O-GlcNAcylation of STAT5 controls tyrosine phosphorylation and oncogenic transcription in STAT5-dependent malignancies
The signal transducer and activator of transcription 5 (STAT5) regulates differentiation, survival, proliferation and transformation of hematopoietic cells. Upon cytokine stimulation, STAT5 tyrosine phosphorylation (pYSTAT5) is transient, while in diverse neoplastic cells persistent overexpression a...
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| Veröffentlicht in: | Leukemia 2017-10, Vol.31 (10), p.2132-2142 |
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| creator | Freund, P Kerenyi, M A Hager, M Wagner, T Wingelhofer, B Pham, H T T Elabd, M Han, X Valent, P Gouilleux, F Sexl, V Krämer, O H Groner, B Moriggl, R |
| description | The signal transducer and activator of transcription 5 (STAT5) regulates differentiation, survival, proliferation and transformation of hematopoietic cells. Upon cytokine stimulation, STAT5 tyrosine phosphorylation (pYSTAT5) is transient, while in diverse neoplastic cells persistent overexpression and enhanced pYSTAT5 are frequently found. Post-translational modifications might contribute to enhanced STAT5 activation in the context of transformation, but the strength and duration of pYSTAT5 are incompletely understood. We found that O-GlcNAcylation and tyrosine phosphorylation act together to trigger pYSTAT5 levels and oncogenic transcription in neoplastic cells. The expression of a mutated hyperactive gain-of-function (GOF) STAT5 without O-GlcNAcylation resulted in decreased tyrosine phosphorylation, oligomerization and transactivation potential and complete loss of oncogenic transformation capacity. The lack of O-GlcNAcylation diminished phospho-ERK and phospho-AKT levels. Our data show that O-GlcNAcylation of STAT5 is an important process that contributes to oncogenic transcription through enhanced STAT5 tyrosine phosphorylation and oligomerization driving myeloid transformation. O-GlcNAcylation of STAT5 could be required for nutrient sensing and metabolism of cancer cells. |
| doi_str_mv | 10.1038/leu.2017.4 |
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Upon cytokine stimulation, STAT5 tyrosine phosphorylation (pYSTAT5) is transient, while in diverse neoplastic cells persistent overexpression and enhanced pYSTAT5 are frequently found. Post-translational modifications might contribute to enhanced STAT5 activation in the context of transformation, but the strength and duration of pYSTAT5 are incompletely understood. We found that O-GlcNAcylation and tyrosine phosphorylation act together to trigger pYSTAT5 levels and oncogenic transcription in neoplastic cells. The expression of a mutated hyperactive gain-of-function (GOF) STAT5 without O-GlcNAcylation resulted in decreased tyrosine phosphorylation, oligomerization and transactivation potential and complete loss of oncogenic transformation capacity. The lack of O-GlcNAcylation diminished phospho-ERK and phospho-AKT levels. Our data show that O-GlcNAcylation of STAT5 is an important process that contributes to oncogenic transcription through enhanced STAT5 tyrosine phosphorylation and oligomerization driving myeloid transformation. O-GlcNAcylation of STAT5 could be required for nutrient sensing and metabolism of cancer cells.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/leu.2017.4</identifier><identifier>PMID: 28074064</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/106 ; 13/109 ; 13/31 ; 13/95 ; 45/77 ; 45/90 ; 631/250/580 ; 631/337/458/1733 ; 631/337/572 ; 631/67/1990 ; 631/67/2327 ; 631/80/86 ; 64/60 ; 692/308/575 ; 82 ; 82/29 ; 96/1 ; Acetylglucosamine - metabolism ; AKT protein ; Animals ; Biochemistry, Molecular Biology ; Cancer ; Cancer Research ; Care and treatment ; Cell Line ; Cell proliferation ; Cell Transformation, Neoplastic ; Cellular Biology ; Critical Care Medicine ; Development and progression ; Differentiation ; Female ; Gene expression ; Gene Expression Regulation, Neoplastic ; Genes, Reporter ; Genetic aspects ; Genetic transformation ; Glycosylation ; Health aspects ; Hematology ; Humans ; Intensive ; Interleukin-3 - pharmacology ; Internal Medicine ; Kinases ; Leukemia ; Life Sciences ; Lymphoid Tissue - cytology ; Male ; Medicine ; Medicine & Public Health ; Metabolism ; Mice ; Mutagenesis, Site-Directed ; Myeloproliferative