p63 deficiency activates a program of cellular senescence and leads to accelerated aging
The p53 tumor suppressor plays a key role in organismal aging. A cellular mechanism postulated to drive the aging process is cellular senescence, mediated in part by p53. Although senescent cells accumulate in elderly individuals, most studies have relied on correlating in vitro senescence assays wi...
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| Veröffentlicht in: | Genes & development 2005-09, Vol.19 (17), p.1986-1999 |
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| container_end_page | 1999 |
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| container_issue | 17 |
| container_start_page | 1986 |
| container_title | Genes & development |
| container_volume | 19 |
| creator | Keyes, William M Wu, Ying Vogel, Hannes Guo, Xuecui Lowe, Scott W Mills, Alea A |
| description | The p53 tumor suppressor plays a key role in organismal aging. A cellular mechanism postulated to drive the aging process is cellular senescence, mediated in part by p53. Although senescent cells accumulate in elderly individuals, most studies have relied on correlating in vitro senescence assays with in vivo phenotypes of aging. Here, using two different mouse models in which the p53-related protein p63 is compromised, we demonstrate that cellular senescence and organismal aging are intimately linked and that these processes are mediated by p63 loss. We found that p63(+/-) mice have a shortened life span and display features of accelerated aging. Both germline and somatically induced p63 deficiency activates widespread cellular senescence with enhanced expression of senescent markers SA-beta-gal, PML, and p16(INK4a). Using an inducible tissue-specific p63 conditional model, we further show that p63 deficiency induces cellular senescence and causes accelerated aging phenotypes in the adult. Our results thus suggest a causative link between cellular senescence and aging in vivo, and demonstrate that p63 deficiency accelerates this process. |
| doi_str_mv | 10.1101/gad.342305 |
| format | Article |
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A cellular mechanism postulated to drive the aging process is cellular senescence, mediated in part by p53. Although senescent cells accumulate in elderly individuals, most studies have relied on correlating in vitro senescence assays with in vivo phenotypes of aging. Here, using two different mouse models in which the p53-related protein p63 is compromised, we demonstrate that cellular senescence and organismal aging are intimately linked and that these processes are mediated by p63 loss. We found that p63(+/-) mice have a shortened life span and display features of accelerated aging. Both germline and somatically induced p63 deficiency activates widespread cellular senescence with enhanced expression of senescent markers SA-beta-gal, PML, and p16(INK4a). Using an inducible tissue-specific p63 conditional model, we further show that p63 deficiency induces cellular senescence and causes accelerated aging phenotypes in the adult. Our results thus suggest a causative link between cellular senescence and aging in vivo, and demonstrate that p63 deficiency accelerates this process.</description><identifier>ISSN: 0890-9369</identifier><identifier>EISSN: 1549-5477</identifier><identifier>DOI: 10.1101/gad.342305</identifier><identifier>PMID: 16107615</identifier><language>eng</language><publisher>United States: Cold Spring Harbor Laboratory Press</publisher><subject>Aging - genetics ; Aging - physiology ; Aging, Premature - etiology ; Aging, Premature - genetics ; Aging, Premature - pathology ; Animals ; Base Sequence ; Cells, Cultured ; Cellular Senescence - genetics ; Cellular Senescence - physiology ; DNA, Complementary - genetics ; Epithelium - pathology ; Female ; Keratinocytes - pathology ; Male ; Mice ; Mice, Mutant Strains ; Mice, Transgenic ; Phenotype ; Phosphoproteins - deficiency ; Phosphoproteins - genetics ; Phosphoproteins - physiology ; Pregnancy ; Research Papers ; Trans-Activators - deficiency ; Trans-Activators - genetics ; Trans-Activators - physiology ; Tumor Suppressor Proteins - deficiency ; Tumor Suppressor Proteins - genetics ; Tumor Suppressor Proteins - physiology</subject><ispartof>Genes & development, 2005-09, Vol.19 (17), p.1986-1999</ispartof><rights>Copyright © 2005, Cold Spring Harbor Laboratory Press 