobiotic contamination of human ESCs grown on murine embryonic fibroblasts, make it a priority to develop chemically defined methods that can be safely used for the expansion of ESCs. Using a high-throughput, cell-based assay, we identified the small molecule IQ-1 that allows for the Wnt/beta-catenin-driven long-term expansion of mouse ESCs and prevents spontaneous differentiation. We demonstrate that IQ-1, by targeting the PR72/130 subunit of the serine/threonine phosphatase PP2A, prevents beta-catenin from switching coactivator usage from CBP to p300. The increase in beta-catenin/CBP-mediated transcription at the expense of beta-catenin/p300-mediated transcription is critical for the maintenance of murine stem cell pluripotency.
Miyabayashi
Tomoyuki
T
Central R&D Laboratories, Asahi Kasei Corporation, Shizuoka 416-8501, Japan. miyabayashi.tb@om.asahi-kasei.co.jp
Teo
Jia-Ling
JL
Yamamoto
Masashi
M
McMillan
Michael
M
Nguyen
Cu
C
Kahn
Michael
M
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D016895:Culture Media, Serum-Free; D008565:Membrane Proteins; C498709:Pag1 protein, mouse; D010750:Phosphoproteins; D051153:Wnt Proteins; D051176:beta Catenin