title: Skp1-Cullin-F-box (SCF)-type ubiquitin ligase FBXW7 negatively regulates spermatogonial stem cell self-renewal.
abstract: Spermatogonial stem cells (SSCs) undergo self-renewal divisions to support spermatogenesis throughout life. Although several positive regulators of SSC self-renewal have been discovered, little is known about the negative regulators. Here, we report that F-box and WD-40 domain protein 7 (FBXW7), a component of the Skp1-Cullin-F-box-type ubiquitin ligase, is a negative regulator of SSC self-renewal. FBXW7 is expressed in undifferentiated spermatogonia in a cell cycle-dependent manner. Although peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1), essential for spermatogenesis, is thought to destroy FBXW7, Pin1 depletion decreased FBXW7 expression. Spermatogonial transplantation showed that Fbxw7 overexpression compromised SSC activity whereas Fbxw7 deficiency enhanced SSC colonization and caused accumulation of undifferentiated spermatogonia, suggesting that the level of FBXW7 is critical for self-renewal and differentiation. Screening of putative FBXW7 targets revealed that Fbxw7 deficiency up-regulated myelocytomatosis oncogene (MYC) and cyclin E1 (CCNE1). Although depletion of Myc/Mycn or Ccne1/Ccne2 compromised SSC activity, overexpression of Myc, but not Ccne1, increased colonization of SSCs. These results suggest that FBXW7 regulates SSC self-renewal in a negative manner by degradation of MYC.
authors.affiliation: Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;Precursory Research for Embryonic Science and Technology (PRESTO) and mshinoha@virus.kyoto-u.ac.jp.
authors.forename: Mito
authors.initials: M
authors.lastname: Kanatsu-Shinohara
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Onoyama
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, JapanCore Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo 102-0076, Japan; and.
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.affiliation: Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo 102-0076, Japan; and.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shinohara
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D044783:F-Box Proteins / Q000235:genetics / Q000502:physiology*; D000073979:F-Box-WD Repeat-Containing Protein 7; D017353:Gene Deletion; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006706:Homeostasis; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012671:Seminiferous Tubules / Q000378:metabolism; D013093:Spermatogonia / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology*; D013737:Testis / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*
chemical_list: D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; C489428:Myc protein, mouse; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc; D049452:Green Fluorescent Proteins; D044767:Ubiquitin-Protein Ligases