title: The SKP2 E3 ligase regulates basal homeostasis and stress-induced regeneration of HSCs.
abstract: Exit from quiescence and reentry into cell cycle is essential for HSC self-renewal and regeneration. Skp2 is the F-box unit of the SCF E3-ligase that targets the CDK inhibitors (CKIs) p21(Cip1), p27(Kip1), p57(Kip2), and p130 for degradation. These CKIs inhibit the G(1) to S-phase transition of the cell cycle, and their deletion results in increased cell proliferation and decreased stem cell self-renewal. Skp2 deletion leads to CKIs stabilization inducing cell-cycle delay or arrest, and conversely, increased Skp2 expression is often found in cancers. Here, we show that SKP2 expression is increased in HSC and progenitors in response to hematopoietic stress from myelosuppression or after transplantation. At steady state, SKP2 deletion decreased the mitotic activity of HSC and progenitors resulting in enhanced HSC quiescence, increased HSC pool size, and maintenance. However, the inability to rapidly enter cell cycle greatly impaired the short-term repopulating potential of SKP2 null HSC and their ability to regenerate after myeloablative stress. Mechanistically, deletion of SKP2 in HSC and progenitors stabilized CKIs in vivo, particularly p27(Kip1), p57(Kip2), and p130. Our results demonstrate a previously unrecognized role for SKP2 in regulating HSC and progenitor expansion and hematopoietic regeneration after stress.
authors.affiliation: Department of Pediatrics, Herman B Wells Center, Indiana University Simon Cancer Center, Indiana University School of Medicine, 1044 W. Walnut, Indianapolis, IN 46202, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Rodriguez
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Christen
authors.initials: C
authors.lastname: Mumaw
authors.forename: Edward F
authors.initials: EF
authors.lastname: Srour
authors.forename: Cristina
authors.initials: C
authors.lastname: Lo Celso
authors.forename: Kei-ichi
authors.initials: K
authors.lastname: Nakayama
authors.forename: Nadia
authors.initials: N
authors.lastname: Carlesso
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D006706:Homeostasis / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D044786:S-Phase Kinase-Associated Proteins; D044767:Ubiquitin-Protein Ligases