Disorders - etiology ; Myeloproliferative Disorders - genetics ; O-GlcNAcylation ; Oligomerization ; Oncology ; Original ; original-article ; Phosphorylation ; Phosphotyrosine - metabolism ; Post-translation ; Protein Processing, Post-Translational ; Radiation Chimera ; Recombinant Fusion Proteins - metabolism ; Signal Transduction ; STAT5 ; Stat5 protein ; STAT5 Transcription Factor - genetics ; STAT5 Transcription Factor - metabolism ; T-Lymphocytes - cytology ; T-Lymphocytes - drug effects ; T-Lymphocytes - metabolism ; Threonine - metabolism ; Transcription ; Transcription (Genetics) ; Transcriptional Activation ; Tumor Suppressor Proteins - genetics ; Tumor Suppressor Proteins - metabolism ; Tyrosine</subject><ispartof>Leukemia, 2017-10, Vol.31 (10), p.2132-2142</ispartof><rights>The Author(s) 2017</rights><rights>COPYRIGHT 2017 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Oct 2017</rights><rights>Attribution</rights><rights>Copyright © 2017 The Author(s) 2017 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c640t-efb2e0ed20806a16e88670be505db71ccd19df4d8b1c0cff70aea77fca909f483</citedby><cites>FETCH-LOGICAL-c640t-efb2e0ed20806a16e88670be505db71ccd19df4d8b1c0cff70aea77fca909f483</cites><orcidid>0000-0003-0918-9463 ; 0000-0001-6047-1718</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/leu.2017.4$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/leu.2017.4$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28074064$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://univ-tours.hal.science/hal-02411725$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Freund, P</creatorcontrib><creatorcontrib>Kerenyi, M A</creatorcontrib><creatorcontrib>Hager, M</creatorcontrib><creatorcontrib>Wagner, T</creatorcontrib><creatorcontrib>Wingelhofer, B</creatorcontrib><creatorcontrib>Pham, H T T</creatorcontrib><creatorcontrib>Elabd, M</creatorcontrib><creatorcontrib>Han, X</creatorcontrib><creatorcontrib>Valent, P</creatorcontrib><creatorcontrib>Gouilleux, F</creatorcontrib><creatorcontrib>Sexl, V</creatorcontrib><creatorcontrib>Krämer, O H</creatorcontrib><creatorcontrib>Groner, B</creatorcontrib><creatorcontrib>Moriggl, R</creatorcontrib><title>O-GlcNAcylation of STAT5 controls tyrosine phosphorylation and oncogenic transcription in STAT5-dependent malignancies</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>The signal transducer and activator of transcription 5 (STAT5) regulates differentiation, survival, proliferation and transformation of hematopoietic cells. Upon cytokine stimulation, STAT5 tyrosine phosphorylation (pYSTAT5) is transient, while in diverse neoplastic cells persistent overexpression and enhanced pYSTAT5 are frequently found. Post-translational modifications might contribute to enhanced STAT5 activation in the context of transformation, but the strength and duration of pYSTAT5 are incompletely understood. We found that O-GlcNAcylation and tyrosine phosphorylation act together to trigger pYSTAT5 levels and oncogenic transcription in neoplastic cells. The expression of a mutated hyperactive gain-of-function (GOF) STAT5 without O-GlcNAcylation resulted in decreased tyrosine phosphorylation, oligomerization and transactivation potential and complete loss of oncogenic transformation capacity. The lack of O-GlcNAcylation diminished phospho-ERK and phospho-AKT levels. Our data show that O-GlcNAcylation of STAT5 is an important process that contributes to oncogenic transcription through enhanced STAT5 tyrosine phosphorylation and oligomerization driving myeloid transformation. O-GlcNAcylation of STAT5 could be required for nutrient sensing and metabolism of cancer cells.</description><subject>13/106</subject><subject>13/109</subject><subject>13/31</subject><subject>13/95</subject><subject>45/77</subject><subject>45/90</subject><subject>631/250/580</subject><subject>631/337/458/1733</subject><subject>631/337/572</subject><subject>631/67/1990</subject><subject>631/67/2327</subject><subject>631/80/86</subject><subject>64/60</subject><subject>692/308/575</subject><subject>82</subject><subject>82/29</subject><subject>96/1</subject><subject>Acetylglucosamine - metabolism</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Biochemistry, Molecular Biology</subject><subject>Cancer</subject><subject>Cancer Research</subject><subject>Care and