O-GlcNAcylation of STAT5 controls tyrosine phosphorylation and oncogenic transcription in STAT5-dependent malignancies

被引：49

作者：

Freund, P. ^{[1
,2
]}

Kerenyi, M. A. ^{[3
]}

Hager, M. ^{[1
]}

Wagner, T. ^{[4
]}

Wingelhofer, B. ^{[1
,2
]}

Pham, H. T. T. ^{[1
,2
]}

Elabd, M. ^{[1
,2
]}

Han, X. ^{[5
,6
,7
,8
]}

Valent, P. ^{[9
,10
]}

Gouilleux, F. ^{[11
]}

Sexl, V. ^{[12
]}

Kraemer, O. H. ^{[13
]}

Groner, B. ^{[14
]}

Moriggl, R. ^{[1
,2
,15
]}

机构：

[1] Ludwig Boltzmann Inst Canc Res, Vienna, Austria

[2] Univ Vet Med, Inst Anim Breeding & Genet, Dept Biomed Sci, Vienna, Austria

[3] Boehringer Ingelheim RCV GmbH & Co KG, Dept Pharmacol, Vienna, Austria

[4] Friedrich Schiller Univ Jena, Ctr Mol Biomed, Dept Biochem, Jena, Germany

[5] Cincinnati Childrens Hosp Med Ctr, Div Gastroenterol Hepatol & Nutr, Cincinnati, OH 45229 USA

[6] Minist Hlth, Key Lab Human Dis Comparat Med, Beijing, Peoples R China

[7] Chinese Acad Med Sci, Inst Lab Anim Sci, Beijing, Peoples R China

[8] Peking Union Med Coll, Beijing, Peoples R China

[9] Med Univ Vienna, Div Hematol & Hemostaseol, Dept Internal Med 1, Vienna, Austria

[10] Med Univ Vienna, Ludwig Boltzmann Cluster Oncol, Vienna, Austria

[11] Univ Tours, CNRS, UMR 7292, Tours, France

[12] Univ Vet Med, Inst Pharmacol & Toxicol, Dept Biomed Sci, Vienna, Austria

[13] Univ Med Ctr, Dept Toxicol, Mainz, Germany

[14] Inst Tumor Biol & Expt Therapy, Georg Speyer Haus, Frankfurt, Germany

[15] Med Univ Vienna, Vienna, Austria

来源：

LEUKEMIA | 2017年 / 31卷 / 10期

基金：

奥地利科学基金会;

关键词：

N-ACETYLGLUCOSAMINE TRANSFERASE; GLCNAC-MODIFIED PROTEINS; SWISS-MODEL; MYELOPROLIFERATIVE NEOPLASMS; SERINE PHOSPHORYLATION; COLORECTAL-CANCER; GENE-EXPRESSION; C-MYC; LEUKEMIA; CELLS;

D O I：

10.1038/leu.2017.4

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：2132 / 2142

页数：11

共 49 条

[1] The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling [J].

Arnold, K ;

Bordoli, L ;

Kopp, J ;

Schwede, T .

BIOINFORMATICS, 2006, 22 (02) :195-201

[2] UniProt: a hub for protein information [J].

Bateman, Alex ;

Martin, Maria Jesus ;

O'Donovan, Claire ;

Magrane, Michele ;

Apweiler, Rolf ;

Alpi, Emanuele ;

Antunes, Ricardo ;

Arganiska, Joanna ;

Bely, Benoit ;

Bingley, Mark ;

Bonilla, Carlos ;

Britto, Ramona ;

Bursteinas, Borisas ;

Chavali, Gayatri ;

Cibrian-Uhalte, Elena ;

Da Silva, Alan ;

De Giorgi, Maurizio ;

Dogan, Tunca ;

Fazzini, Francesco ;

Gane, Paul ;

Cas-tro, Leyla Garcia ;

Garmiri, Penelope ;

Hatton-Ellis, Emma ;

Hieta, Reija ;

Huntley, Rachael ;

Legge, Duncan ;

Liu, Wudong ;

Luo, Jie ;

MacDougall, Alistair ;

Mutowo, Prudence ;

Nightin-gale, Andrew ;

Orchard, Sandra ;

Pichler, Klemens ;

Poggioli, Diego ;

Pundir, Sangya ;

Pureza, Luis ;

Qi, Guoying ;

Rosanoff, Steven ;

Saidi, Rabie ;

Sawford, Tony ;

Shypitsyna, Aleksandra ;

Turner, Edward ;

Volynkin, Vladimir ;

Wardell, Tony ;

Watkins, Xavier ;

Zellner, Hermann ;

Cowley, Andrew ;

Figueira, Luis ;

Li, Weizhong ;

McWilliam, Hamish .

