P16/INK4A up-regulation mediated by SIX6 defines retinal ganglion cell pathogenesis in glaucoma
Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unknown. H...
Gespeichert in:
| Veröffentlicht in: | Molecular cell 2015-09, Vol.59 (6), p.931-940 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 940 |
|---|---|
| container_issue | 6 |
| container_start_page | 931 |
| container_title | Molecular cell |
| container_volume | 59 |
| creator | Skowronska-Krawczyk, Dorota Zhao, Ling Zhu, Jie Weinreb, Robert N. Luo, Jing Flagg, Ken Patel, Sherrina Wen, Cindy Krupa, Martin Luo, Hongrong Ouyang, Hong Lin, Danni Wang, Wengqiu Li, Gen Xu, Yanxin Cao, Guiqun Li, Oulan Chung, Christopher Yeh, Emily Jafari, Maryam Ai, Michael Zhong, Zheng Shi, William Zheng, Lianghong Krawczyk, Michal Chen, Daniel Shi, Catherine Zin, Carolyn Zhu, Jin Mellon, Pamela L. Gao, Weiwei Zhang, Liangfang Sun, Xiaodong Zhong, Sheng Zhuo, Yehong Rosenfeld, Michael G. Liu, Yizhi Zhang, Kang |
| description | Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unknown. Here, we demonstrate that the genetic effect of the
SIX6
risk-variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene
P16/INK4A
(cyclin-dependent kinase inhibitor 2A). We further show that the upregulation of homozygous
SIX6
risk alleles (CC) leads to an increase in
P16/INK4A
expression with a subsequent cellular senescence, as evidenced in a mouse model of elevated IOP and in human POAG eyes. Our data indicate that
SIX6
and/or IOP promotes POAG by directly increasing
P16/INK4A
expression, leading to RGC senescence in adult human retinas. Our study provides important insights linking genetic susceptibility to the underlying mechanism of RGC death and provides a unified theory of glaucoma pathogenesis. |
| doi_str_mv | 10.1016/j.molcel.2015.07.027 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmedcentral</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4648709</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>pubmedcentral_primary_oai_pubmedcentral_nih_gov_4648709</sourcerecordid><originalsourceid>FETCH-pubmedcentral_primary_oai_pubmedcentral_nih_gov_46487093</originalsourceid><addsrcrecordid>eNqljkFLwzAcxYMoblO_gYd8gcakTZP2IogoG4IM9OAt_NdmWUaalCQV9u2tsItnT-_B-_HeQ-ieUcIoEw9HMgTXaUdKympCJaGlvEBLRltZcCb45dmXUtQLtErpSCnjddNeo0UpKlFXDV0itZ2rNu9v_AlPYxG1mRxkGzwedG8h6x7vTvhj8yVwr_fW64SjztaDwwa8cb_k_MHhEfIhGD0DNmHrsXEwdWGAW3S1B5f03Vlv0OPry-fzuhin3TzRaZ8jODVGO0A8qQBW_U28PSgTvhUXvJG0rf5d8AMdF2Sd</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>P16/INK4A up-regulation mediated by SIX6 defines retinal ganglion cell pathogenesis in glaucoma</title><source>Elsevier ScienceDirect Journals Complete</source><source>Cell Press Free Archives</source><source>Free Full-Text Journals in Chemistry</source><source>EZB Electronic Journals Library</source><creator>Skowronska-Krawczyk, Dorota ; Zhao, Ling ; Zhu, Jie ; Weinreb, Robert N. ; Luo, Jing ; Flagg, Ken ; Patel, Sherrina ; Wen, Cindy ; Krupa, Martin ; Luo, Hongrong ; Ouyang, Hong ; Lin, Danni ; Wang, Wengqiu ; Li, Gen ; Xu, Yanxin ; Cao, Guiqun ; Li, Oulan ; Chung, Christopher ; Yeh, Emily ; Jafari, Maryam ; Ai, Michael ; Zhong, Zheng ; Shi, William ; Zheng, Lianghong ; Krawczyk, Michal ; Chen, Daniel ; Shi, Catherine ; Zin, Carolyn ; Zhu, Jin ; Mellon, Pamela L. ; Gao, Weiwei ; Zhang, Liangfang ; Sun, Xiaodong ; Zhong, Sheng ; Zhuo, Yehong ; Rosenfeld, Michael G. ; Liu, Yizhi ; Zhang, Kang</creator><creatorcontrib>Skowronska-Krawczyk, Dorota ; Zhao, Ling ; Zhu, Jie ; Weinreb, Robert N. ; Luo, Jing ; Flagg, Ken ; Patel, Sherrina ; Wen, Cindy ; Krupa, Martin ; Luo, Hongrong ; Ouyang, Hong ; Lin, Danni ; Wang, Wengqiu ; Li, Gen ; Xu, Yanxin ; Cao, Guiqun ; Li, Oulan ; Chung, Christopher ; Yeh, Emily ; Jafari, Maryam ; Ai, Michael ; Zhong, Zheng ; Shi, William ; Zheng, Lianghong ; Krawczyk, Michal ; Chen, Daniel ; Shi, Catherine ; Zin, Carolyn ; Zhu, Jin ; Mellon, Pamela L. ; Gao, Weiwei ; Zhang, Liangfang ; Sun, Xiaodong ; Zhong, Sheng ; Zhuo, Yehong ; Rosenfeld, Michael G. ; Liu, Yizhi ; Zhang, Kang</creatorcontrib><description>Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unknown. Here, we demonstrate that the genetic effect of the
SIX6
risk-variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene
P16/INK4A
(cyclin-dependent kinase inhibitor 2A). We further show that the upregulation of homozygous
SIX6
risk alleles (CC) leads to an increase in
P16/INK4A
expression with a subsequent cellular senescence, as evidenced in a mouse model of elevated IOP and in human POAG eyes. Our data indicate that
SIX6
and/or IOP promotes POAG by directly increasing
P16/INK4A
expression, leading to RGC senescence in adult human retinas. Our study provides important insights linking genetic susceptibility to the underlying mechanism of RGC death and provides a unified theory of glaucoma pathogenesis.</description><identifier>ISSN: 1097-2765</identifier><identifier>EISSN: 1097-4164</identifier><identifier>DOI: 10.1016/j.molcel.2015.07.027</identifier><identifier>PMID: 26365380</identifier><language>eng</language><ispartof>Molecular cell, 2015-09, Vol.59 (6), p.931-940</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>230,314,776,780,881,27901,27902</link.rule.ids></links><search><creatorcontrib>Skowronska-Krawczyk, Dorota</creatorcontrib><creatorcontrib>Zhao, Ling</creatorcontrib><creatorcontrib>Zhu, Jie</creatorcontrib><creatorcontrib>Weinreb, Robert N.</creatorcontrib><creatorcontrib>Luo, Jing</creatorcontrib><creatorcontrib>Flagg, Ken</creatorcontrib><creatorcontrib>Patel, Sherrina</creatorcontrib><creatorcontrib>Wen, Cindy</creatorcontrib><creatorcontrib>Krupa, Martin</creatorcontrib><creatorcontrib>Luo, Hongrong</creatorcontrib><creatorcontrib>Ouyang, Hong</creatorcontrib><creatorcontrib>Lin, Danni</creatorcontrib><creatorcontrib>Wang, Wengqiu</creatorcontrib><creatorcontrib>Li, Gen</creatorcontrib><creatorcontrib>Xu, Yanxin</creatorcontrib><creatorcontrib>Cao, Guiqun</creatorcontrib><creatorcontrib>Li, Oulan</creatorcontrib><creatorcontrib>Chung, Christopher</creatorcontrib><creatorcontrib>Yeh, Emily</creatorcontrib><creatorcontrib>Jafari, Maryam</creatorcontrib><creatorcontrib>Ai, Michael</creatorcontrib><creatorcontrib>Zhong, Zheng</creatorcontrib><creatorcontrib>Shi, William</creatorcontrib><creatorcontrib>Zheng, Lianghong</creatorcontrib><creatorcontrib>Krawczyk, Michal</creatorcontrib><creatorcontrib>Chen, Daniel</creatorcontrib><creatorcontrib>Shi, Catherine</creatorcontrib><creatorcontrib>Zin, Carolyn</creatorcontrib><creatorcontrib>Zhu, Jin</creatorcontrib><creatorcontrib>Mellon, Pamela L.