O-GlcNAcylation of STAT5 controls tyrosine phosphorylation and oncogenic transcription in STAT5-dependent malignancies.
P FreundM A KerenyiM HagerT WagnerB WingelhoferH T T PhamM ElabdX HanP ValentF GouilleuxV SexlO H KrämerB GronerRichard H MorigglPublished in: Leukemia (2017)
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.
Keyphrases
- cell proliferation
- transcription factor
- induced apoptosis
- signaling pathway
- cell cycle arrest
- poor prognosis
- bone marrow
- protein kinase
- pi k akt
- long non coding rna
- immune response
- cell death
- electronic health record
- deep learning
- dendritic cells
- inflammatory response
- acute myeloid leukemia
- climate change
- brain injury
- big data
- toll like receptor
- data analysis