title: The role of Skp2 in hematopoietic stem cell quiescence, pool size, and self-renewal.
abstract: Although the maintenance of HSC quiescence and self-renewal are critical for controlling stem cell pool and transplantation efficiency, the mechanisms by which they are regulated remain largely unknown. Understanding the factors controlling these processes may have important therapeutic potential for BM failure and cancers. Here, we show that Skp2, a component of the Skp2 SCF complex, is an important regulator for HSC quiescence, frequency, and self-renewal capability. Skp2 deficiency displays a marked enhancement of HSC populations through promoting cell cycle entry independently of its role on apoptosis. Surprisingly, Skp2 deficiency in HSCs reduces quiescence and displays increased HSC cycling and proliferation. Importantly, loss of Skp2 not only increases HSC populations and long-term reconstitution ability but also rescues the defect in long-term reconstitution ability of HSCs on PTEN inactivation. Mechanistically, we show that Skp2 deficiency induces Cyclin D1 gene expression, which contributes to an increase in HSC cycling. Finally, we demonstrate that Skp2 deficiency enhances sensitivity of Lin(-) Sca-1(+) c-kit(+) cells and leukemia cells to chemotherapy agents. Our findings show that Skp2 is a novel regulator for HSC quiescence and self-renewal and that targeting Skp2 may have therapeutic implications for BM transplantation and leukemia stem cell treatment.
authors.affiliation: Department of Molecular and Cellular Oncology, M. D. Anderson Cancer Center, The University of Texas, Houston, TX, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Fei
authors.initials: F
authors.lastname: Han
authors.forename: Juan
authors.initials: J
authors.lastname: Wu
authors.forename: Szu-Wei
authors.initials: SW
authors.lastname: Lee
authors.forename: Chia-Hsin
authors.initials: CH
authors.lastname: Chan
authors.forename: Ching-Yuan
authors.initials: CY
authors.lastname: Wu
authors.forename: Wei-Lei
authors.initials: WL
authors.lastname: Yang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.forename: Xian
authors.initials: X
authors.lastname: Zhang
authors.forename: Yun Seong
authors.initials: YS
authors.lastname: Jeong
authors.forename: Asad
authors.initials: A
authors.lastname: Moten
authors.forename: Felipe
authors.initials: F
authors.lastname: Samaniego
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.forename: Hui-Kuan
authors.initials: HK
authors.lastname: Lin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; C530105:Ccnd1 protein, mouse; D044786:S-Phase Kinase-Associated Proteins; D019938:Cyclin D1; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse