Hoxb4 transduction down-regulates Geminin protein, providing hematopoietic stem and progenitor cells with proliferation potential
Retrovirus-mediated transduction of Hoxb4 enhances hematopoietic stem cell (HSC) activity and enforced expression of Hoxb4 induces in vitro development of HSCs from differentiating mouse embryonic stem cells, but the underlying molecular mechanism remains unclear. We previously showed that the HSC a...
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| creator | Ohno, Yoshinori Yasunaga, Shin'ichiro Ohtsubo, Motoaki Mori, Sayaka Tsumura, Miyuki Okada, Satoshi Ohta, Tomohiko Ohtani, Kiyoshi Kobayashi, Masao Takihara, Yoshihiro Mak, Tak Wah |
| description | Retrovirus-mediated transduction of Hoxb4 enhances hematopoietic stem cell (HSC) activity and enforced expression of Hoxb4 induces in vitro development of HSCs from differentiating mouse embryonic stem cells, but the underlying molecular mechanism remains unclear. We previously showed that the HSC activity was abrogated by accumulated Geminin, an inhibitor for the DNA replication licensing factor Cdt1 in mice deficient in Rae28 (also known as Phc1), which encodes a member of Polycomb-group complex 1. In this study we found that Hoxb4 transduction reduced accumulated Geminin in Rae28-deficient mice, despite increasing the mRNA, and restored the impaired HSC activity. Supertransduction of Geminin suppressed the HSC activity induced by Hoxb4 transduction, whereas knockdown of Geminin promoted the clonogenic and replating activities, indicating the importance of Geminin regulation in the molecular mechanism underlying Hoxb4 transduction-mediated enhancement of the HSC activity. This facilitated our investigation of how transduced Hoxb4 reduced Geminin. We showed in vitro and in vivo that Hoxb4 and the Roc1 (also known as Rbx1)-Ddb1-Cul4a ubiquitin ligase core component formed a complex designated as RDCOXB4, which acted as an E3 ubiquitin ligase for Geminin and down-regulated Geminin through the ubiquitin-proteasome system. Down-regulated Geminin and the resultant E2F activation may provide cells with proliferation potential by increasing a DNA prereplicative complex loaded onto chromatin. Here we suggest that transduced Hoxb4 down-regulates Geminin protein probably by constituting the E3 ubiquitin ligase for Geminin to provide hematopoietic stem and progenitor cells with proliferation potential. |
| doi_str_mv | 10.1073/pnas.1011054107 |
| format | Article |
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We previously showed that the HSC activity was abrogated by accumulated Geminin, an inhibitor for the DNA replication licensing factor Cdt1 in mice deficient in Rae28 (also known as Phc1), which encodes a member of Polycomb-group complex 1. In this study we found that Hoxb4 transduction reduced accumulated Geminin in Rae28-deficient mice, despite increasing the mRNA, and restored the impaired HSC activity. Supertransduction of Geminin suppressed the HSC activity induced by Hoxb4 transduction, whereas knockdown of Geminin promoted the clonogenic and replating activities, indicating the importance of Geminin regulation in the molecular mechanism underlying Hoxb4 transduction-mediated enhancement of the HSC activity. This facilitated our investigation of how transduced Hoxb4 reduced Geminin. We showed in vitro and in vivo that Hoxb4 and the Roc1 (also known as Rbx1)-Ddb1-Cul4a ubiquitin ligase core component formed a complex designated as RDCOXB4, which acted as an E3 ubiquitin ligase for Geminin and down-regulated Geminin through the ubiquitin-proteasome system. Down-regulated Geminin and the resultant E2F activation may provide cells with proliferation potential by increasing a DNA prereplicative complex loaded onto chromatin. Here we suggest that transduced Hoxb4 down-regulates Geminin protein probably by constituting the E3 ubiquitin ligase for Geminin to provide hematopoietic stem and progenitor cells with proliferation potential.