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Mechanism of prostaglandin E 2 -induced transcriptional up-regulation of Oncostatin-M by CREB and Sp1.
- Source :
-
The Biochemical journal [Biochem J] 2018 Jan 31; Vol. 475 (2), pp. 477-494. Date of Electronic Publication: 2018 Jan 31. - Publication Year :
- 2018
-
Abstract
- Oncostatin-M (OSM) is a pleotropic cytokine belonging to the interleukin-6 family. Differential expression of OSM in response to varying stimuli and exhibiting repertoire of functions in different cells renders it challenging to study the mechanism of its expression. Prostaglandin E <subscript>2</subscript> (PGE <subscript>2</subscript> ) transcriptionally increased osm levels. In silico studies of ∼1 kb upstream of osm promoter region yielded the presence of CRE (cyclic AMP response element)-like sites at the distal end (CRE <subscript>osm</subscript> ). Deletion and point mutation of CRE <subscript>osm</subscript> clearly indicated that this region imparted an important role in PGE <subscript>2</subscript> -mediated transcription. Nuclear protein(s) from PGE <subscript>2</subscript> -treated U937 cells, bound to this region, was identified as CRE-binding protein (CREB). CREB was phosphorylated on treatment and was found to be directly associated with CRE <subscript>osm</subscript> The presence of cofactors p300 and CREB-binding protein in the complex was confirmed. A marked decrease in CREB phosphorylation, binding and transcriptional inhibition on treatment with PKA (protein kinase A) inhibitor, H89 ( N -[2-[[3-(4-bromophenyl)-2-propenyl]amino]ethyl]-5-soquinolinesulfonamide), revealed the role of phosphorylated CREB in osm transcription. Additionally, other nuclear protein(s) were specifically associated with the proximal GC region (GC <subscript>osm</subscript> ) post PGE <subscript>2</subscript> treatment, later confirmed to be specificity protein 1 (Sp1). Interestingly, Sp1 bound to the proximal osm promoter was found to be associated with phospho-CREB-p300 complex bound to the distal osm promoter. Knockdown of Sp1 abrogated the expression and functionality of OSM. Thus, the present study conclusively proves that these transcription factors, bound at the distal and proximal promoter elements are found to associate with each other in a DNA-dependent manner and both are responsible for the PGE <subscript>2</subscript> -mediated transcriptional up-regulation of Oncostatin-M.<br /> (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
- Subjects :
- Binding Sites
CREB-Binding Protein genetics
CREB-Binding Protein metabolism
Cyclic AMP metabolism
Cyclic AMP Response Element-Binding Protein metabolism
Cyclic AMP-Dependent Protein Kinases antagonists & inhibitors
Cyclic AMP-Dependent Protein Kinases genetics
Cyclic AMP-Dependent Protein Kinases metabolism
E1A-Associated p300 Protein genetics
E1A-Associated p300 Protein metabolism
Humans
Isoquinolines pharmacology
Mutagenesis, Site-Directed
Oncostatin M metabolism
Phosphorylation drug effects
Point Mutation
Promoter Regions, Genetic
Protein Binding
Protein Kinase Inhibitors pharmacology
Response Elements
Signal Transduction
Sp1 Transcription Factor metabolism
Sulfonamides pharmacology
U937 Cells
Cyclic AMP Response Element-Binding Protein genetics
Dinoprostone pharmacology
Gene Expression Regulation
Oncostatin M genetics
Sp1 Transcription Factor genetics
Transcription, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 1470-8728
- Volume :
- 475
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Biochemical journal
- Publication Type :
- Academic Journal
- Accession number :
- 29269396
- Full Text :
- https://doi.org/10.1042/BCJ20170545