Activation of the transcription factor gli1 by wnt signaling underlies the role of SULFATASE 2 as a regulator of tissue regeneration
issue regeneration requires the activation of a set of specific growth signaling pathways. The identity of these cascades and their biological roles are known; however, the molecular mechanisms regulating the interplay between these pathways remain poorly understood. Here, we define a new role for S...
| Autores: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | artículo |
| Fecha de publicación: | 2013 |
| País: | España |
| Recursos: | Universidad de Navarra |
| Repositorio: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglés |
| OAI Identifier: | oai:dadun.unav.edu:10171/121014 |
| Acesso em linha: | https://hdl.handle.net/10171/121014 |
| Access Level: | acceso abierto |
| Palavra-chave: | Gene Knockout Liver Regeneration Transcription Factors Wnt Signaling |
| id |
ES_281d5e01cc3e6f63dfd035824a34129e |
|---|---|
| oai_identifier_str |
oai:dadun.unav.edu:10171/121014 |
| network_acronym_str |
ES |
| network_name_str |
España |
| repository_id_str |
|
| spelling |
Activation of the transcription factor gli1 by wnt signaling underlies the role of SULFATASE 2 as a regulator of tissue regenerationNakamura, I. (Ikuo)|||/items/17bbe2f0-037c-4f6d-b43c-f10e173698abGarcía-Fernández-de-Barrena, M. (Maite)|||/items/cfa77580-40b9-43a4-b237-b234ef7fb6cbOrtiz-Ruiz, M.C. (Maria C.)|||/items/09b93e00-0da7-4e32-9886-c38de07ab5f6Almada, L.L. (Luciana L.)|||/items/29677c79-da0b-4a29-bd71-e9decae1754cHu, C. (Chunling)|||/items/04d72539-99e2-4a40-9d9a-fe4332595efeElsawa, S.F. (Sherine F.)|||/items/02d1ebd6-836d-4779-bf7f-1e1ec8d3eca4Mills, L.D. (Lisa D.)|||/items/b81b93df-bff2-442f-b492-56f24ed207e2Romecin, P.A. (Paola A.)|||/items/33e6aef0-baf2-4fff-8713-a939bc5b5208Gulaid, K.H. (Kadra H.)|||/items/3ef3f71a-343d-497d-bdfb-289f38c7ad06Moser, C.D. (Catherine D.)|||/items/3d8e33b8-8262-427a-93ab-539c1e4a0ee6Han, J.J. (Jing-Jing)|||/items/5e8b3ed8-ecf1-48c1-95ce-0211edb115d3Vrabel, A. (Anne)|||/items/03e9ec35-008f-48ed-888d-1d25b4b38612Hanse, E.A. (Eric A.)|||/items/9870e4ef-6d80-42f5-8c8c-2a8b921b211bAkogyeram, N.A. (Nicholas A.)|||/items/7279c976-f97e-489f-95b1-b12703773889Albrecht, J.H. (Jeffrey H.)|||/items/f9b39250-7c51-4c1f-891f-7fa16145edbcMonga, S.P. (Satdarshan P.)|||/items/068189ef-613a-48f4-9e6d-fc7ae6b5a6daSanderson, S.O. (Schuyler O.)|||/items/d012fcf9-0953-422c-acf1-2157ecf9152bPrieto, J. (Jesús)|||/items/0d9c3dec-4a09-400d-8c83-23ece1096c71Roberts, L.R. (Lewis R.)|||/items/53e58801-8eb8-49f9-9fd2-46b93d01e35bFernandez-Zapico, M.E. (Martín E.)|||/items/4c4f76f4-afec-47be-91c9-c67d0d54ac41Gene KnockoutLiverRegenerationTranscription FactorsWnt Signalingissue regeneration requires the activation of a set of specific growth signaling pathways. The identity of these cascades and their biological roles are known; however, the molecular mechanisms regulating the interplay between these pathways remain poorly understood. Here, we define a new role for SULFATASE 2 (SULF2) in regulating tissue regeneration and define the WNT-GLI1 axis as a novel downstream effector for this sulfatase in a liver model of tissue regeneration. SULF2 is a heparan sulfate 6-O-endosulfatase, which releases growth factors from extracellular storage sites turning active multiple