treatment</subject><subject>Cell Line</subject><subject>Cell proliferation</subject><subject>Cell Transformation, Neoplastic</subject><subject>Cellular Biology</subject><subject>Critical Care 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malignancies</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2017-10-01</date><risdate>2017</risdate><volume>31</volume><issue>10</issue><spage>2132</spage><epage>2142</epage><pages>2132-2142</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><abstract>The signal transducer and activator of transcription 5 (STAT5) regulates differentiation, survival, proliferation and transformation of hematopoietic cells. Upon cytokine stimulation, STAT5 tyrosine phosphorylation (pYSTAT5) is transient, while in diverse neoplastic cells persistent overexpression and enhanced pYSTAT5 are frequently found. Post-translational modifications might contribute to enhanced STAT5 activation in the context of transformation, but the strength and duration of pYSTAT5 are incompletely understood. We found that O-GlcNAcylation and tyrosine phosphorylation act together to trigger pYSTAT5 levels and oncogenic transcription in neoplastic cells. The expression of a mutated hyperactive gain-of-function (GOF) STAT5 without O-GlcNAcylation resulted in decreased tyrosine phosphorylation, oligomerization and transactivation potential and complete loss of oncogenic transformation capacity. The lack of O-GlcNAcylation diminished phospho-ERK and phospho-AKT levels. Our data show that O-GlcNAcylation of STAT5 is an important process that contributes to oncogenic transcription through enhanced STAT5 tyrosine phosphorylation and oligomerization driving myeloid transformation. O-GlcNAcylation of STAT5 could be required for nutrient sensing and metabolism of cancer cells.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28074064</pmid><doi>10.1038/leu.2017.4</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-0918-9463</orcidid><orcidid>https://orcid.org/0000-0001-6047-1718</orcidid><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5629373 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online |
| subjects | 13/106 13/109 13/31 13/95 45/77 45/90 631/250/580 631/337/458/1733 631/337/572 631/67/1990 631/67/2327 631/80/86 64/60 692/308/575 82 82/29 96/1 Acetylglucosamine - metabolism AKT protein Animals Biochemistry, Molecular Biology Cancer Cancer Research Care and treatment Cell Line Cell proliferation Cell Transformation, Neoplastic Cellular Biology Critical Care Medicine Development and progression Differentiation Female Gene expression Gene Expression Regulation, Neoplastic Genes, Reporter Genetic aspects Genetic transformation Glycosylation Health aspects Hematology Humans Intensive Interleukin-3 - pharmacology Internal Medicine Kinases Leukemia Life Sciences Lymphoid Tissue - cytology Male Medicine Medicine & Public Health Metabolism Mice Mutagenesis, Site-Directed Myeloproliferative Disorders - etiology Myeloproliferative Disorders - genetics O-GlcNAcylation Oligomerization Oncology Original original-article Phosphorylation Phosphotyrosine - metabolism Post-translation Protein Processing, Post-Translational Radiation Chimera Recombinant Fusion Proteins - metabolism Signal Transduction STAT5 Stat5 protein STAT5 Transcription Factor - genetics STAT5 Transcription Factor - metabolism T-Lymphocytes - cytology T-Lymphocytes - drug effects T-Lymphocytes - metabolism Threonine - metabolism Transcription Transcription (Genetics) Transcriptional Activation Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Tyrosine |
| title | O-GlcNAcylation of STAT5 controls tyrosine phosphorylation and oncogenic transcription in STAT5-dependent malignancies |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-30T23%3A26%3A00IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=O-GlcNAcylation%20of%20STAT5%20controls%20tyrosine%20phosphorylation%20and%20oncogenic%20transcription%20in%20STAT5-dependent%20malignancies&rft.jtitle=Leukemia&rft.au=Freund,%20P&rft.date=2017-10-01&rft.volume=31&rft.issue=10&rft.spage=2132&rft.epage=2142&rft.pages=2132-2142&rft.issn=0887-6924&rft.eissn=1476-5551&rft_id=info:doi/10.1038/leu.2017.4&rft_dat=%3Cgale_pubme%3EA507901060%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1946281932&rft_id=info:pmid/28074064&rft_galeid=A507901060&rfr_iscdi=true |