title: The Trp53-Trp53inp1-Tnfrsf10b pathway regulates the radiation response of mouse spermatogonial stem cells.
abstract: Germ cells are thought to exhibit a unique DNA damage response that differs from that of somatic stem cells, and previous studies suggested that Trp53 is not involved in the survival of spermatogonial stem cells (SSCs) after irradiation. Here, we report a critical role for the Trp53-Trp53inp1-Tnfrsf10b pathway during radiation-induced SSC apoptosis. Spermatogonial transplantation revealed that Trp53 deficiency increased the survival of SSCs after irradiation. Although Bbc3, a member of the intrinsic apoptotic pathway, was implicated in apoptosis of germ and somatic stem cells, Bbc3 depletion inhibited apoptosis in committed spermatogonia, but not in SSCs. In contrast, inhibition of Tnfrsf10b, an extrinsic apoptosis regulator, rescued SSCs. Tnfrsf10b, whose deficiency protected SSCs, was upregulated by Trp53inp1 upon irradiation. These results suggest that the Trp53-Trp53inp1-Tnfrsf10b pathway responds to genotoxic damage in SSCs and that stem and progenitor cells exhibit distinct DNA damage responses in self-renewing tissue.
authors.affiliation: Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan. Electronic address: ishii.kei.55x@st.kyoto-u.ac.jp.
authors.forename: Kei
authors.initials: K
authors.lastname: Ishii
authors.affiliation: Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Ishiai
authors.affiliation: Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Morimoto
authors.affiliation: Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Mito
authors.initials: M
authors.lastname: Kanatsu-Shinohara
authors.affiliation: Radiation Medical Science Center for the Fukushima Health Management Survey, Fukushima Medical University, Fukushima 960-1295, Japan.
authors.forename: Ohtsura
authors.initials: O
authors.lastname: Niwa
authors.affiliation: Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Takata
authors.affiliation: Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; Japan Science and Technology Agency, CREST, Kyoto 606-8501, Japan. Electronic address: tshinoha@virus.kyoto-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shinohara
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism* / Q000528:radiation effects; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D013093:Spermatogonia / Q000378:metabolism* / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D006360:Heat-Shock Proteins; C488588:PUMA protein, mouse; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505640:Tnfrsf10b protein, mouse; C498965:Trp53inp1 protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins