[Avenues of reflection for endometriosis research in France].

Endometriosis is a chronic disease in which lesions resembling endometrial tissue are found outside the uterus, mainly in the pelvis or abdomen. It may affect 10% of women of childbearing age. It is the cause of a significant alteration in quality of life and a major cost to the health system.

The Oxygen Paradox, the French Paradox, and age-related diseases.

A paradox is a seemingly absurd or impossible concept, proposition, or theory that is often difficult to understand or explain, sometimes apparently self-contradictory, and yet ultimately correct or true. How is it possible, for example, that oxygen "a toxic environmental poison" could be also indispensable for life (Beckman and Ames Physiol Rev 78(2):547-81, 1998; Stadtman and Berlett Chem Res Toxicol 10(5):485-94, 1997)?: the so-called Oxygen Paradox (Davies and Ursini 1995; Davies Biochem Soc Symp 61:1-31, 1995). How can French people apparently disregard the rule that high dietary intakes of cholesterol and saturated fats (e.

Liver Reptin/RUVBL2 controls glucose and lipid metabolism with opposite actions on mTORC1 and mTORC2 signalling.

Objective: The AAA+ ATPase Reptin is overexpressed in hepatocellular carcinoma and preclinical studies indicate that it could be a relevant therapeutic target. However, its physiological and pathophysiological roles in vivo remain unknown. This study aimed to determine the role of Reptin in mammalian adult liver.

Reptin regulates insulin-stimulated Akt phosphorylation in hepatocellular carcinoma via the regulation of SHP-1/PTPN6.

Hepatocellular carcinoma (HCC) is the main primary cancer of the liver. Many studies have shown that insulin resistance is a risk factor for HCC. We previously discovered the overexpression and oncogenic role of the Reptin/RUVBL2 ATPase in HCC.

Metalloproteinase meprin α regulates migration and invasion of human hepatocarcinoma cells and is a mediator of the oncoprotein Reptin.

Hepatocellular carcinoma is associated with a high rate of intra-hepatic invasion that carries a poor prognosis. Meprin alpha (Mep1A) is a secreted metalloproteinase with many substrates relevant to cancer invasion. We found that Mep1A was a target of Reptin, a protein that is oncogenic in HCC.

The AAA+ proteins Pontin and Reptin enter adult age: from understanding their basic biology to the identification of selective inhibitors.

Pontin and Reptin are related partner proteins belonging to the AAA+ (ATPases Associated with various cellular Activities) family. They are implicated in multiple and seemingly unrelated processes encompassing the regulation of gene transcription, the remodeling of chromatin, DNA damage sensing and repair, and the assembly of protein and ribonucleoprotein complexes, among others. The 2nd International Workshop on Pontin and Reptin took place at the Instituto de Tecnologia Química e Biológica António Xavier in Oeiras, Portugal on October 10-12, 2014, and reported significant new advances on the mechanisms of action of these two AAA+ ATPases.

Reptin regulates DNA double strand breaks repair in human hepatocellular carcinoma.

Reptin/RUVBL2 is overexpressed in most hepatocellular carcinomas and is required for the growth and viability of HCC cells. Reptin is involved in several chromatin remodeling complexes, some of which are involved in the detection and repair of DNA damage, but data on Reptin involvement in the repair of DNA damage are scarce and contradictory. Our objective was to study the effects of Reptin silencing on the repair of DNA double-strand breaks (DSB) in HCC cells.

Discoidin domain receptor 1 controls linear invadosome formation via a Cdc42-Tuba pathway.

Accumulation of type I collagen fibrils in tumors is associated with an increased risk of metastasis. Invadosomes are F-actin structures able to degrade the extracellular matrix. We previously found that collagen I fibrils induced the formation of peculiar linear invadosomes in an unexpected integrin-independent manner.

Design, synthesis and biological evaluation of Pontin ATPase inhibitors through a molecular docking approach.

