Skp1-Cullin-F-box (SCF)-type ubiquitin ligase FBXW7 negatively regulates spermatogonial stem cell self-renewal
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 c...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2014-06, Vol.111 (24), p.8826-8831 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Kanatsu-Shinohara, Mito Onoyama, Ichiro Nakayama, Keiichi I. Shinohara, Takashi |
| description | 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. |
| doi_str_mv | 10.1073/pnas.1401837111 |
| format | Article |
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1401837111</identifier><identifier>PMID: 24879440</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Biological Sciences ; Cell cycle ; Cell Differentiation ; Cell Lineage ; Cell Proliferation ; Cells ; Cells, Cultured ; Cellular biology ; Enzymes ; F-Box Proteins - genetics ; F-Box Proteins - physiology ; F-Box-WD Repeat-Containing Protein 7 ; Gene Deletion ; Gene expression regulation ; Germ cells ; Green Fluorescent Proteins - metabolism ; Homeostasis ; Kinetics ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Molecules ; Protein expression ; Protein Isoforms - metabolism ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-myc - metabolism ; Seminiferous Tubules - metabolism ; Sertoli cells ; Spermatogenesis ; Spermatogonia ; Spermatogonia - metabolism ; Stem cells ; Stem Cells - cytology ; Testes ; Testis - metabolism ; Transplantation ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - physiology</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2014-06, Vol.111 (24), p.8826-8831</ispartof><rights>copyright © 1993—2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Jun 17, 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c557t-8539efadef45af9c63def56a862b722a8d5f9a0844680d8c079dc7f956225f223</citedby><cites>FETCH-LOGICAL-c557t-8539efadef45af9c63def56a862b722a8d5f9a0844680d8c079dc7f956225f223</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/111/24.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/23802011$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/23802011$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24879440$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kanatsu-Shinohara, Mito</creatorcontrib><creatorcontrib>Onoyama, Ichiro</creatorcontrib><creatorcontrib>Nakayama, Keiichi I.</creatorcontrib><creatorcontrib>Shinohara, Takashi</creatorcontrib><title>Skp1-Cullin-F-box (SCF)-type ubiquitin ligase FBXW7 negatively regulates spermatogonial stem cell self-renewal</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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.</description><subject>Animals</subject><subject>Biological Sciences</subject><subject>Cell cycle</subject><subject>Cell Differentiation</subject><subject>Cell Lineage</subject><subject>Cell Proliferation</subject><subject>Cells</subject><subject>Cells, Cultured</subject><subject>Cellular biology</subject><subject>Enzymes</subject><subject>F-Box Proteins - genetics</subject><subject>F-Box Proteins - physiology</subject><subject>F-Box-WD Repeat-Containing Protein 7</subject><subject>Gene Deletion</subject><subject>Gene expression regulation</subject><subject>Germ cells</subject><subject>Green Fluorescent Proteins - metabolism</subject><subject>Homeostasis</subject><subject>Kinetics</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Molecules</subject><subject>Protein expression</subject><subject>Protein Isoforms - metabolism</subject><subject>Protein Structure, Tertiary</subject><subject>Proto-Oncogene Proteins c-myc - metabolism</subject><subject>Seminiferous Tubules - metabolism</subject><subject>Sertoli cells</subject><subject>Spermatogenesis</subject><subject>Spermatogonia</subject><subject>Spermatogonia - metabolism</subject><subject>Stem cells</subject><subject>Stem Cells - cytology</subject><subject>Testes</subject><subject>Testis - metabolism</subject><subject>Transplantation</subject><subject>Ubiquitin-Protein Ligases - genetics</subject><subject>Ubiquitin-Protein Ligases - physiology</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc1vEzEQxS0EoqFw5gSsxAUO2469_toLEkQEkCpxCBXcLGdjLw6OvbW9hfz3bEhI4TQjzW_ee9JD6CmGCwyiuRyCzheYApaNwBjfQzMMLa45beE-mgEQUUtK6Bl6lPMGAFom4SE6I1SKllKYobD8MeB6PnrvQr2oV_FX9Wo5X7yuy24w1bhyN6MrLlTe9TqbavHu21dRBdPr4m6N31XJ9KPXxeQqDyZtdYl9DE77KhezrTrjp814WycTzE_tH6MHVvtsnhznObpevP8y_1hfff7waf72qu4YE6WWrGmN1WtjKdO27XgzrYxryclKEKLlmtlWg6SUS1jLDkS77oRtGSeEWUKac_TmoDuMq61ZdyaUpL0aktvqtFNRO_X_Jbjvqo-3igLnVMAk8PIokOLNaHJRmzimMGVWmFFgUxLBJ-ryQHUp5pyMPTlgUPuC1L4gdVfQ9PH832An_m8jE_DiCOw_T3IYT4iSkuxNnx2ITS4x3Sk0Egj8sTgqWB2V7pPL6no5XTgAphQDb34D4naqWQ</recordid><startdate>20140617</startdate><enddate>20140617</enddate><creator>Kanatsu-Shinohara, Mito</creator><creator>Onoyama, Ichiro</creator><creator>Nakayama, Keiichi I.</creator><creator>Shinohara, Takashi</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20140617</creationdate><title>Skp1-Cullin-F-box (SCF)-type ubiquitin ligase FBXW7 negatively regulates spermatogonial stem cell self-renewal</title><author>Kanatsu-Shinohara, Mito ; 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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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>24879440</pmid><doi>10.1073/pnas.1401837111</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological Sciences Cell cycle Cell Differentiation Cell Lineage Cell Proliferation Cells Cells, Cultured Cellular biology Enzymes F-Box Proteins - genetics F-Box Proteins - physiology F-Box-WD Repeat-Containing Protein 7 Gene Deletion Gene expression regulation Germ cells Green Fluorescent Proteins - metabolism Homeostasis Kinetics Male Mice Mice, Inbred C57BL Mice, Knockout Molecules Protein expression Protein Isoforms - metabolism Protein Structure, Tertiary Proto-Oncogene Proteins c-myc - metabolism Seminiferous Tubules - metabolism Sertoli cells Spermatogenesis Spermatogonia Spermatogonia - metabolism Stem cells Stem Cells - cytology Testes Testis - metabolism Transplantation Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - physiology |
| title | Skp1-Cullin-F-box (SCF)-type ubiquitin ligase FBXW7 negatively regulates spermatogonial stem cell self-renewal |
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