Regulation of the transforming growth factor beta-responsive transcription factor CTF-1 by calcineurin and calcium/calmodulin-dependent protein kinase IV

被引:57
作者
Alevizopoulos, A
Dusserre, Y
Ruegg, U
Mermod, N
机构
[1] ECOLE POLYTECH FED LAUSANNE,INST GENIE CHIM,DC,LAB MOL BIOTECHNOL,CTR BIOTECHNOL,UNIL,CH-1015 LAUSANNE,SWITZERLAND
[2] UNIV LAUSANNE,SCH PHARM,PHARMACOL GRP,CH-1015 LAUSANNE,SWITZERLAND
关键词
D O I
10.1074/jbc.272.38.23597
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Transforming growth factor beta (TGF-beta) is a pluripotent peptide hormone that regulates various cellular activities, including growth, differentiation, and extracellular matrix protein gene expression, We previously showed that TGF-beta 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-beta. However, the mechanisms of TGF-beta signal transduction remain poorly understood. Here, we analyzed the role of free calcium signaling in the induction of CTF-1 transcriptional activity by TGF-beta, We found that TGF-beta stimulates calcium influx and mediates an increase of the cytoplasmic calcium concentration in NIH3T3 cells. TGF-beta 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-beta 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 (Delta CaMKIV) specifically induces the CTF-1 TAD and the endogenous mouse CTF/NF-I proteins, Both calcineurin- and Delta CaMKIV-mediated induction require the previously identified TGF-beta responsive domain of CTF-1. The immunosuppressants cyclosporin A and FK506 abolish calcineurin-mediated induction of CTF-1 activity, However, TGF-beta still induces the CTF-1 TAD in cells treated with these compounds or in cells overexpressing both calcineurin and Delta CaMKIV, suggesting that other calcium-sensitive enzymes might mediate TGF-beta 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.
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收藏
页码:23597 / 23605
页数:9
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