title: Self-renewal versus lineage commitment of embryonic stem cells: protein kinase C signaling shifts the balance.
abstract: The intricate molecular mechanisms that regulate ESC pluripotency are incompletely understood. Prior research indicated that activation of the Janus kinase-signal transducer and activator of transcription (STAT3) pathway or inhibition of extracellular signal-regulated kinase/glycogen synthase kinase 3 (ERK/GSK3) signaling maintains mouse ESC (mESC) pluripotency. Here, we demonstrate that inhibition of protein kinase C (PKC) isoforms maintains mESC pluripotency without the activation of STAT3 or inhibition of ERK/GSK3 signaling pathways. Our analyses revealed that the atypical PKC isoform, PKCζ plays an important role in inducing lineage commitment in mESCs through a PKCζ-nuclear factor kappa-light-chain-enhancer of activated B cells signaling axis. Furthermore, inhibition of PKC isoforms permits derivation of germline-competent ESCs from mouse blastocysts and also facilitates reprogramming of mouse embryonic fibroblasts toward induced pluripotent stem cells. Our results indicate that PKC signaling is critical to balancing ESC self-renewal and lineage commitment.
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Debasree
authors.initials: D
authors.lastname: Dutta
authors.forename: Soma
authors.initials: S
authors.lastname: Ray
authors.forename: Pratik
authors.initials: P
authors.lastname: Home
authors.forename: Melissa
authors.initials: M
authors.lastname: Larson
authors.forename: Michael W
authors.initials: MW
authors.lastname: Wolfe
authors.forename: Soumen
authors.initials: S
authors.lastname: Paul
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D065150:Cellular Reprogramming; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005347:Fibroblasts / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D057026:Induced Pluripotent Stem Cells; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3