p21cip/WAF is a key regulator of long-term radiation damage in mesenchyme-derived tissues
This study aimed to determine the mechanisms responsible for long-term tissue damage following radiation injury. We irradiated p21-knockout (p21⁻/⁻) and wild-type (WT) mice and determined the long-term deleterious effects of this intervention on mesenchyme-derived tissues. In addition, we explored t...
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| Veröffentlicht in: | The FASEB journal 2010-12, Vol.24 (12), p.4877-4888 |
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| creator | Mehrara, Babak J Avraham, Tomer Soares, Marc Fernandez, John G Yan, Alan Zampell, Jamie C Andrade, Victor P Cordeiro, Andrew P Sorrento, Cristina M |
| description | This study aimed to determine the mechanisms responsible for long-term tissue damage following radiation injury. We irradiated p21-knockout (p21⁻/⁻) and wild-type (WT) mice and determined the long-term deleterious effects of this intervention on mesenchyme-derived tissues. In addition, we explored the mechanisms of radiation-induced mesenchymal stem cell (MSC) dysfunction in isolated bone marrow-derived cells. p21 expression was chronically elevated >200-fold in irradiated tissues. Loss of p21 function resulted in a >4-fold increase in the number of skin MSCs remaining after radiation. p21⁻/⁻ mice had significantly less radiation damage, including 6-fold less scarring, 40% increased growth potential, and 4-fold more hypertrophic chondrocytes in the epiphyseal plate (P |
| doi_str_mv | 10.1096/fj.10-155762 |
| format | Article |
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We irradiated p21-knockout (p21⁻/⁻) and wild-type (WT) mice and determined the long-term deleterious effects of this intervention on mesenchyme-derived tissues. In addition, we explored the mechanisms of radiation-induced mesenchymal stem cell (MSC) dysfunction in isolated bone marrow-derived cells. p21 expression was chronically elevated >200-fold in irradiated tissues. Loss of p21 function resulted in a >4-fold increase in the number of skin MSCs remaining after radiation. p21⁻/⁻ mice had significantly less radiation damage, including 6-fold less scarring, 40% increased growth potential, and 4-fold more hypertrophic chondrocytes in the epiphyseal plate (P<0.01). Irradiated p21⁻/⁻ MSCs had 4-fold increased potential for bone or fat differentiation, 4-fold greater proliferation rate, and nearly 7-fold lower senescence as compared to WT MSCs (P<0.01). Ectopic expression of p21 in knockout cells decreased proliferation and differentiation potential and recapitulated the WT phenotype. Loss of p21 function markedly decreases the deleterious effects of radiation injury in mesenchyme-derived tissues and preserves tissue-derived MSCs. In addition, p21 is a critical regulator of MSC proliferation, differentiation, and senescence both at baseline and in response to radiation.--Mehrara, B. J., Avraham, T., Soares, M., Fernandez, J. G., Yan, A., Zampell, J. C., Andrade, V. P., Cordeiro, A. P., Sorrento, C. M. p21cip/WAF is a key regulator of long-term radiation damage in mesenchyme-derived tissues.</description><identifier>ISSN: 0892-6638</identifier><identifier>EISSN: 1530-6860</identifier><identifier>DOI: 10.1096/fj.10-155762</identifier><identifier>PMID: 20720160</identifier><language>eng</language><publisher>United States: The Federation of American Societies for Experimental Biology</publisher><subject>Animals ; Blotting, Western ; Cell Cycle - radiation effects ; Cell Differentiation - radiation effects ; Cell Proliferation - radiation effects ; Cells, Cultured ; Cellular Senescence - radiation effects ; Cyclin-Dependent Kinase Inhibitor p21 - genetics ; Cyclin-Dependent Kinase Inhibitor p21 - metabolism ; Mesenchymal Stromal Cells - cytology ; Mesenchymal Stromal Cells - metabolism ; Mesenchymal Stromal Cells - radiation effects ; Mice ; Mice, Knockout ; Radiation, Ionizing ; Reverse Transcriptase Polymerase Chain Reaction</subject><ispartof>The FASEB journal, 2010-12, Vol.24 (12), p.4877-4888</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20720160$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mehrara, Babak