signaling pathways. We demonstrate that SULF2-KO mice display delayed regeneration after partial hepatectomy (PH). Mechanistic analysis of the SULF2-KO phenotype showed a decrease in WNT signaling pathway activity in vivo. In isolated hepatocytes, SULF2 deficiency blocked WNT-induced β-CATENIN nuclear translocation, TCF activation, and proliferation. Furthermore, we identified the transcription factor GLI1 as a novel target of the SULF2-WNT cascade. WNT induces GLI1 expression in a SULF2- and β-CATENIN-dependent manner. GLI1-KO mice phenocopied the SULF2-KO, showing delayed regeneration and decreased hepatocyte proliferation. Moreover, we identified CYCLIN D1, a key mediator of cell growth during tissue regeneration, as a GLI1 transcriptional target. GLI1 binds to the cyclin d1 promoter and regulates its activity and expression. Finally, restoring GLI1 expression in the liver of SULF2-KO mice after PH rescues CYCLIN D1 expression and hepatocyte proliferation to wild-type levels. Thus, together these findings define a novel pathway in which SULF2 regulates tissue regeneration in part via the activation of a novel WNT-GLI1-CYCLIN D1 pathway.ElsevierDadun. Depósito Académico Digital Universidad de Navarra20132013-01-0120132013-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/121014reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/1210142026-06-21T12:47:57Z |
| dc.title.none.fl_str_mv |
Activation of the transcription factor gli1 by wnt signaling underlies the role of SULFATASE 2 as a regulator of tissue regeneration |
| title |
Activation of the transcription factor gli1 by wnt signaling underlies the role of SULFATASE 2 as a regulator of tissue regeneration |
| spellingShingle |
Activation of the transcription factor gli1 by wnt signaling underlies the role of SULFATASE 2 as a regulator of tissue regeneration Nakamura, I. (Ikuo)|||/items/17bbe2f0-037c-4f6d-b43c-f10e173698ab Gene Knockout Liver Regeneration Transcription Factors Wnt Signaling |
| title_short |
Activation of the transcription factor gli1 by wnt signaling underlies the role of SULFATASE 2 as a regulator of tissue regeneration |
| title_full |
Activation of the transcription factor gli1 by wnt signaling underlies the role of SULFATASE 2 as a regulator of tissue regeneration |
| title_fullStr |
Activation of the transcription factor gli1 by wnt signaling underlies the role of SULFATASE 2 as a regulator of tissue regeneration |
| title_full_unstemmed |
Activation of the transcription factor gli1 by wnt signaling underlies the role of SULFATASE 2 as a regulator of tissue regeneration |
| title_sort |
Activation of the transcription factor gli1 by wnt signaling underlies the role of SULFATASE 2 as a regulator of tissue regeneration |
| dc.creator.none.fl_str_mv |
Nakamura, I. (Ikuo)|||/items/17bbe2f0-037c-4f6d-b43c-f10e173698ab García-Fernández-de-Barrena, M. (Maite)|||/items/cfa77580-40b9-43a4-b237-b234ef7fb6cb Ortiz-Ruiz, M.C. (Maria C.)|||/items/09b93e00-0da7-4e32-9886-c38de07ab5f6 Almada, L.L. (Luciana L.)|||/items/29677c79-da0b-4a29-bd71-e9decae1754c Hu, C. (Chunling)|||/items/04d72539-99e2-4a40-9d9a-fe4332595efe Elsawa, S.F. (Sherine F.)|||/items/02d1ebd6-836d-4779-bf7f-1e1ec8d3eca4 Mills, L.D. (Lisa D.)|||/items/b81b93df-bff2-442f-b492-56f24ed207e2 Romecin, P.A. (Paola A.)|||/items/33e6aef0-baf2-4fff-8713-a939bc5b5208 Gulaid, K.H. (Kadra H.)