title: Runx1 and p21 synergistically limit the extent of hair follicle stem cell quiescence in vivo.
abstract: Mechanisms of tissue stem cell (SC) quiescence control are important for normal homeostasis and for preventing cancer. Cyclin-dependent kinase inhibitors (CDKis) are known inhibitors of cell cycle progression. We document CDKis expression in vivo during hair follicle stem cell (HFSC) homeostasis and find p21 (cyclin-dependent kinase inhibitor 1a, Cdkn1a), p57, and p15 up-regulated at quiescence onset. p21 appears important for HFSC timely onset of quiescence. Conversely, we find that Runx1 (runt related transcription factor 1), which is known for promoting HFSC proliferation, represses p21, p27, p57, and p15 transcription in HFSC in vivo. Intriguingly, in cell culture, tumors, and normal homeostasis, Runx1 and p21 interplay modulates proliferation in opposing directions under the different conditions. Unexpectedly, Runx1 and p21 synergistically limit the extent of HFSC quiescence in vivo, which antagonizes the role of p21 as a cell cycle inhibitor. Importantly, we find in cultured keratinocytes that Runx1 and p21 bind to the p15 promoter and synergistically repress p15 mRNA transcription, thereby restraining cell cycle arrest. This documents a surprising ability of a CDKi (p21) to act as a direct transcriptional repressor of another CDKi (p15). We unveil a robust in vivo mechanism that enforces quiescence of HFSCs, and a context-dependent role of a CDKi (p21) to limit quiescence of SCs, potentially by directly down-regulating mRNA levels of (an)other CDKi(s).
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Jayhun
authors.initials: J
authors.lastname: Lee
authors.forename: Charlene S L
authors.initials: CS
authors.lastname: Hoi
authors.forename: Karin C
authors.initials: KC
authors.lastname: Lilja
authors.forename: Brian S
authors.initials: BS
authors.lastname: White
authors.forename: Song Eun
authors.initials: SE
authors.lastname: Lee
authors.forename: David
authors.initials: D
authors.lastname: Shalloway
authors.forename: Tudorita
authors.initials: T
authors.lastname: Tumbar
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology*; D018859:Hair Follicle / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*; D054462:p21-Activated Kinases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C493965:Cdkn1c protein, mouse; D050676:Core Binding Factor Alpha 2 Subunit; D050761:Cyclin-Dependent Kinase Inhibitor p57; C493726:Runx1 protein, mouse; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases