title: E3-ligase Skp2 regulates β-catenin expression and maintains hematopoietic stem cell homing.
abstract: The homing ability of hematopoietic stem cells (HSCs) was a critical step for transplantation and subsequent hematopoiesis. Although the HSC transplantation was widely used for many diseases, the mechanism by which HSC homing was regulated remained poorly understood. F-box protein S-phase kinase associated protein2 (Skp2), a component of the Skp2-SCF E3 ligase complex, was regarded as a cell cycle regulator by controlling the level of p21 and p27 through ubiquitination. We recently reported an important role of Skp2 in maintaining HSC pool size, quiescent stage and self-renewal ability. In this current study, we showed that Skp2 was a novel and critical regulator for maintaining the homing of HSCs as well as their residence in the endosteal niche. Microarray analysis together with biochemical validations revealed that Skp2 deficiency profoundly reduced the expression of β-catenin and its target genes. Knockdown of β-catenin mimicked the decline of HSC homing upon Skp2 deficiency, suggesting that Skp2 may regulate β-catenin and its target gene expression to orchestrate HSC homing. Our study not only identified Skp2 as a new regulator for maintaining β-catenin expression and HSC homing, but also suggested that Skp2 may serve as a predictive marker for monitoring the transplantation efficiency.
authors.affiliation: State Key Laboratory of Oncology in South China and Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China; Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Han
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
authors.forename: Szu-Wei
authors.initials: SW
authors.lastname: Lee
authors.affiliation: State Key Laboratory of Oncology in South China and Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China; Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA.
authors.forename: Chia-Hsin
authors.initials: CH
authors.lastname: Chan
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
authors.forename: Xian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Oncology in South China and Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China.
authors.forename: Hong-Kai
authors.initials: HK
authors.lastname: Su
authors.affiliation: State Key Laboratory of Oncology in South China and Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China; Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA.
authors.forename: Zi-Zhen
authors.initials: ZZ
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Oncology in South China and Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China; Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA.
authors.forename: Da-Zhi
authors.initials: DZ
authors.lastname: Xu
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA; Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 404, Taiwan. Electronic address: hklin@mdanderson.org.
authors.forename: Hui-Kuan
authors.initials: HK
authors.lastname: Lin
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002465:Cell Movement; D002478:Cells, Cultured; D015536:Down-Regulation; D017353:Gene Deletion; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D044786:S-Phase Kinase-Associated Proteins; D051176:beta Catenin; D044767:Ubiquitin-Protein Ligases
keywords: Hematopoietic stem cell; Homing; S-phase kinase associated protein2 (Skp2); β-Catenin