|||/items/3ef3f71a-343d-497d-bdfb-289f38c7ad06 Moser, C.D. (Catherine D.)|||/items/3d8e33b8-8262-427a-93ab-539c1e4a0ee6 Han, J.J. (Jing-Jing)|||/items/5e8b3ed8-ecf1-48c1-95ce-0211edb115d3 Vrabel, A. (Anne)|||/items/03e9ec35-008f-48ed-888d-1d25b4b38612 Hanse, E.A. (Eric A.)|||/items/9870e4ef-6d80-42f5-8c8c-2a8b921b211b Akogyeram, N.A. (Nicholas A.)|||/items/7279c976-f97e-489f-95b1-b12703773889 Albrecht, J.H. (Jeffrey H.)|||/items/f9b39250-7c51-4c1f-891f-7fa16145edbc Monga, S.P. (Satdarshan P.)|||/items/068189ef-613a-48f4-9e6d-fc7ae6b5a6da Sanderson, S.O. (Schuyler O.)|||/items/d012fcf9-0953-422c-acf1-2157ecf9152b Prieto, J. (Jesús)|||/items/0d9c3dec-4a09-400d-8c83-23ece1096c71 Roberts, L.R. (Lewis R.)|||/items/53e58801-8eb8-49f9-9fd2-46b93d01e35b Fernandez-Zapico, M.E. (Martín E.)|||/items/4c4f76f4-afec-47be-91c9-c67d0d54ac41 |
| author |
Nakamura, I. (Ikuo)|||/items/17bbe2f0-037c-4f6d-b43c-f10e173698ab |
| author_facet |
Nakamura, I. (Ikuo)|||/items/17bbe2f0-037c-4f6d-b43c-f10e173698ab García-Fernández-de-Barrena, M. (Maite)|||/items/cfa77580-40b9-43a4-b237-b234ef7fb6cb Ortiz-Ruiz, M.C. (Maria C.)|||/items/09b93e00-0da7-4e32-9886-c38de07ab5f6 Almada, L.L. (Luciana L.)|||/items/29677c79-da0b-4a29-bd71-e9decae1754c Hu, C. (Chunling)|||/items/04d72539-99e2-4a40-9d9a-fe4332595efe Elsawa, S.F. (Sherine F.)|||/items/02d1ebd6-836d-4779-bf7f-1e1ec8d3eca4 Mills, L.D. (Lisa D.)|||/items/b81b93df-bff2-442f-b492-56f24ed207e2 Romecin, P.A. (Paola A.)|||/items/33e6aef0-baf2-4fff-8713-a939bc5b5208 Gulaid, K.H. (Kadra H.)|||/items/3ef3f71a-343d-497d-bdfb-289f38c7ad06 Moser, C.D. (Catherine D.)|||/items/3d8e33b8-8262-427a-93ab-539c1e4a0ee6 Han, J.J. (Jing-Jing)|||/items/5e8b3ed8-ecf1-48c1-95ce-0211edb115d3 Vrabel, A. (Anne)|||/items/03e9ec35-008f-48ed-888d-1d25b4b38612 Hanse, E.A. (Eric A.)|||/items/9870e4ef-6d80-42f5-8c8c-2a8b921b211b Akogyeram, N.A. (Nicholas A.)|||/items/7279c976-f97e-489f-95b1-b12703773889 Albrecht, J.H. (Jeffrey H.)|||/items/f9b39250-7c51-4c1f-891f-7fa16145edbc Monga, S.P. (Satdarshan P.)|||/items/068189ef-613a-48f4-9e6d-fc7ae6b5a6da Sanderson, S.O. (Schuyler O.)|||/items/d012fcf9-0953-422c-acf1-2157ecf9152b Prieto, J. (Jesús)|||/items/0d9c3dec-4a09-400d-8c83-23ece1096c71 Roberts, L.R. (Lewis R.)|||/items/53e58801-8eb8-49f9-9fd2-46b93d01e35b Fernandez-Zapico, M.E. (Martín E.)|||/items/4c4f76f4-afec-47be-91c9-c67d0d54ac41 |
| author_role |
author |
| author2 |
García-Fernández-de-Barrena, M. (Maite)|||/items/cfa77580-40b9-43a4-b237-b234ef7fb6cb Ortiz-Ruiz, M.C. (Maria C.)|||/items/09b93e00-0da7-4e32-9886-c38de07ab5f6 Almada, L.L. (Luciana L.)|||/items/29677c79-da0b-4a29-bd71-e9decae1754c Hu, C. (Chunling)|||/items/04d72539-99e2-4a40-9d9a-fe4332595efe Elsawa, S.F. (Sherine F.)|||/items/02d1ebd6-836d-4779-bf7f-1e1ec8d3eca4 Mills, L.D. (Lisa D.)|||/items/b81b93df-bff2-442f-b492-56f24ed207e2 Romecin, P.A. (Paola A.)|||/items/33e6aef0-baf2-4fff-8713-a939bc5b5208 Gulaid, K.H. (Kadra H.)|||/items/3ef3f71a-343d-497d-bdfb-289f38c7ad06 Moser, C.D. (Catherine D.)|||/items/3d8e33b8-8262-427a-93ab-539c1e4a0ee6 Han, J.J. (Jing-Jing)|||/items/5e8b3ed8-ecf1-48c1-95ce-0211edb115d3 Vrabel, A. (Anne)|||/items/03e9ec35-008f-48ed-888d-1d25b4b38612 Hanse, E.A. (Eric A.)|||/items/9870e4ef-6d80-42f5-8c8c-2a8b921b211b Akogyeram, N.A. (Nicholas A.)|||/items/7279c976-f97e-489f-95b1-b12703773889 Albrecht, J.H. (Jeffrey H.)|||/items/f9b39250-7c51-4c1f-891f-7fa16145edbc Monga, S.P. (Satdarshan P.)|||/items/068189ef-613a-48f4-9e6d-fc7ae6b5a6da Sanderson, S.O. (Schuyler O.)|||/items/d012fcf9-0953-422c-acf1-2157ecf9152b Prieto, J. (Jesús)|||/items/0d9c3dec-4a09-400d-8c83-23ece1096c71 Roberts, L.R. (Lewis R.)|||/items/53e58801-8eb8-49f9-9fd2-46b93d01e35b Fernandez-Zapico, M.E. (Martín E.)|||/items/4c4f76f4-afec-47be-91c9-c67d0d54ac41 |
