Partial Proteasome Inhibitors Induce Hair Follicle Growth by Stabilizing β-Catenin

Author:

Yucel Gozde1,Arnam John1,Means Paula Casey1,Huntzicker Erik1,Altindag Banu1,Lara Maria Fernanda1,Yuan Jenny2,Kuo Calvin2,Oro Anthony E.1

Affiliation:

1. Program in Epithelial Biology Stanford University School of Medicine, Stanford, California, USA

2. Department of Medicine Stanford University School of Medicine, Stanford, California, USA

Abstract

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. Stem Cells  2014;32:85–92

Funder

NIH

NIH Intestinal Stem Cell Consortium

Stanford Medical Scientist Training program and Howard Hughes Institute

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,Molecular Medicine

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