Fusion protein-driven IGF-IR/PI3K/AKT signals deregulate Hippo pathway promoting oncogenic cooperation of YAP1 and FUS-DDIT3 in myxoid liposarcoma
Myxoid liposarcoma (MLS) represents a common subtype of liposarcoma molecularly characterized by a recurrent chromosomal translocation that generates a chimeric FUS-DDIT3 fusion gene. The FUS-DDIT3 oncoprotein has been shown to be crucial in MLS pathogenesis. Acting as a transcriptional dysregulator...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
22 April 2022
|
| In: |
Oncogenesis
Year: 2022, Volume: 11, Issue: 1, Pages: 1-12 |
| ISSN: | 2157-9024 |
| DOI: | 10.1038/s41389-022-00394-7 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41389-022-00394-7 Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41389-022-00394-7 
|
| Author Notes: | Ruth Berthold, Ilka Isfort, Cihan Erkut, Lorena Heinst, Inga Grünewald, Eva Wardelmann, Thomas Kindler, Pierre Åman, Thomas G. P. Grünewald, Florencia Cidre-Aranaz, Marcel Trautmann, Stefan Fröhling, Claudia Scholl and Wolfgang Hartmann |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1816623652 | ||
| 003 | DE-627 | ||
| 005 | 20250109055112.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 220914s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41389-022-00394-7 |2 doi | |
| 035 | |a (DE-627)1816623652 | ||
| 035 | |a (DE-599)KXP1816623652 | ||
| 035 | |a (OCoLC)1361696460 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Berthold, Ruth |e VerfasserIn |0 (DE-588)1268031224 |0 (DE-627)181662361X |4 aut | |
| 245 | 1 | 0 | |a Fusion protein-driven IGF-IR/PI3K/AKT signals deregulate Hippo pathway promoting oncogenic cooperation of YAP1 and FUS-DDIT3 in myxoid liposarcoma |c Ruth Berthold, Ilka Isfort, Cihan Erkut, Lorena Heinst, Inga Grünewald, Eva Wardelmann, Thomas Kindler, Pierre Åman, Thomas G. P. Grünewald, Florencia Cidre-Aranaz, Marcel Trautmann, Stefan Fröhling, Claudia Scholl and Wolfgang Hartmann |
| 246 | 3 | 0 | |a IGF-IR, PI3K, AKT |
| 264 | 1 | |c 22 April 2022 | |
| 300 | |a 12 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Gesehen am 14.09.2022 | ||
| 520 | |a Myxoid liposarcoma (MLS) represents a common subtype of liposarcoma molecularly characterized by a recurrent chromosomal translocation that generates a chimeric FUS-DDIT3 fusion gene. The FUS-DDIT3 oncoprotein has been shown to be crucial in MLS pathogenesis. Acting as a transcriptional dysregulator, FUS-DDIT3 stimulates proliferation and interferes with adipogenic differentiation. As the fusion protein represents a therapeutically challenging target, a profound understanding of MLS biology is elementary to uncover FUS-DDIT3-dependent molecular vulnerabilities. Recently, a specific reliance on the Hippo pathway effector and transcriptional co-regulator YAP1 was detected in MLS; however, details on the molecular mechanism of FUS-DDIT3-dependent YAP1 activation, and YAP1´s precise mode of action remain unclear. In elaborate in vitro studies, employing RNA interference-based approaches, small-molecule inhibitors, and stimulation experiments with IGF-II, we show that FUS-DDIT3-driven IGF-IR/PI3K/AKT signaling promotes stability and nuclear accumulation of YAP1 via deregulation of the Hippo pathway. Co-immunoprecipitation and proximity ligation assays revealed nuclear co-localization of FUS-DDIT3 and YAP1/TEAD in FUS-DDIT3-expressing mesenchymal stem cells and MLS cell lines. Transcriptome sequencing of MLS cells demonstrated that FUS-DDIT3 and YAP1 co-regulate oncogenic gene signatures related to proliferation, cell cycle progression, apoptosis, and adipogenesis. In adipogenic differentiation assays, we show that YAP1 critically contributes to FUS-DDIT3-mediated adipogenic differentiation arrest. Taken together, our study provides mechanistic insights into a complex FUS-DDIT3-driven network involving IGF-IR/PI3K/AKT signals acting on Hippo/YAP1, and uncovers substantial cooperative effects of YAP1 and FUS-DDIT3 in the pathogenesis of MLS. | ||