| author2_role |
author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Dadun. Depósito Académico Digital Universidad de Navarra |
| dc.subject.none.fl_str_mv |
Gene Knockout Liver Regeneration Transcription Factors Wnt Signaling |
| topic |
Gene Knockout Liver Regeneration Transcription Factors Wnt Signaling |
| description |
issue regeneration requires the activation of a set of specific growth signaling pathways. The identity of these cascades and their biological roles are known; however, the molecular mechanisms regulating the interplay between these pathways remain poorly understood. Here, we define a new role for SULFATASE 2 (SULF2) in regulating tissue regeneration and define the WNT-GLI1 axis as a novel downstream effector for this sulfatase in a liver model of tissue regeneration. SULF2 is a heparan sulfate 6-O-endosulfatase, which releases growth factors from extracellular storage sites turning active multiple signaling pathways. We demonstrate that SULF2-KO mice display delayed regeneration after partial hepatectomy (PH). Mechanistic analysis of the SULF2-KO phenotype showed a decrease in WNT signaling pathway activity in vivo. In isolated hepatocytes, SULF2 deficiency blocked WNT-induced β-CATENIN nuclear translocation, TCF activation, and proliferation. Furthermore, we identified the transcription factor GLI1 as a novel target of the SULF2-WNT cascade. WNT induces GLI1 expression in a SULF2- and β-CATENIN-dependent manner. GLI1-KO mice phenocopied the SULF2-KO, showing delayed regeneration and decreased hepatocyte proliferation. Moreover, we identified CYCLIN D1, a key mediator of cell growth during tissue regeneration, as a GLI1 transcriptional target. GLI1 binds to the cyclin d1 promoter and regulates its activity and expression. Finally, restoring GLI1 expression in the liver of SULF2-KO mice after PH rescues CYCLIN D1 expression and hepatocyte proliferation to wild-type levels. Thus, together these findings define a novel pathway in which SULF2 regulates tissue regeneration in part via the activation of a novel WNT-GLI1-CYCLIN D1 pathway. |
| publishDate |
2013 |
| dc.date.none.fl_str_mv |
2013 2013-01-01 2013 2013-01-01 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10171/121014 |
| url |
https://hdl.handle.net/10171/121014 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.publisher.none.fl_str_mv |
Elsevier |
| publisher.none.fl_str_mv |
Elsevier |
| dc.source.none.fl_str_mv |
reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra instname:Universidad de Navarra |
| instname_str |
Universidad de Navarra |
| reponame_str |
Dadun. Depósito Académico Digital de la Universidad de Navarra |
| collection |
Dadun. Depósito Académico Digital de la Universidad de Navarra |
| repository.name.fl_str_mv |
|
| repository.mail.fl_str_mv |
|
| _version_ |
1869404926490181633 |
| score |
15,811543 |