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1011054107</identifier><identifier>PMID: 21098278</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Biological Sciences ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Cell cycle ; Cell Cycle Proteins - genetics ; Cell Cycle Proteins - metabolism ; Cell Differentiation - physiology ; Cell lines ; Cell Proliferation ; Cells ; Chromatin ; Cullin Proteins - genetics ; Cullin Proteins - metabolism ; DNA Replication ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Down regulation ; E2F Transcription Factors - genetics ; E2F Transcription Factors - metabolism ; Geminin ; Gene expression ; Gene expression regulation ; HEK293 Cells ; Hematopoietic stem cells ; Hematopoietic Stem Cells - cytology ; Hematopoietic Stem Cells - physiology ; Homeodomain Proteins - genetics ; Homeodomain Proteins - metabolism ; Humans ; Messenger RNA ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Minichromosome Maintenance Complex Component 2 ; Molecules ; Multiprotein Complexes - metabolism ; Nuclear Matrix-Associated Proteins - genetics ; Nuclear Matrix-Associated Proteins - metabolism ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Nucleocytoplasmic Transport Proteins - genetics ; Nucleocytoplasmic Transport Proteins - metabolism ; Progenitor cells ; Rodents ; Signal transduction ; Stem cells ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transduction, Genetic ; Ubiquitins</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2010-12, Vol.107 (50), p.21529-21534</ispartof><rights>Copyright National Academy of Sciences Dec 14, 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c510t-ef2d6706ec15043972129f33cb393bac9e64bef12fb99f5b2320175bbedd79e33</citedby><cites>FETCH-LOGICAL-c510t-ef2d6706ec15043972129f33cb393bac9e64bef12fb99f5b2320175bbedd79e33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/107/50.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/25756918$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/25756918$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,724,777,781,800,882,27905,27906,53772,53774,57998,58231</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21098278$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ohno, Yoshinori</creatorcontrib><creatorcontrib>Yasunaga, Shin'ichiro</creatorcontrib><creatorcontrib>Ohtsubo, Motoaki</creatorcontrib><creatorcontrib>Mori, Sayaka</creatorcontrib><creatorcontrib>Tsumura, Miyuki</creatorcontrib><creatorcontrib>Okada, Satoshi</creatorcontrib><creatorcontrib>Ohta, Tomohiko</creatorcontrib><creatorcontrib>Ohtani, Kiyoshi</creatorcontrib><creatorcontrib>Kobayashi, Masao</creatorcontrib><creatorcontrib>Takihara, Yoshihiro</creatorcontrib><creatorcontrib>Mak, Tak Wah</creatorcontrib><title>Hoxb4 transduction down-regulates Geminin protein, providing hematopoietic stem and progenitor cells with proliferation potential</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Retrovirus-mediated transduction of Hoxb4 enhances hematopoietic stem cell (HSC) activity and enforced expression of Hoxb4 induces in vitro development of HSCs from differentiating mouse embryonic stem cells, but the underlying molecular mechanism remains unclear. We previously showed that the HSC activity was abrogated by accumulated Geminin, an inhibitor for the DNA replication licensing factor Cdt1 in mice deficient in Rae28 (also known as Phc1), which encodes a member of Polycomb-group complex 1. In this study we found that Hoxb4 transduction reduced accumulated Geminin in Rae28-deficient mice, despite increasing the mRNA, and restored the impaired HSC activity. Supertransduction of Geminin suppressed the HSC activity induced by Hoxb4 transduction, whereas knockdown of Geminin promoted the clonogenic and replating activities, indicating the importance of Geminin regulation in the molecular mechanism underlying Hoxb4 transduction-mediated enhancement of the HSC activity. This facilitated our investigation of how transduced Hoxb4 reduced Geminin. We showed in vitro and in vivo that Hoxb4 and the Roc1 (also known as Rbx1)-Ddb1-Cul4a ubiquitin ligase core component formed a complex designated as RDCOXB4, which acted as an E3 ubiquitin ligase for Geminin and down-regulated Geminin through the ubiquitin-proteasome system. Down-regulated Geminin and the resultant E2F activation may provide cells with proliferation potential by increasing a DNA prereplicative complex loaded onto chromatin. Here we suggest that transduced Hoxb4 down-regulates Geminin protein probably by constituting the E3 ubiquitin ligase for Geminin to provide hematopoietic stem and progenitor cells with proliferation potential.