| 650 | 4 | |a Growth factor signalling | |
| 650 | 4 | |a Molecular biology | |
| 650 | 4 | |a Oncogenes | |
| 650 | 4 | |a Sarcoma | |
| 700 | 1 | |8 1\p |a Isfort, Ilka |d 1990- |e VerfasserIn |0 (DE-588)1206944684 |0 (DE-627)1693180545 |4 aut | |
| 700 | 1 | |a Erkut, Cihan |d 1983- |e VerfasserIn |0 (DE-588)1031159304 |0 (DE-627)735744157 |0 (DE-576)377236624 |4 aut | |
| 700 | 1 | |a Heinst, Lorena |e VerfasserIn |4 aut | |
| 700 | 1 | |a Grünewald, Inga |e VerfasserIn |4 aut | |
| 700 | 1 | |8 2\p |a Wardelmann, Eva |d 1964- |e VerfasserIn |0 (DE-588)121391175 |0 (DE-627)081277458 |0 (DE-576)292686145 |4 aut | |
| 700 | 1 | |8 3\p |a Kindler, Thomas |d 1969- |e VerfasserIn |0 (DE-588)121883973 |0 (DE-627)705689441 |0 (DE-576)292936664 |4 aut | |
| 700 | 1 | |a Åman, Pierre |e VerfasserIn |4 aut | |
| 700 | 1 | |a Grünewald, Thomas G. P. |d 1980- |e VerfasserIn |0 (DE-588)13673426X |0 (DE-627)585870365 |0 (DE-576)301246432 |4 aut | |
| 700 | 1 | |a Cidre-Aranaz, Florencia |e VerfasserIn |0 (DE-588)1230808973 |0 (DE-627)1753154049 |4 aut | |
| 700 | 1 | |8 4\p |a Trautmann, Marcel |e VerfasserIn |0 (DE-588)1054566585 |0 (DE-627)791615901 |0 (DE-576)410332097 |4 aut | |
| 700 | 1 | |a Fröhling, Stefan |d 1969- |e VerfasserIn |0 (DE-588)120890046 |0 (DE-627)080950302 |0 (DE-576)188733930 |4 aut | |
| 700 | 1 | |a Scholl, Claudia |d 1971- |e VerfasserIn |0 (DE-588)128803533 |0 (DE-627)380643197 |0 (DE-576)187440271 |4 aut | |
| 700 | 1 | |8 5\p |a Hartmann, Wolfgang |e VerfasserIn |0 (DE-588)121932695X |0 (DE-627)1735275301 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Oncogenesis |d [Erscheinungsort nicht ermittelbar] : Nature Publ., 2012 |g 11(2022), 1, Artikel-ID 20, Seite 1-12 |h Online-Ressource |w (DE-627)72158022X |w (DE-600)2674437-5 |w (DE-576)369466284 |x 2157-9024 |7 nnas |a Fusion protein-driven IGF-IR/PI3K/AKT signals deregulate Hippo pathway promoting oncogenic cooperation of YAP1 and FUS-DDIT3 in myxoid liposarcoma |
| 773 | 1 | 8 | |g volume:11 |g year:2022 |g number:1 |g elocationid:20 |g pages:1-12 |g extent:12 |a Fusion protein-driven IGF-IR/PI3K/AKT signals deregulate Hippo pathway promoting oncogenic cooperation of YAP1 and FUS-DDIT3 in myxoid liposarcoma |
| 856 | 4 | 0 | |u https://doi.org/10.1038/s41389-022-00394-7 |x Verlag |x Resolving-System |z lizenzpflichtig |3 Volltext |7 1 |
| 856 | 4 | 0 | |u https://www.nature.com/articles/s41389-022-00394-7 |x Verlag |z lizenzpflichtig |3 Volltext |7 1 |
| 883 | |8 1\p |a cgwrk |d 20241001 |q DE-101 |u https://d-nb.info/provenance/plan#cgwrk | ||
| 883 | |8 2\p |a cgwrk |d 20241001 |q DE-101 |u https://d-nb.info/provenance/plan#cgwrk | ||
| 883 | |8 3\p |a cgwrk |d 20241001 |q DE-101 |u https://d-nb.info/provenance/plan#cgwrk | ||
| 883 | |8 4\p |a cgwrk |d 20241001 |q DE-101 |u https://d-nb.info/provenance/plan#cgwrk | ||
| 883 | |8 5\p |a cgwrk |d 20241001 |q DE-101 |u https://d-nb.info/provenance/plan#cgwrk | ||
| 951 | |a AR | ||
| 992 | |a 20220914 | ||
| 993 | |a Article | ||
| 994 | |a 2022 | ||
| 998 | |g 128803533 |a Scholl, Claudia |m 128803533:Scholl, Claudia |d 50000 |e 50000PS128803533 |k 0/50000/ |p 13 | ||
