RRC ID 31843
Author Kanatsu-Shinohara M, Onoyama I, Nakayama KI, Shinohara T.
Title Skp1-Cullin-F-box (SCF)-type ubiquitin ligase FBXW7 negatively regulates spermatogonial stem cell self-renewal.
Journal Proc Natl Acad Sci U S A
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.
Volume 111(24)
Pages 8826-31
Published 2014-6-17
DOI 10.1073/pnas.1401837111
PII 1401837111
PMID 24879440
PMC PMC4066470
MeSH Animals Cell Differentiation Cell Lineage Cell Proliferation Cells, Cultured F-Box Proteins / genetics F-Box Proteins / physiology* F-Box-WD Repeat-Containing Protein 7 Gene Deletion Green Fluorescent Proteins / metabolism Homeostasis Kinetics Male Mice Mice, Inbred C57BL Mice, Knockout Protein Isoforms / metabolism Protein Structure, Tertiary Proto-Oncogene Proteins c-myc / metabolism Seminiferous Tubules / metabolism Spermatogonia / metabolism* Stem Cells / cytology* Testis / metabolism Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / physiology*
IF 9.412
Times Cited 35
DNA material AxCANCre (RDB01748) AxCANLacZ (RDB01749).