</description><subject>Animals</subject><subject>Biological Sciences</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Cell cycle</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Cell Differentiation - physiology</subject><subject>Cell lines</subject><subject>Cell Proliferation</subject><subject>Cells</subject><subject>Chromatin</subject><subject>Cullin Proteins - genetics</subject><subject>Cullin Proteins - metabolism</subject><subject>DNA Replication</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Down regulation</subject><subject>E2F Transcription Factors - genetics</subject><subject>E2F Transcription Factors - metabolism</subject><subject>Geminin</subject><subject>Gene expression</subject><subject>Gene expression regulation</subject><subject>HEK293 Cells</subject><subject>Hematopoietic stem cells</subject><subject>Hematopoietic Stem Cells - cytology</subject><subject>Hematopoietic Stem Cells - physiology</subject><subject>Homeodomain Proteins - genetics</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Humans</subject><subject>Messenger RNA</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Minichromosome Maintenance Complex Component 2</subject><subject>Molecules</subject><subject>Multiprotein Complexes - metabolism</subject><subject>Nuclear Matrix-Associated Proteins - genetics</subject><subject>Nuclear Matrix-Associated Proteins - metabolism</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>Nucleocytoplasmic Transport Proteins - genetics</subject><subject>Nucleocytoplasmic Transport Proteins - metabolism</subject><subject>Progenitor cells</subject><subject>Rodents</subject><subject>Signal transduction</subject><subject>Stem cells</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Transduction, Genetic</subject><subject>Ubiquitins</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1v1DAQxS0EokvhzAlkceFCqD_ixL4goQpapEpc4Gw5zmTXq8QOttPCkf8ch126wMmj8W_e-Pkh9JySt5S0_GL2JpWKUiLq0niANpQoWjW1Ig_RhhDWVrJm9Rl6ktKeEKKEJI_RGSuUZK3coJ_X4XtX4xyNT_1iswse9-HOVxG2y2gyJHwFk_PO4zmGDM6_WYtb1zu_xTuYTA5zcJCdxSnDhI3vV2AL3uUQsYVxTPjO5d3aHd0A0fxeMhcxn50Zn6JHgxkTPDue5-jrxw9fLq-rm89Xny7f31RWUJIrGFjftKQBSwWpuWoZZWrg3HZc8c5YBU3dwUDZ0Ck1iI5xRmgrug76vlXA-Tl6d9Cdl26C3pbt0Yx6jm4y8YcOxul_b7zb6W241ZwQXr64CLw-CsTwbYGU9eTS6s94CEvSUkgma85lIV_9R-7DEn1xpyWVooSj6gJdHCAbQ0oRhvunUKLXcPUarj6FWyZe_u3gnv-TZgHwEVgnT3KtFqRQgqmCvDgg-1TiOUmIVjSKSv4LZiy4tw</recordid><startdate>20101214</startdate><enddate>20101214</enddate><creator>Ohno, Yoshinori</creator><creator>Yasunaga, Shin'ichiro</creator><creator>Ohtsubo, Motoaki</creator><creator>Mori, Sayaka</creator><creator>Tsumura, Miyuki</creator><creator>Okada, Satoshi</creator><creator>Ohta, Tomohiko</creator><creator>Ohtani, Kiyoshi</creator><creator>Kobayashi, Masao</creator><creator>Takihara, Yoshihiro</creator><creator>Mak, Tak Wah</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20101214</creationdate><title>Hoxb4 transduction down-regulates Geminin protein, providing hematopoietic stem and progenitor cells with proliferation potential</title><author>Ohno, Yoshinori ; Yasunaga, Shin'ichiro ; Ohtsubo, Motoaki ; Mori, Sayaka ; Tsumura, Miyuki ; Okada, Satoshi ; Ohta, Tomohiko ; Ohtani, Kiyoshi ; Kobayashi, Masao ; Takihara, Yoshihiro ; Mak, Tak Wah</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c510t-ef2d6706ec15043972129f33cb393bac9e64bef12fb99f5b2320175bbedd79e33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Biological Sciences</topic><topic>Carrier Proteins - 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metabolism</topic><topic>Humans</topic><topic>Messenger RNA</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Minichromosome Maintenance Complex Component 2</topic><topic>Molecules</topic><topic>Multiprotein Complexes - metabolism</topic><topic>Nuclear Matrix-Associated Proteins - genetics</topic><topic>Nuclear