2005</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c473t-e7d11036e955d043db8fe8e4697ac40e4c7da5e5c7dc9e0ac4a7a5fdee18fd13</citedby><cites>FETCH-LOGICAL-c473t-e7d11036e955d043db8fe8e4697ac40e4c7da5e5c7dc9e0ac4a7a5fdee18fd13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1199570/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1199570/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16107615$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Keyes, William M</creatorcontrib><creatorcontrib>Wu, Ying</creatorcontrib><creatorcontrib>Vogel, Hannes</creatorcontrib><creatorcontrib>Guo, Xuecui</creatorcontrib><creatorcontrib>Lowe, Scott W</creatorcontrib><creatorcontrib>Mills, Alea A</creatorcontrib><title>p63 deficiency activates a program of cellular senescence and leads to accelerated aging</title><title>Genes & development</title><addtitle>Genes Dev</addtitle><description>The p53 tumor suppressor plays a key role in organismal aging. A cellular mechanism postulated to drive the aging process is cellular senescence, mediated in part by p53. Although senescent cells accumulate in elderly individuals, most studies have relied on correlating in vitro senescence assays with in vivo phenotypes of aging. Here, using two different mouse models in which the p53-related protein p63 is compromised, we demonstrate that cellular senescence and organismal aging are intimately linked and that these processes are mediated by p63 loss. We found that p63(+/-) mice have a shortened life span and display features of accelerated aging. Both germline and somatically induced p63 deficiency activates widespread cellular senescence with enhanced expression of senescent markers SA-beta-gal, PML, and p16(INK4a). Using an inducible tissue-specific p63 conditional model, we further show that p63 deficiency induces cellular senescence and causes accelerated aging phenotypes in the adult. Our results thus suggest a causative link between cellular senescence and aging in vivo, and demonstrate that p63 deficiency accelerates this process.</description><subject>Aging - genetics</subject><subject>Aging - physiology</subject><subject>Aging, Premature - etiology</subject><subject>Aging, Premature - genetics</subject><subject>Aging, Premature - pathology</subject><subject>Animals</subject><subject>Base Sequence</subject><subject>Cells, Cultured</subject><subject>Cellular Senescence - genetics</subject><subject>Cellular Senescence - physiology</subject><subject>DNA, Complementary - genetics</subject><subject>Epithelium - pathology</subject><subject>Female</subject><subject>Keratinocytes - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Mutant Strains</subject><subject>Mice, Transgenic</subject><subject>Phenotype</subject><subject>Phosphoproteins - deficiency</subject><subject>Phosphoproteins - genetics</subject><subject>Phosphoproteins - physiology</subject><subject>Pregnancy</subject><subject>Research Papers</subject><subject>Trans-Activators - deficiency</subject><subject>Trans-Activators - genetics</subject><subject>Trans-Activators - physiology</subject><subject>Tumor Suppressor Proteins - deficiency</subject><subject>Tumor Suppressor Proteins - genetics</subject><subject>Tumor Suppressor Proteins - physiology</subject><issn>0890-9369</issn><issn>1549-5477</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUtLAzEUhYMoWqsbf4Bk5UKYmpjXZCNI8QUFNy7chWtyZxyZztRkWui_N6XFx8rVhXu_eziHQ8gZZxPOGb-qIUyEvBZM7ZERV9IWShqzT0astKywQtsjcpzSB2NMM60PyRHXnBnN1Yi8LrSgAavGN9j5NQU_NCsYMFGgi9jXEea0r6jHtl22EGnCDpPPKFLoAm0RQqJDn_8ygjF_Bgp109Un5KCCNuHpbo7Jy_3dy_SxmD0_PE1vZ4WXRgwFmpAzCI1WqcCkCG9lhSVKbQ14yVB6E0ChysNbZHkHBlQVEHlZBS7G5GYru1i-zTFkZ0OE1i1iM4e4dj007u-la95d3a8c59Yqw7LAxU4g9p9LTIObN2kTFzrsl8npUinFhPwX5Ebya2E3li63oI99ShGrbzecuU1hLhfmtoVl-Py3_x9015D4Au6Jk0A</recordid><startdate>20050901</startdate><enddate>20050901</enddate><creator>Keyes, William M</creator><creator>Wu, Ying</creator><creator>Vogel, Hannes</creator><creator>Guo, Xuecui</creator><creator>Lowe, Scott W</creator><creator>Mills, Alea A</creator><general>Cold Spring Harbor Laboratory Press</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>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20050901</creationdate><title>p63 deficiency activates a program of cellular senescence and leads to accelerated aging</title><author>Keyes, William M ; Wu, Ying ; Vogel, Hannes ; Guo, Xuecui ; Lowe, Scott W ; Mills, Alea