RRC ID 48550
Author Tanaka T, Kanatsu-Shinohara M, Shinohara T.
Title The CDKN1B-RB1-E2F1 pathway protects mouse spermatogonial stem cells from genomic damage.
Journal J Reprod Dev
Abstract Spermatogonial stem cells (SSCs) undergo self-renewal divisions to provide the foundation for spermatogenesis. Although Rb1 deficiency is reportedly essential for SSC self-renewal, its mechanism has remained unknown. Here we report that Rb1 is critical for cell cycle progression and protection of SSCs from DNA double-strand breaks (DSBs). Cultured SSCs depleted of Cdkn1b proliferated poorly and showed diminished expression of CDK4 and RB1, thereby leading to hypophosphorylation of RB1. Rb1 deficiency induced cell cycle arrest and apoptosis in cultured SSCs, which expressed markers for DNA DSBs. This DNA damage is caused by increased E2F1 activity, the depletion of which decreased DNA DSBs caused by Rb1 deficiency. Depletion of Cdkn1a and Bbc3, which were upregulated by Trp53, rescued Rb1-deficient cells from undergoing cell cycle arrest and apoptosis. These results suggest that the CDKN1B-RB1-E2F1 pathway is essential for SSC self-renewal and protects SSCs against genomic damage.
Volume 61(4)
Pages 305-16
Published 2015-1-1
DOI 10.1262/jrd.2015-027
PMID 25959802
PMC PMC4547988
MeSH Animals Apoptosis Apoptosis Regulatory Proteins / genetics Apoptosis Regulatory Proteins / metabolism Biomarkers / metabolism Cell Cycle Cells, Cultured Crosses, Genetic Cyclin-Dependent Kinase 4 / genetics Cyclin-Dependent Kinase 4 / metabolism Cyclin-Dependent Kinase Inhibitor p27 / genetics Cyclin-Dependent Kinase Inhibitor p27 / metabolism* DNA Breaks, Double-Stranded* E2F1 Transcription Factor / genetics E2F1 Transcription Factor / metabolism* Gene Expression Regulation, Developmental* Male Mice, Inbred Strains Mice, Knockout Mice, Transgenic Phosphorylation Protein Processing, Post-Translational Retinoblastoma Protein / genetics Retinoblastoma Protein / metabolism* Spermatogonia / cytology Spermatogonia / metabolism* Tumor Suppressor Proteins / genetics Tumor Suppressor Proteins / metabolism
IF 1.735
Times Cited 1
DNA material AxCANCre (RDB01748)