NUCLEIC ACIDS RESEARCH, 2015, 43 (D1) :D204-D212

[3] PAK-dependent STAT5 serine phosphorylation is required for BCR-ABL-induced leukemogenesis [J].

Berger, A. ;

Hoelbl-Kovacic, A. ;

Bourgeais, J. ;

Hoefling, L. ;

Warsch, W. ;

Grundschober, E. ;

Uras, I. Z. ;

Menzl, I. ;

Putz, E. M. ;

Hoermann, G. ;

Schuster, C. ;

Fajmann, S. ;

Leitner, E. ;

Kubicek, S. ;

Moriggl, R. ;

Gouilleux, F. ;

Sexl, V. .

LEUKEMIA, 2014, 28 (03) :629-641

[4] The Protein Data Bank [J].

Berman, HM ;

Westbrook, J ;

Feng, Z ;

Gilliland, G ;

Bhat, TN ;

Weissig, H ;

Shindyalov, IN ;

Bourne, PE .

NUCLEIC ACIDS RESEARCH, 2000, 28 (01) :235-242

[5] SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information [J].

Biasini, Marco ;

Bienert, Stefan ;

Waterhouse, Andrew ;

Arnold, Konstantin ;

Studer, Gabriel ;

Schmidt, Tobias ;

Kiefer, Florian ;

Cassarino, Tiziano Gallo ;

Bertoni, Martino ;

Bordoli, Lorenza ;

Schwede, Torsten .

NUCLEIC ACIDS RESEARCH, 2014, 42 (W1) :W252-W258

[6] STAT5 signaling in normal and pathologic hematopoiesis [J].

Bunting, Kevin D. .

FRONTIERS IN BIOSCIENCE-LANDMARK, 2007, 12 :2807-2820

[7] Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1 [J].

Caldwell, S. A. ;

Jackson, S. R. ;

Shahriari, K. S. ;

Lynch, T. P. ;

Sethi, G. ;

Walker, S. ;

Vosseller, K. ;

Reginato, M. J. .

ONCOGENE, 2010, 29 (19) :2831-2842

[8] Alteration of O-GlcNAcylation affects serine phosphorylation and regulates gene expression and activity of pyruvate kinase M2 in colorectal cancer cells [J].

Chaiyawat, Parunya ;

Chokchaichamnankit, Daranee ;

Lirdprapamongkol, Kriengsak ;

Srisomsap, Chantragan ;

Svasti, Jisnuson ;

Champattanachai, Voraratt .

ONCOLOGY REPORTS, 2015, 34 (04) :1933-1942

[9] Aberrant O-GIcNAcylated proteins: new perspectives in breast and colorectal cancer [J].

Chaiyawat, Parunya ;

Netsirisawan, Pukkavadee ;

Svasti, Jisnuson ;

Champattanachai, Voraratt .

FRONTIERS IN ENDOCRINOLOGY, 2014, 5

[10] Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3-and KIT-Driven Leukemogenesis [J].

Chatterjee, Anindya ;

Ghosh, Joydeep ;

Ramdas, Baskar ;

Mali, Raghuveer Singh ;

Martin, Holly ;

Kobayashi, Michihiro ;

Vemula, Sasidhar ;

Canela, Victor H. ;

Waskow, Emily R. ;

Visconte, Valeria ;

Tiu, Ramon V. ;

Smith, Catherine C. ;

Shah, Neil ;

Bunting, Kevin D. ;

Boswell, H. Scott ;

Liu, Yan ;

Chan, Rebecca J. ;

Kapur, Reuben .

CELL REPORTS, 2014, 9 (04) :1333-1348

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