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GLI1/GLI2 functional interplay is required to control Hedgehog/GLI targets gene expression.
Tolosa, Ezequiel J; Fernandez-Barrena, Maite G; Iguchi, Eriko; McCleary-Wheeler, Angela L; Carr, Ryan M; Almada, Luciana L; Flores, Luis F; Vera, Renzo E; Alfonse, Germine W; Marks, David L; Hogenson, Tara L; Vrabel, Anne M; Horn, Isaac P; Koenig, Amanda N; Safgren, Stephanie L; Sigafoos, Ashley N; Erkan, Mert; Romecin-Duran, Paola A; Sarabia Gonzalez, Alejandro; Zhou, Bo; Javelaud, Delphine; Marsaud, Veronique; Graham, Rondell P; Mauviel, Alain; Elsawa, Sherine F; Fernandez-Zapico, Martin E.
Afiliación
  • Tolosa EJ; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.
  • Fernandez-Barrena MG; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.
  • Iguchi E; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.
  • McCleary-Wheeler AL; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.
  • Carr RM; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.
  • Almada LL; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.
  • Flores LF; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.
  • Vera RE; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.
  • Alfonse GW; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.
  • Marks DL; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.
  • Hogenson TL; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.
  • Vrabel AM; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.
  • Horn IP; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.
  • Koenig AN; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.
  • Safgren SL; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.
  • Sigafoos AN; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.
  • Erkan M; Department of Surgery, Koc University School of Medicine, Istanbul, Turkey.
  • Romecin-Duran PA; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.
  • Sarabia Gonzalez A; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.
  • Zhou B; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.
  • Javelaud D; Institut Curie, PSL Research University, INSERM U1021, CNRS UMR3347, Team 'TGF-ß and Oncogenesis', Equipe Labellisée LIGUE 2016, F-91400, Orsay, France.
  • Marsaud V; Université Paris-Sud, F-91400, Orsay, France.
  • Graham RP; Institut Curie, PSL Research University, INSERM U1021, CNRS UMR3347, Team 'TGF-ß and Oncogenesis', Equipe Labellisée LIGUE 2016, F-91400, Orsay, France.
  • Mauviel A; Université Paris-Sud, F-91400, Orsay, France.
  • Elsawa SF; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, U.S.A.
  • Fernandez-Zapico ME; Institut Curie, PSL Research University, INSERM U1021, CNRS UMR3347, Team 'TGF-ß and Oncogenesis', Equipe Labellisée LIGUE 2016, F-91400, Orsay, France.
Biochem J ; 477(17): 3131-3145, 2020 09 18.
Article en En | MEDLINE | ID: mdl-32766732
The Hedgehog-regulated transcription factors GLI1 and GLI2 play overlapping roles in development and disease; however, the mechanisms underlying their interplay remain elusive. We report for the first time that GLI1 and GLI2 physically and functionally interact in cancer cells. GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells. Mapping analysis demonstrated that the zinc finger domains of both proteins are required for their heteromerization. RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells, whereas PTCH1 expression was only inhibited by GLI1 depletion. qPCR screening of a large set of putative canonical and non-canonical Hedgehog/GLI targets identified further genes (e.g. E2F1, BMP1, CDK2) strongly down-regulated by GLI1 and/or GLI2 depletion in PANC1 cells, and demonstrated that ANO1, AQP1 and SOCS1 are up-regulated by knockdown of either GLI1 or GLI2. Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. Together, these findings indicate that GLI1 and GLI2 co-ordinately regulate the transcription of some genes, and provide mechanistic insight into the roles of GLI proteins in carcinogenesis.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Rabdomiosarcoma / Proteínas Nucleares / Regulación Neoplásica de la Expresión Génica / Proteínas Hedgehog / Proteína con Dedos de Zinc GLI1 / Proteína Gli2 con Dedos de Zinc Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Biochem J Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Rabdomiosarcoma / Proteínas Nucleares / Regulación Neoplásica de la Expresión Génica / Proteínas Hedgehog / Proteína con Dedos de Zinc GLI1 / Proteína Gli2 con Dedos de Zinc Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Biochem J Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos