16 research outputs found
TP53 transcription factor for the NEDD9/HEF1/Cas-L gene: potential targets in Non-Small Cell Lung Cancer treatment
International audienceLung cancer is a serious public health problem. Although there has been significant progress in chemotherapy, non-small cell lung cancer is still resistant to current treatments, primarily because of the slow rate of cell development. It is thus important to find new molecules directed against targets other than proliferation agents. Considering the high proportion of mutant proteins in tumor cells, and the high rate of mutation of the TP53 gene in all cancers, and in NSCLC in particular, this gene is a perfect target. Certain new molecules have been shown to restore the activity of mutated p53 protein, for example PRIMA-1, which reactivates the His273 mutant p53. In a previous study, we presented triazine A190, a molecule with a cytostatic activity that blocks cells in the G1 phase and induces apoptosis. Here, we show that A190 not only restores mutant p53 activity, but also induces an overexpression of the NEDD9 gene, leading to apoptotic death. These findings might offer hope for the development of new targeted therapies, specific to tumor cells, which spare healthy cell
CD95-mediated calcium signaling promotes T helper 17 trafficking to inflamed organs in lupus-prone mice
CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95L and that after cleavage, cl-CD95L promoted T helper 17 (Th17) lymphocyte transmigration across the endothelial barrier at the expense of T regulatory cells. T cell migration relied on a direct interaction between the CD95 domain called calcium-inducing domain (CID) and the Src homology 3 domain of phospholipase Cγ1. Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3. We generated a cell-penetrating CID peptide that prevented Th17 cell transmigration and alleviated clinical symptoms in lupus mice. Therefore, neutralizing the CD95 non-apoptotic signaling pathway could be an attractive therapeutic approach for SLE treatment
CD95 recruits PLCγ1 to trigger a calcium response promoting Th17 accumulation in inflamed organs of lupus mice
CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95L, and that after cleavage, cl-CD95L promoted T helper 17 (Th17) lymphocyte transmigration across the endothelial barrier at the expense of T regulatory cells. T cell migration relied on a direct interaction between the CD95 domain called calcium-inducing domain (CID) and the Src homology 3 domain of phospholipase Cγ1. Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3. We generated a cell-penetrating CID peptide that prevented Th17 cell transmigration and alleviated clinical symptoms in lupus mice. Therefore, neutralizing the CD95 non-apoptotic signaling pathway may be attractive therapeutic approach for SLE treatment
Fine and ultrafine particles issued from oil fuels and second-generation biofuels combustion: development of a standardized tool to evaluate particles toxicity
International audienc
Fine and ultrafine particles issued from oil fuels and second-generation biofuels combustion: a comparative study of the physico-chemical and in vitro toxicological characteristics
International audienc
Fine and ultrafine particles issued from oil fuels and second-generation biofuels combustion: development of a standardized tool to evaluate particles toxicity
International audienc
A novel large regulator RNA, B2, partially overlaps the HEF1/NEDD9/Cas-L gene
The non-coding RNAs are new players in cellular and molecular biology.
Indeed, quantitative and functional non-coding RNA has long been
underestimated. There is a great diversity and it seems that much of the
genome is transcribed into RNA, while only 1.2% of DNA information is
translated into proteins. Non-coding RNA has been categorized according
to different specifications so large non-coding RNA includes RNA with
300 to more than 10,000 bp. In this study, we propose a new non-coding
RNA named 82 discovered by differential display. 82 is a nuclear RNA
which is 51,011 bp long with no significant open reading frame. This RNA
has a continuous homology with the genomic DNA of the HEF1/NEDD9/Cas-L
gene located on 6p24-p25. This homology has enabled us to characterize
its structure by choosing overlapping fragments to perform several
RT-PCRs. B2 RNA extends from 10 kb upstream of exon 1 of the HEF1 gene
on the 5 end to exon 4 HEF1 on the 3’ end. In addition, a strategic
choice of PCR primers enabled us to determine the location of B2 in the
subcellular compartment and then real-time PCR revealed overexpression
of 82 and HEF1 in certain tissues such as thymus, cervix, liver, and
spleen (among the 20 tissues analysed). 82 seems especially interesting
in that it can regulate apoptosis and cell proliferation by modulating
HEF1 In addition, the fact that cytostatic treatments can induce B2
reinforces the interest in this new potential target in the development
of anticancer treatments. These results show that this novel non-coding
RNA is an attractive target
Correction to A Novel Covalent mTOR Inhibitor, DHM25, Shows in Vivo Antitumor Activity against Triple-Negative Breast Cancer Cells
International audienc
A Novel Covalent mTOR Inhibitor, DHM25, Shows in Vivo Antitumor Activity against Triple-Negative Breast Cancer Cells
International audienceConstitutive activation of the PI3K/mTOR signaling pathway contributes to carcinogenesis and metastasis in most, if not all, breast cancers. From a chromene backbone reported to inhibit class I PI3K catalytic subunits, several rounds of chemical syntheses led to the generation of a new collection of chromologues that showed enhanced ability to kill PI3K-addicted cancer cells and to inhibit Akt phosphorylation at serine 473, a hallmark of PI3K/mTOR activation. This initial screen uncovered a chromene designated DHM25 that exerted potent antitumor activity against breast tumor cell lines. Strikingly, DHM25 was shown to be a selective and covalent inhibitor of mTOR using biochemical and cellular analyses, modeling, and a large panel of kinase activity assays spanning the human kinome (243 kinases). Finally, in vivo, this novel drug was an efficient inhibitor of growth and metastasis of triple-negative breast cancer cells, paving the way for its clinical application in oncolog