PMID:21470923

Citation	Shu, M, Zhou, Y, Zhu, W, Wu, S, Zheng, X and Yan, G (2011) Activation of a pro-survival pathway IL-6/JAK2/STAT3 contributes to glial fibrillary acidic protein induction during the cholera toxin-induced differentiation of C6 malignant glioma cells. Mol Oncol 5:265-72
Abstract	Differentiation-inducing therapy has been proposed to be a novel potential approach to treat malignant gliomas. Glial fibrillary acidic protein (GFAP) is a well-known specific astrocyte biomarker and acts as a tumor suppressor gene (TSG) in glioma pathogenesis. Previously we reported that a traditional biotoxin cholera toxin could induce malignant glioma cell differentiation characterized by morphologic changes and dramatic GFAP expression. However, the molecular mechanisms underlying GFAP induction are still largely unknown. Here we demonstrate that an oncogenic pathway interleukin-6/janus kinase-2/signal transducer and activator of transcription 3 (IL-6/JAK2/STAT3) cascade mediates the cholera toxin-induced GFAP expression. Cholera toxin dramatically stimulated GFAP expression at the transcriptional level in C6 glioma cells. Meanwhile, phosphorylation of STAT3 and JAK2 was highly induced in a time-dependent manner after cholera toxin incubation, whereas no changes of STAT3 and JAK2 were observed. Furthermore, the IL-6 gene was quickly induced by cholera toxin and subsequent IL-6 protein secretion was stimulated. Importantly, exogenous recombinant rat IL-6 can also induce phosphorylation of STAT3 concomitant with GFAP expression while JAK2 specific inhibitor AG490 could effectively block both cholera toxin- and IL-6-induced GFAP expression. Given that the methylation of the STAT3 binding element can suppress GFAP expression, we detected the methylation status of the critical recognition sequence of STAT3 in the promoter of GFAP gene (-1518 ∼ -1510) and found that it was unmethylated in C6 glioma cells. In addition, neither DNA methyltransferase1 (DNMT1) inhibitor 5-Aza-2'-deoxycytidine (5-AZa-CdR) nor silencing DNMT1 can stimulate GFAP expression, indicating that the loss of GFAP expression in C6 cells is not caused by its promoter hypermethylation. Taken together, our findings suggest that activation of a pro-survival IL-6/JAK2/STAT3 cascade contributes to cholera toxin-induced GFAP expression, which implies that a survival-promoting signal may also play a differentiation-supporting role in malignant gliomas.
Links	PubMed Online version:10.1016/j.molonc.2011.03.003
Keywords	Animals; Cell Differentiation/drug effects; Cell Line, Tumor; Cell Survival/drug effects; Cholera Toxin/pharmacology; DNA Methylation/drug effects; Enzyme Activation/drug effects; Gene Expression Regulation, Neoplastic/drug effects; Glial Fibrillary Acidic Protein/metabolism; Glioma/enzymology; Glioma/genetics; Glioma/pathology; Interleukin-6/genetics; Interleukin-6/metabolism; Janus Kinase 2/metabolism; Promoter Regions, Genetic/genetics; Rats; STAT3 Transcription Factor/metabolism; Signal Transduction/drug effects; Transcription, Genetic/drug effects; Up-Regulation/drug effects
edit table

Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
VIBCH:CHTA		GO:0042517: positive regulation of tyrosine phosphorylation of Stat3 protein	ECO:0000314:		P		Figure 2 (A) Shows Cholera elevates the levels of phosphorylation in STAT3 over time.	complete CACAO 7321
VIBCH:CHTA	involved_in	GO:0042531: positive regulation of tyrosine phosphorylation of STAT protein	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
VIBCH:CHTB	involved_in	GO:0042531: positive regulation of tyrosine phosphorylation of STAT protein	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
VIBCH:CHTB		GO:0042517: positive regulation of tyrosine phosphorylation of Stat3 protein	ECO:0000314:		P		Figure 2 (A) Shows Cholera elevates the levels of phosphorylation in STAT3 over time.	complete CACAO 6794
VIBCH:CHTB		GO:0042977: activation of JAK2 kinase activity	ECO:0000314:		P		Figure 2 (B) Shows that Cholera elevates levels of phosphorylation in JAK2 overtime.	complete CACAO 6796

References

See Help:References for how to manage references in GONUTS.