</creatorcontrib><creatorcontrib>Gao, Weiwei</creatorcontrib><creatorcontrib>Zhang, Liangfang</creatorcontrib><creatorcontrib>Sun, Xiaodong</creatorcontrib><creatorcontrib>Zhong, Sheng</creatorcontrib><creatorcontrib>Zhuo, Yehong</creatorcontrib><creatorcontrib>Rosenfeld, Michael G.</creatorcontrib><creatorcontrib>Liu, Yizhi</creatorcontrib><creatorcontrib>Zhang, Kang</creatorcontrib><title>P16/INK4A up-regulation mediated by SIX6 defines retinal ganglion cell pathogenesis in glaucoma</title><title>Molecular cell</title><description>Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unknown. Here, we demonstrate that the genetic effect of the
SIX6
risk-variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene
P16/INK4A
(cyclin-dependent kinase inhibitor 2A). We further show that the upregulation of homozygous
SIX6
risk alleles (CC) leads to an increase in
P16/INK4A
expression with a subsequent cellular senescence, as evidenced in a mouse model of elevated IOP and in human POAG eyes. Our data indicate that
SIX6
and/or IOP promotes POAG by directly increasing
P16/INK4A
expression, leading to RGC senescence in adult human retinas. Our study provides important insights linking genetic susceptibility to the underlying mechanism of RGC death and provides a unified theory of glaucoma pathogenesis.</description><issn>1097-2765</issn><issn>1097-4164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><recordid>eNqljkFLwzAcxYMoblO_gYd8gcakTZP2IogoG4IM9OAt_NdmWUaalCQV9u2tsItnT-_B-_HeQ-ieUcIoEw9HMgTXaUdKympCJaGlvEBLRltZcCb45dmXUtQLtErpSCnjddNeo0UpKlFXDV0itZ2rNu9v_AlPYxG1mRxkGzwedG8h6x7vTvhj8yVwr_fW64SjztaDwwa8cb_k_MHhEfIhGD0DNmHrsXEwdWGAW3S1B5f03Vlv0OPry-fzuhin3TzRaZ8jODVGO0A8qQBW_U28PSgTvhUXvJG0rf5d8AMdF2Sd</recordid><startdate>20150910</startdate><enddate>20150910</enddate><creator>Skowronska-Krawczyk, Dorota</creator><creator>Zhao, Ling</creator><creator>Zhu, Jie</creator><creator>Weinreb, Robert N.</creator><creator>Luo, Jing</creator><creator>Flagg, Ken</creator><creator>Patel, Sherrina</creator><creator>Wen, Cindy</creator><creator>Krupa, Martin</creator><creator>Luo, Hongrong</creator><creator>Ouyang, Hong</creator><creator>Lin, Danni</creator><creator>Wang, Wengqiu</creator><creator>Li, Gen</creator><creator>Xu, Yanxin</creator><creator>Cao, Guiqun</creator><creator>Li, Oulan</creator><creator>Chung, Christopher</creator><creator>Yeh, Emily</creator><creator>Jafari, Maryam</creator><creator>Ai, Michael</creator><creator>Zhong, Zheng</creator><creator>Shi, William</creator><creator>Zheng, Lianghong</creator><creator>Krawczyk, Michal</creator><creator>Chen, Daniel</creator><creator>Shi, Catherine</creator><creator>Zin, Carolyn</creator><creator>Zhu, Jin</creator><creator>Mellon, Pamela L.