Regulation of the Transforming Growth Factor β-responsive Transcription Factor CTF-1 by Calcineurin and Calcium/ Calmodulin-dependent Protein Kinase IV

• Published in: The Journal of biological chemistry 1997-09, Vol.272 (38), p.23597-23605
• Main Authors: Alevizopoulos, Athanassios, Dusserre, Yves, Rüegg, Urs, Mermod, Nicolas
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Calcineurin; Calcium - metabolism; Calcium-Calmodulin-Dependent Protein Kinase Type 4; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Calmodulin-Binding Proteins - metabolism; CCAAT-Enhancer-Binding Proteins; Cyclosporine - pharmacology; DNA-Binding Proteins - metabolism; Mice; NFI Transcription Factors; Phosphoprotein Phosphatases - metabolism; Signal Transduction; Tacrolimus - pharmacology; Transcription Factors - metabolism; Transcriptional Activation; Transforming Growth Factor beta - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.272.38.23597

Transforming growth factor β (TGF-β) is a pluripotent peptide hormone that regulates various cellular activities, including growth, differentiation, and extracellular matrix protein gene expression. We previously showed that TGF-β induces the transcriptional activation domain (TAD) of CTF-1, the prototypic member of the CTF/NF-I family of transcription factors. This induction correlates with the proposed role of CTF/NF-I binding sites in collagen gene induction by TGF-β. However, the mechanisms of TGF-β signal transduction remain poorly understood. Here, we analyzed the role of free calcium signaling in the induction of CTF-1 transcriptional activity by TGF-β. We found that TGF-β stimulates calcium influx and mediates an increase of the cytoplasmic calcium concentration in NIH3T3 cells. TGF-β induction of CTF-1 is inhibited in cells pretreated with thapsigargin, which depletes the endoplasmic reticulum calcium stores, thus further arguing for the potential relevance of calcium mobilization in TGF-β action. Consistent with this possibility, expression of a constitutively active form of the calcium/calmodulin-dependent phosphatase calcineurin or of the calcium/calmodulin-dependent kinase IV (ΔCaMKIV) specifically induces the CTF-1 TAD and the endogenous mouse CTF/NF-I proteins. Both calcineurin- and ΔCaMKIV-mediated induction require the previously identified TGF-β-responsive domain of CTF-1. The immunosuppressants cyclosporin A and FK506 abolish calcineurin-mediated induction of CTF-1 activity. However, TGF-β still induces the CTF-1 TAD in cells treated with these compounds or in cells overexpressing both calcineurin and ΔCaMKIV, suggesting that other calcium-sensitive enzymes might mediate TGF-β action. These results identify CTF/NF-I as a novel calcium signaling pathway-responsive transcription factor and further suggest multiple molecular mechanisms for the induction of CTF/NF-I transcriptional activity by growth factors.