title: Partial proteasome inhibitors induce hair follicle growth by stabilizing β-catenin.
abstract: The activation of tissue stem cells from their quiescent state represents the initial step in the complex process of organ regeneration and tissue repair. While the identity and location of tissue stem cells are becoming known, how key regulators control the balance of activation and quiescence remains mysterious. The vertebrate hair is an ideal model system where hair cycling between growth and resting phases is precisely regulated by morphogen signaling pathways, but how these events are coordinated to promote orderly signaling in a spatial and temporal manner remains unclear. Here, we show that hair cycle timing depends on regulated stability of signaling substrates by the ubiquitin-proteasome system. Topical application of partial proteasomal inhibitors (PaPIs) inhibits epidermal and dermal proteasome activity throughout the hair cycle. PaPIs prevent the destruction of the key anagen signal β-catenin, resulting in more rapid hair growth and dramatically shortened telogen. We show that PaPIs induce excess β-catenin, act similarly to the GSK3β antagonist LiCl, and antagonize Dickopf-related protein-mediated inhibition of anagen. PaPIs thus represent a novel class of hair growth agents that act through transiently modifying the balance of stem cell activation and quiescence pathways.
authors: Program in Epithelial Biology, Stanford University, School of Medicine, Stanford, California, USA.
authors: Gozde
authors: G
authors: Yucel
authors: John
authors: J
authors: Van Arnam
authors: Paula Casey
authors: PC
authors: Means
authors: Erik
authors: E
authors: Huntzicker
authors: Banu
authors: B
authors: Altindag
authors: Maria Fernanda
authors: MF
authors: Lara
authors: Jenny
authors: J
authors: Yuan
authors: Calvin
authors: C
authors: Kuo
authors: Anthony E
authors: AE
authors: Oro
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D005260:Female; D018859:Hair Follicle / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D061988:Proteasome Inhibitors; D051176:beta Catenin; D046988:Proteasome Endopeptidase Complex
keywords: Hair growth; Proteasome; Stem cells; Tissue regeneration; Wnt signaling
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