</creator><creator>Gao, Weiwei</creator><creator>Zhang, Liangfang</creator><creator>Sun, Xiaodong</creator><creator>Zhong, Sheng</creator><creator>Zhuo, Yehong</creator><creator>Rosenfeld, Michael G.</creator><creator>Liu, Yizhi</creator><creator>Zhang, Kang</creator><scope>5PM</scope></search><sort><creationdate>20150910</creationdate><title>P16/INK4A up-regulation mediated by SIX6 defines retinal ganglion cell pathogenesis in glaucoma</title><author>Skowronska-Krawczyk, Dorota ; Zhao, Ling ; Zhu, Jie ; Weinreb, Robert N. ; Luo, Jing ; Flagg, Ken ; Patel, Sherrina ; Wen, Cindy ; Krupa, Martin ; Luo, Hongrong ; Ouyang, Hong ; Lin, Danni ; Wang, Wengqiu ; Li, Gen ; Xu, Yanxin ; Cao, Guiqun ; Li, Oulan ; Chung, Christopher ; Yeh, Emily ; Jafari, Maryam ; Ai, Michael ; Zhong, Zheng ; Shi, William ; Zheng, Lianghong ; Krawczyk, Michal ; Chen, Daniel ; Shi, Catherine ; Zin, Carolyn ; Zhu, Jin ; Mellon, Pamela L. ; Gao, Weiwei ; Zhang, Liangfang ; Sun, Xiaodong ; Zhong, Sheng ; Zhuo, Yehong ; Rosenfeld, Michael G. ; Liu, Yizhi ; Zhang, Kang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmedcentral_primary_oai_pubmedcentral_nih_gov_46487093</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Skowronska-Krawczyk, Dorota</creatorcontrib><creatorcontrib>Zhao, Ling</creatorcontrib><creatorcontrib>Zhu, Jie</creatorcontrib><creatorcontrib>Weinreb, Robert N.</creatorcontrib><creatorcontrib>Luo, Jing</creatorcontrib><creatorcontrib>Flagg, Ken</creatorcontrib><creatorcontrib>Patel, Sherrina</creatorcontrib><creatorcontrib>Wen, Cindy</creatorcontrib><creatorcontrib>Krupa, Martin</creatorcontrib><creatorcontrib>Luo, Hongrong</creatorcontrib><creatorcontrib>Ouyang, Hong</creatorcontrib><creatorcontrib>Lin, Danni</creatorcontrib><creatorcontrib>Wang, Wengqiu</creatorcontrib><creatorcontrib>Li, Gen</creatorcontrib><creatorcontrib>Xu, Yanxin</creatorcontrib><creatorcontrib>Cao, Guiqun</creatorcontrib><creatorcontrib>Li, Oulan</creatorcontrib><creatorcontrib>Chung, Christopher</creatorcontrib><creatorcontrib>Yeh, Emily</creatorcontrib><creatorcontrib>Jafari, Maryam</creatorcontrib><creatorcontrib>Ai, Michael</creatorcontrib><creatorcontrib>Zhong, Zheng</creatorcontrib><creatorcontrib>Shi, William</creatorcontrib><creatorcontrib>Zheng, Lianghong</creatorcontrib><creatorcontrib>Krawczyk, Michal</creatorcontrib><creatorcontrib>Chen, Daniel</creatorcontrib><creatorcontrib>Shi, Catherine</creatorcontrib><creatorcontrib>Zin, Carolyn</creatorcontrib><creatorcontrib>Zhu, Jin</creatorcontrib><creatorcontrib>Mellon, Pamela L.</creatorcontrib><creatorcontrib>Gao, Weiwei</creatorcontrib><creatorcontrib>Zhang, Liangfang</creatorcontrib><creatorcontrib>Sun, Xiaodong</creatorcontrib><creatorcontrib>Zhong, Sheng</creatorcontrib><creatorcontrib>Zhuo, Yehong</creatorcontrib><creatorcontrib>Rosenfeld, Michael G.</creatorcontrib><creatorcontrib>Liu, Yizhi</creatorcontrib><creatorcontrib>Zhang, Kang</creatorcontrib><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Skowronska-Krawczyk, Dorota</au><au>Zhao, Ling</au><au>Zhu, Jie</au><au>Weinreb, Robert N.