A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c473t-e7d11036e955d043db8fe8e4697ac40e4c7da5e5c7dc9e0ac4a7a5fdee18fd13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Aging - genetics</topic><topic>Aging - physiology</topic><topic>Aging, Premature - etiology</topic><topic>Aging, Premature - genetics</topic><topic>Aging, Premature - pathology</topic><topic>Animals</topic><topic>Base Sequence</topic><topic>Cells, Cultured</topic><topic>Cellular Senescence - genetics</topic><topic>Cellular Senescence - physiology</topic><topic>DNA, Complementary - genetics</topic><topic>Epithelium - pathology</topic><topic>Female</topic><topic>Keratinocytes - pathology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Mutant Strains</topic><topic>Mice, Transgenic</topic><topic>Phenotype</topic><topic>Phosphoproteins - deficiency</topic><topic>Phosphoproteins - genetics</topic><topic>Phosphoproteins - physiology</topic><topic>Pregnancy</topic><topic>Research Papers</topic><topic>Trans-Activators - deficiency</topic><topic>Trans-Activators - genetics</topic><topic>Trans-Activators - physiology</topic><topic>Tumor Suppressor Proteins - deficiency</topic><topic>Tumor Suppressor Proteins - genetics</topic><topic>Tumor Suppressor Proteins - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Keyes, William M</creatorcontrib><creatorcontrib>Wu, Ying</creatorcontrib><creatorcontrib>Vogel, Hannes</creatorcontrib><creatorcontrib>Guo, Xuecui</creatorcontrib><creatorcontrib>Lowe, Scott W</creatorcontrib><creatorcontrib>Mills, Alea A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genes & development</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Keyes, William M</au><au>Wu, Ying</au><au>Vogel, Hannes</au><au>Guo, Xuecui</au><au>Lowe, Scott W</au><au>Mills, Alea A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>p63 deficiency activates a program of cellular senescence and leads to accelerated aging</atitle><jtitle>Genes & development</jtitle><addtitle>Genes Dev</addtitle><date>2005-09-01</date><risdate>2005</risdate><volume>19</volume><issue>17</issue><spage>1986</spage><epage>1999</epage><pages>1986-1999</pages><issn>0890-9369</issn><eissn>1549-5477</eissn><abstract>The p53 tumor suppressor plays a key role in organismal aging. A cellular mechanism postulated to drive the aging process is cellular senescence, mediated in part by p53. Although senescent cells accumulate in elderly individuals, most studies have relied on correlating in vitro senescence assays with in vivo phenotypes of aging. Here, using two different mouse models in which the p53-related protein p63 is compromised, we demonstrate that cellular senescence and organismal aging are intimately linked and that these processes are mediated by p63 loss. We found that p63(+/-) mice have a shortened life span and display features of accelerated aging. Both germline and somatically induced p63 deficiency activates widespread cellular senescence with enhanced expression of senescent markers SA-beta-gal, PML, and p16(INK4a). Using an inducible tissue-specific p63 conditional model, we further show that p63 deficiency induces cellular senescence and causes accelerated aging phenotypes in the adult. Our results thus suggest a causative link between cellular senescence and aging in vivo, and demonstrate that p63 deficiency accelerates this process.</abstract><cop>United States</cop><pub>Cold Spring Harbor Laboratory Press</pub><pmid>16107615</pmid><doi>10.1101/gad.342305</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Genes & development, 2005-09, Vol.19 (17), p.1986-1999 |
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| source | MEDLINE; PubMed Central; EZB Electronic Journals Library |
| subjects | Aging - genetics Aging - physiology Aging, Premature - etiology Aging, Premature - genetics Aging, Premature - pathology Animals Base Sequence Cells, Cultured Cellular Senescence - genetics Cellular Senescence - physiology DNA, Complementary - genetics Epithelium - pathology Female Keratinocytes - pathology Male Mice Mice, Mutant Strains Mice, Transgenic Phenotype Phosphoproteins - deficiency Phosphoproteins - genetics Phosphoproteins - physiology Pregnancy Research Papers Trans-Activators - deficiency Trans-Activators - genetics Trans-Activators - physiology Tumor Suppressor Proteins - deficiency Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - physiology |
| title | p63 deficiency activates a program of cellular senescence and leads to accelerated aging |
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