| 998 | |g 120890046 |a Fröhling, Stefan |m 120890046:Fröhling, Stefan |d 50000 |e 50000PF120890046 |k 0/50000/ |p 12 | ||
| 998 | |g 1230808973 |a Cidre-Aranaz, Florencia |m 1230808973:Cidre-Aranaz, Florencia |d 140000 |e 140000PC1230808973 |k 0/140000/ |p 10 | ||
| 998 | |g 13673426X |a Grünewald, Thomas G. P. |m 13673426X:Grünewald, Thomas G. P. |d 910000 |d 912000 |e 910000PG13673426X |e 912000PG13673426X |k 0/910000/ |k 1/910000/912000/ |p 9 | ||
| 998 | |g 1031159304 |a Erkut, Cihan |m 1031159304:Erkut, Cihan |d 50000 |e 50000PE1031159304 |k 0/50000/ |p 3 | ||
| 999 | |a KXP-PPN1816623652 |e 4188084200 | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"note":["Gesehen am 14.09.2022"],"type":{"media":"Online-Ressource","bibl":"article-journal"},"language":["eng"],"relHost":[{"language":["eng"],"type":{"bibl":"periodical","media":"Online-Ressource"},"note":["Gesehen am 08.11.13"],"title":[{"title":"Oncogenesis","title_sort":"Oncogenesis"}],"physDesc":[{"extent":"Online-Ressource"}],"origin":[{"dateIssuedKey":"2012","publisher":"Nature Publ.","publisherPlace":"[Erscheinungsort nicht ermittelbar]","dateIssuedDisp":"2012-"}],"pubHistory":["1.2012 -"],"disp":"Fusion protein-driven IGF-IR/PI3K/AKT signals deregulate Hippo pathway promoting oncogenic cooperation of YAP1 and FUS-DDIT3 in myxoid liposarcomaOncogenesis","part":{"volume":"11","extent":"12","year":"2022","text":"11(2022), 1, Artikel-ID 20, Seite 1-12","pages":"1-12","issue":"1"},"recId":"72158022X","id":{"zdb":["2674437-5"],"issn":["2157-9024"],"eki":["72158022X"]}}],"title":[{"title_sort":"Fusion protein-driven IGF-IR/PI3K/AKT signals deregulate Hippo pathway promoting oncogenic cooperation of YAP1 and FUS-DDIT3 in myxoid liposarcoma","title":"Fusion protein-driven IGF-IR/PI3K/AKT signals deregulate Hippo pathway promoting oncogenic cooperation of YAP1 and FUS-DDIT3 in myxoid liposarcoma"}],"origin":[{"dateIssuedDisp":"22 April 2022","dateIssuedKey":"2022"}],"physDesc":[{"extent":"12 S."}],"recId":"1816623652","id":{"eki":["1816623652"],"doi":["10.1038/s41389-022-00394-7"]},"name":{"displayForm":["Ruth Berthold, Ilka Isfort, Cihan Erkut, Lorena Heinst, Inga Grünewald, Eva Wardelmann, Thomas Kindler, Pierre Åman, Thomas G. P. Grünewald, Florencia Cidre-Aranaz, Marcel Trautmann, Stefan Fröhling, Claudia Scholl and Wolfgang Hartmann"]},"person":[{"display":"Berthold, Ruth","given":"Ruth","role":"aut","family":"Berthold"},{"family":"Isfort","role":"aut","given":"Ilka","display":"Isfort, Ilka"},{"role":"aut","family":"Erkut","display":"Erkut, Cihan","given":"Cihan"},{"given":"Lorena","display":"Heinst, Lorena","family":"Heinst","role":"aut"},{"given":"Inga","display":"Grünewald, Inga","family":"Grünewald","role":"aut"},{"given":"Eva","display":"Wardelmann, Eva","family":"Wardelmann","role":"aut"},{"given":"Thomas","display":"Kindler, Thomas","family":"Kindler","role":"aut"},{"given":"Pierre","display":"Åman, Pierre","family":"Åman","role":"aut"},{"display":"Grünewald, Thomas G. P.","given":"Thomas G. P.","role":"aut","family":"Grünewald"},{"role":"aut","family":"Cidre-Aranaz","display":"Cidre-Aranaz, Florencia","given":"Florencia"},{"given":"Marcel","display":"Trautmann, Marcel","family":"Trautmann","role":"aut"},{"family":"Fröhling","role":"aut","given":"Stefan","display":"Fröhling, Stefan"},{"family":"Scholl","role":"aut","given":"Claudia","display":"Scholl, Claudia"},{"display":"Hartmann, Wolfgang","given":"Wolfgang","role":"aut","family":"Hartmann"}]} | ||
| SRT | |a BERTHOLDRUFUSIONPROT2220 | ||