</au><au>Luo, Jing</au><au>Flagg, Ken</au><au>Patel, Sherrina</au><au>Wen, Cindy</au><au>Krupa, Martin</au><au>Luo, Hongrong</au><au>Ouyang, Hong</au><au>Lin, Danni</au><au>Wang, Wengqiu</au><au>Li, Gen</au><au>Xu, Yanxin</au><au>Cao, Guiqun</au><au>Li, Oulan</au><au>Chung, Christopher</au><au>Yeh, Emily</au><au>Jafari, Maryam</au><au>Ai, Michael</au><au>Zhong, Zheng</au><au>Shi, William</au><au>Zheng, Lianghong</au><au>Krawczyk, Michal</au><au>Chen, Daniel</au><au>Shi, Catherine</au><au>Zin, Carolyn</au><au>Zhu, Jin</au><au>Mellon, Pamela L.</au><au>Gao, Weiwei</au><au>Zhang, Liangfang</au><au>Sun, Xiaodong</au><au>Zhong, Sheng</au><au>Zhuo, Yehong</au><au>Rosenfeld, Michael G.</au><au>Liu, Yizhi</au><au>Zhang, Kang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>P16/INK4A up-regulation mediated by SIX6 defines retinal ganglion cell pathogenesis in glaucoma</atitle><jtitle>Molecular cell</jtitle><date>2015-09-10</date><risdate>2015</risdate><volume>59</volume><issue>6</issue><spage>931</spage><epage>940</epage><pages>931-940</pages><issn>1097-2765</issn><eissn>1097-4164</eissn><abstract>Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unknown. Here, we demonstrate that the genetic effect of the
SIX6
risk-variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene
P16/INK4A
(cyclin-dependent kinase inhibitor 2A). We further show that the upregulation of homozygous
SIX6
risk alleles (CC) leads to an increase in
P16/INK4A
expression with a subsequent cellular senescence, as evidenced in a mouse model of elevated IOP and in human POAG eyes. Our data indicate that
SIX6
and/or IOP promotes POAG by directly increasing
P16/INK4A
expression, leading to RGC senescence in adult human retinas. Our study provides important insights linking genetic susceptibility to the underlying mechanism of RGC death and provides a unified theory of glaucoma pathogenesis.</abstract><pmid>26365380</pmid><doi>10.1016/j.molcel.2015.07.027</doi></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1097-2765 |
| ispartof | Molecular cell, 2015-09, Vol.59 (6), p.931-940 |
| issn | 1097-2765 1097-4164 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4648709 |
| source | Elsevier ScienceDirect Journals Complete; Cell Press Free Archives; Free Full-Text Journals in Chemistry; EZB Electronic Journals Library |
| title | P16/INK4A up-regulation mediated by SIX6 defines retinal ganglion cell pathogenesis in glaucoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-18T19%3A31%3A54IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmedcentral&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=P16/INK4A%20up-regulation%20mediated%20by%20SIX6%20defines%20retinal%20ganglion%20cell%20pathogenesis%20in%20glaucoma&rft.jtitle=Molecular%20cell&rft.au=Skowronska-Krawczyk,%20Dorota&rft.date=2015-09-10&rft.volume=59&rft.issue=6&rft.spage=931&rft.epage=940&rft.pages=931-940&rft.issn=1097-2765&rft.eissn=1097-4164&rft_id=info:doi/10.1016/j.molcel.2015.07.027&rft_dat=%3Cpubmedcentral%3Epubmedcentral_primary_oai_pubmedcentral_nih_gov_4648709%3C/pubmedcentral%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/26365380&rfr_iscdi=true |