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RNF4~RGMb~BMP6 axis required for osteogenic differentiation and cancer cell survival

Molecular understanding of osteogenic differentiation (OD) of human bone marrow-derived mesenchymal stem cells (hBMSCs) is important for regenerative medicine and has direct implications for cancer. We report that the RNF4 ubiquitin ligase is essential for OD of hBMSCs, and that RNF4-deficient hBMSC...

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Autores principales: Novak, Rostislav, Ahmad, Yamen Abu, Timaner, Michael, Bitman-Lotan, Eliya, Oknin-Vaisman, Avital, Horwitz, Roi, Hartmann, Oliver, Reissland, Michaela, Buck, Viktoria, Rosenfeldt, Mathias, Nikomarov, David, Diefenbacher, Markus Elmar, Shaked, Yuval, Orian, Amir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9509360/
https://www.ncbi.nlm.nih.gov/pubmed/36153321
http://dx.doi.org/10.1038/s41419-022-05262-1
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author Novak, Rostislav
Ahmad, Yamen Abu
Timaner, Michael
Bitman-Lotan, Eliya
Oknin-Vaisman, Avital
Horwitz, Roi
Hartmann, Oliver
Reissland, Michaela
Buck, Viktoria
Rosenfeldt, Mathias
Nikomarov, David
Diefenbacher, Markus Elmar
Shaked, Yuval
Orian, Amir
author_facet Novak, Rostislav
Ahmad, Yamen Abu
Timaner, Michael
Bitman-Lotan, Eliya
Oknin-Vaisman, Avital
Horwitz, Roi
Hartmann, Oliver
Reissland, Michaela
Buck, Viktoria
Rosenfeldt, Mathias
Nikomarov, David
Diefenbacher, Markus Elmar
Shaked, Yuval
Orian, Amir
author_sort Novak, Rostislav
collection PubMed
description Molecular understanding of osteogenic differentiation (OD) of human bone marrow-derived mesenchymal stem cells (hBMSCs) is important for regenerative medicine and has direct implications for cancer. We report that the RNF4 ubiquitin ligase is essential for OD of hBMSCs, and that RNF4-deficient hBMSCs remain as stalled progenitors. Remarkably, incubation of RNF4-deficient hBMSCs in conditioned media of differentiating hBMSCs restored OD. Transcriptional analysis of RNF4-dependent gene signatures identified two secreted factors that act downstream of RNF4 promoting OD: (1) BMP6 and (2) the BMP6 co-receptor, RGMb (Dragon). Indeed, knockdown of either RGMb or BMP6 in hBMSCs halted OD, while only the combined co-addition of purified RGMb and BMP6 proteins to RNF4-deficient hBMSCs fully restored OD. Moreover, we found that the RNF4-RGMb-BMP6 axis is essential for survival and tumorigenicity of osteosarcoma and therapy-resistant melanoma cells. Importantly, patient-derived sarcomas such as osteosarcoma, Ewing sarcoma, liposarcomas, and leiomyosarcomas exhibit high levels of RNF4 and BMP6, which are associated with reduced patient survival. Overall, we discovered that the RNF4~BMP6~RGMb axis is required for both OD and tumorigenesis.
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spelling pubmed-95093602022-09-26 RNF4~RGMb~BMP6 axis required for osteogenic differentiation and cancer cell survival Novak, Rostislav Ahmad, Yamen Abu Timaner, Michael Bitman-Lotan, Eliya Oknin-Vaisman, Avital Horwitz, Roi Hartmann, Oliver Reissland, Michaela Buck, Viktoria Rosenfeldt, Mathias Nikomarov, David Diefenbacher, Markus Elmar Shaked, Yuval Orian, Amir Cell Death Dis Article Molecular understanding of osteogenic differentiation (OD) of human bone marrow-derived mesenchymal stem cells (hBMSCs) is important for regenerative medicine and has direct implications for cancer. We report that the RNF4 ubiquitin ligase is essential for OD of hBMSCs, and that RNF4-deficient hBMSCs remain as stalled progenitors. Remarkably, incubation of RNF4-deficient hBMSCs in conditioned media of differentiating hBMSCs restored OD. Transcriptional analysis of RNF4-dependent gene signatures identified two secreted factors that act downstream of RNF4 promoting OD: (1) BMP6 and (2) the BMP6 co-receptor, RGMb (Dragon). Indeed, knockdown of either RGMb or BMP6 in hBMSCs halted OD, while only the combined co-addition of purified RGMb and BMP6 proteins to RNF4-deficient hBMSCs fully restored OD. Moreover, we found that the RNF4-RGMb-BMP6 axis is essential for survival and tumorigenicity of osteosarcoma and therapy-resistant melanoma cells. Importantly, patient-derived sarcomas such as osteosarcoma, Ewing sarcoma, liposarcomas, and leiomyosarcomas exhibit high levels of RNF4 and BMP6, which are associated with reduced patient survival. Overall, we discovered that the RNF4~BMP6~RGMb axis is required for both OD and tumorigenesis. Nature Publishing Group UK 2022-09-24 /pmc/articles/PMC9509360/ /pubmed/36153321 http://dx.doi.org/10.1038/s41419-022-05262-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Novak, Rostislav
Ahmad, Yamen Abu
Timaner, Michael
Bitman-Lotan, Eliya
Oknin-Vaisman, Avital
Horwitz, Roi
Hartmann, Oliver
Reissland, Michaela
Buck, Viktoria
Rosenfeldt, Mathias
Nikomarov, David
Diefenbacher, Markus Elmar
Shaked, Yuval
Orian, Amir
RNF4~RGMb~BMP6 axis required for osteogenic differentiation and cancer cell survival
title RNF4~RGMb~BMP6 axis required for osteogenic differentiation and cancer cell survival
title_full RNF4~RGMb~BMP6 axis required for osteogenic differentiation and cancer cell survival
title_fullStr RNF4~RGMb~BMP6 axis required for osteogenic differentiation and cancer cell survival
title_full_unstemmed RNF4~RGMb~BMP6 axis required for osteogenic differentiation and cancer cell survival
title_short RNF4~RGMb~BMP6 axis required for osteogenic differentiation and cancer cell survival
title_sort rnf4~rgmb~bmp6 axis required for osteogenic differentiation and cancer cell survival
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9509360/
https://www.ncbi.nlm.nih.gov/pubmed/36153321
http://dx.doi.org/10.1038/s41419-022-05262-1
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