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THE JAULIAC LAB: NFAT AND CANCER
 new critical players in cancer
 
NFAT AND CELLULAR MOTILITY REGULATION IN BREAST CARCINOMA

NFAT isotypes cellular distribution

We have shown that NFAT transcription factors are expressed and active ind are differentially expressed in breast carcinoma (Jauliac et al. 2002), (Yoeli-Lerner et al. 2005) (Germann et al. 2012).  We found that RNA of every gene -but NFAT3- are similarly detected independently of the cells' ERalpha (ERA) status Remarkably, NFAT3 expression at the RNA as well as at the protein level is restricted to ERA+ cells, whereas neither NFAT1 nor NFAT2 proteins are detected in ERA+ cells ; NFAT1 protein is present only in ERA- cells, NFAT2 protein is absent in the ERA- cells, and NFAT5 is found in both type of cells (Fougère et al.2010)

Differential regulation of cellular motility by NFAT isotypes

NFAT1, NFAT3 and NFAT5 differentially regulate LCN2 expression to modulate breast cancer cell motility

- We identifIied that some of members of the NFAT isotypes, NFAT1 and NFAT5, have pro migratory and pro invasive capabilities compared to other members, like NFAT3, that is found in less aggressive ERA+ breast cancer and has anti migratory and anti invasive actions by inhibiting the LCN2 gene transcription in cooperation with other genes targeted by ERA yet to be identified (Fougère et al.2010).

- NFAT1 is a transcription factor that elicits breast carcinoma cells to become invasive, thus contributing to metastasis. The molecular mechanisms by which NFAT1 operates in this respect are still poorly known. Here, we report that NFAT1 increases lipocalin 2 (LCN2) mRNA and protein expression by binding to specific sites in the LCN2 gene promoter region. We show that the LCN2 protein is required downstream of NFAT1 to increase breast cancer cell invasion. We demonstrate that the NFAT1-LCN2 axis is sufficient to regulate expression of the TNF-like receptor TWEAKR at the RNA level and of its ligand, TWEAK, at the protein level. We show, however, that TWEAKR mediates an anti-invasive effect in breast cancer cells whereas, depending on LCN2 expression, TWEAK has either anti- or pro-invasive capacities. Thus, we identify LCN2 and TWEAKR-TWEAK as crucial downstream effectors of NFAT1 that regulate breast cancer cell motility and invasive capacity (Gaudineau et al., 2012).

- Ddx5 and ddx17 are two highly related RNA helicases involved in both transcription and splicing. These proteins coactivate transcription factors involved in cancer such as the estrogen receptor alpha, p53 and beta-catenin. Ddx5 and ddx17 are part of the splicing machinery and can modulate alternative splicing, the main mechanism increasing the proteome diversity. Alternative splicing also has a role in gene expression level regulation when it is coupled to the nonsense-mediated mRNA decay (NMD) pathway. In this work, we report that ddx5 and ddx17 have a dual role in the control of the pro-migratory NFAT5 transcription factor. First, ddx5 and ddx17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration. Second, at the splicing level, ddx5 and ddx17 increase the inclusion of NFAT5 exon 5. As exon 5 contains a pre-mature translation termination codon, its inclusion leads to the regulation of NFAT5 mRNAs by the NMD pathway and to a decrease in NFAT5 protein level. Therefore, we demonstrated for the first time that a transcriptional coregulator can simultaneously regulate the transcriptional activity and alternative splicing of a transcription factor. This dual regulation, where ddx5 and ddx17 enhance the transcriptional activity of NFAT5 although reducing its protein expression level, suggests a critical role for ddx5 and ddx17 in tumor cell migration through the fine regulation of NFAT5 pathway (Germann et al., 2012).

Work in progress

We currently work on both the identification of the mechanisms of NFAT transcription factors activation and the identification of their downstream genes required to increase or blunt the cellular motility. The goals of these studies are to be able to provide new therapeutic targets to prevent or cure breast cancer metastases
2017
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