J</creatorcontrib><creatorcontrib>Avraham, Tomer</creatorcontrib><creatorcontrib>Soares, Marc</creatorcontrib><creatorcontrib>Fernandez, John G</creatorcontrib><creatorcontrib>Yan, Alan</creatorcontrib><creatorcontrib>Zampell, Jamie C</creatorcontrib><creatorcontrib>Andrade, Victor P</creatorcontrib><creatorcontrib>Cordeiro, Andrew P</creatorcontrib><creatorcontrib>Sorrento, Cristina M</creatorcontrib><title>p21cip/WAF is a key regulator of long-term radiation damage in mesenchyme-derived tissues</title><title>The FASEB journal</title><addtitle>FASEB J</addtitle><description>This study aimed to determine the mechanisms responsible for long-term tissue damage following radiation injury. We irradiated p21-knockout (p21⁻/⁻) and wild-type (WT) mice and determined the long-term deleterious effects of this intervention on mesenchyme-derived tissues. In addition, we explored the mechanisms of radiation-induced mesenchymal stem cell (MSC) dysfunction in isolated bone marrow-derived cells. p21 expression was chronically elevated >200-fold in irradiated tissues. Loss of p21 function resulted in a >4-fold increase in the number of skin MSCs remaining after radiation. p21⁻/⁻ mice had significantly less radiation damage, including 6-fold less scarring, 40% increased growth potential, and 4-fold more hypertrophic chondrocytes in the epiphyseal plate (P<0.01). Irradiated p21⁻/⁻ MSCs had 4-fold increased potential for bone or fat differentiation, 4-fold greater proliferation rate, and nearly 7-fold lower senescence as compared to WT MSCs (P<0.01). Ectopic expression of p21 in knockout cells decreased proliferation and differentiation potential and recapitulated the WT phenotype. Loss of p21 function markedly decreases the deleterious effects of radiation injury in mesenchyme-derived tissues and preserves tissue-derived MSCs. In addition, p21 is a critical regulator of MSC proliferation, differentiation, and senescence both at baseline and in response to radiation.--Mehrara, B. J., Avraham, T., Soares, M., Fernandez, J. G., Yan, A., Zampell, J. C., Andrade, V. P., Cordeiro, A. P., Sorrento, C. M. p21cip/WAF is a key regulator of long-term radiation damage in mesenchyme-derived tissues.</description><subject>Animals</subject><subject>Blotting, Western</subject><subject>Cell Cycle - radiation effects</subject><subject>Cell Differentiation - radiation effects</subject><subject>Cell Proliferation - radiation effects</subject><subject>Cells, Cultured</subject><subject>Cellular Senescence - radiation effects</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</subject><subject>Mesenchymal Stromal Cells - cytology</subject><subject>Mesenchymal Stromal Cells - metabolism</subject><subject>Mesenchymal Stromal Cells - radiation effects</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Radiation, Ionizing</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kEtPwzAQhC0EoqVw4wy-cQr1K459rBAFpEocKEKcIifeBJe8sBOk_nsstZxmtftpZrQIXVNyT4mWy2oXNaFpmkl2guY05SSRSpJTNCdKs0RKrmboIoQdIYQSKs_RjJGMxYnM0efAaOmG5cdqjV3ABn_DHnuop8aMvcd9hZu-q5MRfIu9sc6Mru-wNa2pAbsOtxCgK7_2LSQWvPsFi0cXwgThEp1VpglwddQF2q4ftw_Pyeb16eVhtUmqTMemQmdcCEFVEftIZbmSTEFVqLIsgGkqtGQlhZRRLlJWioxYYYhQ1pKsiMsFujvYDr7_ibFj3rpQQtOYDvop5IqmWnLBZCRvjuRUtGDzwbvW-H3-_4wI3B6AyvS5qb0L-ftbPHFCNc0Yp_wP8U5nog</recordid><startdate>201012</startdate><enddate>201012</enddate><creator>Mehrara, Babak J</creator><creator>Avraham, Tomer</creator><creator>Soares, Marc</creator><creator>Fernandez, John G</creator><creator>Yan, Alan</creator><creator>Zampell, Jamie C</creator><creator>Andrade, Victor P</creator><creator>Cordeiro, Andrew P</creator><creator>Sorrento, Cristina M</creator><general>The Federation of American Societies for Experimental Biology</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>201012</creationdate><title>p21cip/WAF is a key regulator of long-term radiation damage in mesenchyme-derived tissues</title><author>Mehrara, Babak J ; Avraham, Tomer ; Soares, Marc ; Fernandez, John G ; Yan, Alan ; Zampell, Jamie C ; Andrade, Victor P ; Cordeiro, Andrew P ; Sorrento, Cristina M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-f790-6497344418b16068d38628efb8ccbe2914962c1e5213452c470d4a048dd07b213</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Blotting, Western</topic><topic>Cell Cycle - radiation effects</topic><topic>Cell