The carboxyl-terminal region of STAT3 controls gene induction by the mouse haptoglobin promoter.
Haptoglobin (HP) is one of the major acute phase plasma proteins in the mouse, and its synthesis is additively induced by interleukin (IL)-6 and glucocorticoids. STAT3 serves as the mediator of the IL-6 receptor signal and appears to contribute to the transcriptional induction of acute phase protein genes. The carboxyl-terminal region of STAT3, consisting of an acidic domain and containing a serine phosphorylation site, has been proposed to contribute to the induction process. To assess the role of STAT3 in the transcriptional control of the HP promoter, we applied two mutant forms of STAT3: one with a deletion of the carboxyl-terminal 55 amino acid residues, STAT3Delta55C, and the other with a substitution of serine 727 to alanine, STAT3SA. Like the wild-type STAT3, both mutant STAT3 forms are activated by the signal-transducing subunit of the IL-6 receptor, gp130, or by co-transfected IL-3 receptor. Ectopic expression and activation of wild-type STAT3 or STAT3SA in HepG2 hepatoma cells similarly enhance transcription through the IL-6-response element of the HP promoter. This enhancement is specific for STAT3 and cannot be reproduced by STAT1 or STAT5. In contrast, STAT3Delta55C inhibits IL-6-induced transcriptional activation. Interestingly, whereas receptor-activated STAT3 also enhances stimulation of the haptoglobin promoter by dexamethasone through the glucocorticoid receptor, activated STAT3Delta55C reduces the regulation below the level achieved by the glucocorticoid receptor alone. This transdominant action by STAT3Delta55C is dependent on a functional IL-6-responsive element. The data suggest that the carboxyl-terminal domain, but not its serine phosphorylation site of STAT3, is required for transcription as part of the hematopoietin receptor signaling as well as for cooperation with other transcription factors such as the glucocorticoid receptor.
Kim
H
H
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Baumann
H
H
D000409:Alanine; D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D001483:Base Sequence; D001665:Binding Sites; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D006242:Haptoglobins / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D018123:Receptors, Interleukin / Q000502:physiology; D016185:Receptors, Interleukin-3 / Q000502:physiology; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D050796:STAT3 Transcription Factor; D017384:Sequence Deletion; D012694:Serine; D015398:Signal Transduction; D015534:Trans-Activators / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D006242:Haptoglobins; D015850:Interleukin-6; D018123:Receptors, Interleukin; D016185:Receptors, Interleukin-3; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D012694:Serine; D003907:Dexamethasone; D000409:Alanine