Matrix-Associated Proteins - metabolism</topic><topic>Nuclear Proteins - genetics</topic><topic>Nuclear Proteins - metabolism</topic><topic>Nucleocytoplasmic Transport Proteins - genetics</topic><topic>Nucleocytoplasmic Transport Proteins - metabolism</topic><topic>Progenitor cells</topic><topic>Rodents</topic><topic>Signal transduction</topic><topic>Stem cells</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Transduction, Genetic</topic><topic>Ubiquitins</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ohno, Yoshinori</creatorcontrib><creatorcontrib>Yasunaga, Shin'ichiro</creatorcontrib><creatorcontrib>Ohtsubo, Motoaki</creatorcontrib><creatorcontrib>Mori, Sayaka</creatorcontrib><creatorcontrib>Tsumura, Miyuki</creatorcontrib><creatorcontrib>Okada, Satoshi</creatorcontrib><creatorcontrib>Ohta, Tomohiko</creatorcontrib><creatorcontrib>Ohtani, Kiyoshi</creatorcontrib><creatorcontrib>Kobayashi, Masao</creatorcontrib><creatorcontrib>Takihara, Yoshihiro</creatorcontrib><creatorcontrib>Mak, Tak Wah</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - 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We previously showed that the HSC activity was abrogated by accumulated Geminin, an inhibitor for the DNA replication licensing factor Cdt1 in mice deficient in Rae28 (also known as Phc1), which encodes a member of Polycomb-group complex 1. In this study we found that Hoxb4 transduction reduced accumulated Geminin in Rae28-deficient mice, despite increasing the mRNA, and restored the impaired HSC activity. Supertransduction of Geminin suppressed the HSC activity induced by Hoxb4 transduction, whereas knockdown of Geminin promoted the clonogenic and replating activities, indicating the importance of Geminin regulation in the molecular mechanism underlying Hoxb4 transduction-mediated enhancement of the HSC activity. This facilitated our investigation of how transduced Hoxb4 reduced Geminin. We showed in vitro and in vivo that Hoxb4 and the Roc1 (also known as Rbx1)-Ddb1-Cul4a ubiquitin ligase core component formed a complex designated as RDCOXB4, which acted as an E3 ubiquitin ligase for Geminin and down-regulated Geminin through the ubiquitin-proteasome system. Down-regulated Geminin and the resultant E2F activation may provide cells with proliferation potential by increasing a DNA prereplicative complex loaded onto chromatin. Here we suggest that transduced Hoxb4 down-regulates Geminin protein probably by constituting the E3 ubiquitin ligase for Geminin to provide hematopoietic stem and progenitor cells with proliferation potential.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>21098278</pmid><doi>10.1073/pnas.1011054107</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological Sciences Carrier Proteins - genetics Carrier Proteins - metabolism Cell cycle Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell Differentiation - physiology Cell lines Cell Proliferation Cells Chromatin Cullin Proteins - genetics Cullin Proteins - metabolism DNA Replication DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Down regulation E2F Transcription Factors - genetics E2F Transcription Factors - metabolism Geminin Gene expression Gene expression regulation HEK293 Cells Hematopoietic stem cells Hematopoietic Stem Cells - cytology Hematopoietic Stem Cells - physiology Homeodomain Proteins - genetics Homeodomain Proteins - metabolism Humans Messenger RNA Mice Mice, Inbred C57BL Mice, Knockout Minichromosome Maintenance Complex Component 2 Molecules Multiprotein Complexes - metabolism Nuclear Matrix-Associated Proteins - genetics Nuclear Matrix-Associated Proteins - metabolism Nuclear Proteins - genetics Nuclear Proteins - metabolism Nucleocytoplasmic Transport Proteins - genetics Nucleocytoplasmic Transport Proteins - metabolism Progenitor cells Rodents Signal transduction Stem cells Transcription Factors - genetics Transcription Factors - metabolism Transduction, Genetic Ubiquitins |
| title | Hoxb4 transduction down-regulates Geminin protein, providing hematopoietic stem and progenitor cells with proliferation potential |
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