Differentiation - radiation effects</topic><topic>Cell Proliferation - radiation effects</topic><topic>Cells, Cultured</topic><topic>Cellular Senescence - radiation effects</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - genetics</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</topic><topic>Mesenchymal Stromal Cells - cytology</topic><topic>Mesenchymal Stromal Cells - metabolism</topic><topic>Mesenchymal Stromal Cells - radiation effects</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Radiation, Ionizing</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mehrara, Babak J</creatorcontrib><creatorcontrib>Avraham, Tomer</creatorcontrib><creatorcontrib>Soares, Marc</creatorcontrib><creatorcontrib>Fernandez, John G</creatorcontrib><creatorcontrib>Yan, Alan</creatorcontrib><creatorcontrib>Zampell, Jamie C</creatorcontrib><creatorcontrib>Andrade, Victor P</creatorcontrib><creatorcontrib>Cordeiro, Andrew P</creatorcontrib><creatorcontrib>Sorrento, Cristina M</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>The FASEB journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mehrara, Babak J</au><au>Avraham, Tomer</au><au>Soares, Marc</au><au>Fernandez, John G</au><au>Yan, Alan</au><au>Zampell, Jamie C</au><au>Andrade, Victor P</au><au>Cordeiro, Andrew P</au><au>Sorrento, Cristina M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>p21cip/WAF is a key regulator of long-term radiation damage in mesenchyme-derived tissues</atitle><jtitle>The FASEB journal</jtitle><addtitle>FASEB J</addtitle><date>2010-12</date><risdate>2010</risdate><volume>24</volume><issue>12</issue><spage>4877</spage><epage>4888</epage><pages>4877-4888</pages><issn>0892-6638</issn><eissn>1530-6860</eissn><abstract>This study aimed to determine the mechanisms responsible for long-term tissue damage following radiation injury. We irradiated p21-knockout (p21⁻/⁻) and wild-type (WT) mice and determined the long-term deleterious effects of this intervention on mesenchyme-derived tissues. In addition, we explored the mechanisms of radiation-induced mesenchymal stem cell (MSC) dysfunction in isolated bone marrow-derived cells. p21 expression was chronically elevated >200-fold in irradiated tissues. Loss of p21 function resulted in a >4-fold increase in the number of skin MSCs remaining after radiation. p21⁻/⁻ mice had significantly less radiation damage, including 6-fold less scarring, 40% increased growth potential, and 4-fold more hypertrophic chondrocytes in the epiphyseal plate (P<0.01). Irradiated p21⁻/⁻ MSCs had 4-fold increased potential for bone or fat differentiation, 4-fold greater proliferation rate, and nearly 7-fold lower senescence as compared to WT MSCs (P<0.01). Ectopic expression of p21 in knockout cells decreased proliferation and differentiation potential and recapitulated the WT phenotype. Loss of p21 function markedly decreases the deleterious effects of radiation injury in mesenchyme-derived tissues and preserves tissue-derived MSCs. In addition, p21 is a critical regulator of MSC proliferation, differentiation, and senescence both at baseline and in response to radiation.--Mehrara, B. J., Avraham, T., Soares, M., Fernandez, J. G., Yan, A., Zampell, J. C., Andrade, V. P., Cordeiro, A. P., Sorrento, C. M. p21cip/WAF is a key regulator of long-term radiation damage in mesenchyme-derived tissues.</abstract><cop>United States</cop><pub>The Federation of American Societies for Experimental Biology</pub><pmid>20720160</pmid><doi>10.1096/fj.10-155762</doi><tpages>12</tpages></addata></record> |
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| subjects | Animals Blotting, Western Cell Cycle - radiation effects Cell Differentiation - radiation effects Cell Proliferation - radiation effects Cells, Cultured Cellular Senescence - radiation effects Cyclin-Dependent Kinase Inhibitor p21 - genetics Cyclin-Dependent Kinase Inhibitor p21 - metabolism Mesenchymal Stromal Cells - cytology Mesenchymal Stromal Cells - metabolism Mesenchymal Stromal Cells - radiation effects Mice Mice, Knockout Radiation, Ionizing Reverse Transcriptase Polymerase Chain Reaction |
| title | p21cip/WAF is a key regulator of long-term radiation damage in mesenchyme-derived tissues |
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