A virtual screening strategy, through molecular docking, for the elaboration of an electronic library of Pontin inhibitors has resulted in the identification of two original scaffolds. The chemical synthesis of four candidates allowed extensive biological evaluations for their anticancer activity. Two compounds displayed an effect on Pontin ATPase activity, and one of them also exhibited a noticeable effect on cell growth.

Posttranscriptional regulation of PER1 underlies the oncogenic function of IREα.

Growing evidence supports a role for the unfolded protein response (UPR) in carcinogenesis; however, the precise molecular mechanisms underlying this phenomenon remain elusive. Herein, we identified the circadian clock PER1 mRNA as a novel substrate of the endoribonuclease activity of the UPR sensor IRE1α. Analysis of the mechanism shows that IRE1α endoribonuclease activity decreased PER1 mRNA in tumor cells without affecting PER1 gene transcription.

The emergence of the conserved AAA+ ATPases Pontin and Reptin on the signaling landscape.

Pontin (also known as RUVBL1 and RVB1) and Reptin (also called RUVBL2 and RVB2) are related members of the large AAA+ (adenosine triphosphatase associated with diverse cellular activities) superfamily of conserved proteins. Various cellular functions depend on Pontin and Reptin, mostly because of their functions in the assembly of protein complexes that play a role in the regulation of cellular energetic metabolism, transcription, chromatin remodeling, and the DNA damage response. Little is known, though, about the interconnections between these multiple functions, how the relevant signaling pathways are regulated, whether the interconnections are affected in human disease, and whether components of these pathways are suitable targets for therapeutic intervention.

The ATPase activity of reptin is required for its effects on tumor cell growth and viability in hepatocellular carcinoma.

Reptin is overexpressed in most human hepatocellular carcinomas. Reptin is involved in chromatin remodeling, transcription regulation, or supramolecular complexes assembly. Its silencing leads to growth arrest and apoptosis in cultured hepatocellular carcinoma cells and stops hepatocellular carcinoma progression in xenografts.

A novel small-molecule screening strategy identifies mitoxantrone as a RhoGTPase inhibitor.

RhoGTPases are GDP/GTP molecular switches that control a wide variety of cellular processes, thereby contributing to many diseases, including cancer. As a consequence, there is great interest in the identification of small-molecule inhibitors of RhoGTPases. In the present paper, using the property of GTP-loaded RhoGTPases to bind to their effectors, we describe a miniaturized and robust assay to monitor Rac1 GTPase activation that is suitable for large-scale high-throughput screening.

Extracellular matrix rigidity controls podosome induction in microvascular endothelial cells.

Background Information: Podosomes are actin-based structures involved in cell adhesion, migration, invasion and extracellular matrix degradation. They have been described in large vessel endothelial cells, but nothing is known concerning microvascular endothelial cells. Here, we focussed on liver sinusoidal endothelial cells (LSECs), fenestrated microvascular cells that play major roles in liver physiology.

Hepatic lesions observed in hepatitis C virus transgenic mice infected by Helicobacter hepaticus.

Background: The heterogeneity of hepatitis C virus (HCV) infection cannot always be explained by HCV genotypes or host genetic factors, raising the issue of possible cofactors. A new form of hepatitis leading to liver cancer was discovered in 1992 in mice, owing to an infection by Helicobacter hepaticus. Moreover, several studies showed an association between the presence of HCV and Helicobacter in the liver of patients with severe liver diseases suggesting a possible synergism between the two pathogens.

Sorafenib-mediated targeting of the AAA⁺ ATPase p97/VCP leads to disruption of the secretory pathway, endoplasmic reticulum stress, and hepatocellular cancer cell death.

The molecular mechanisms and cellular targets of sorafenib, a multikinase inhibitor used for the treatment of hepatocellular carcinoma (HCC), remain to be fully characterized. Recent studies have shown that sorafenib induces tumor cell death through the activation of endoplasmic reticulum stress signaling and/or autophagy in various cellular models. Using liver cancer-derived cell lines, we specifically show that the IRE1 and phosphorylated extracellular signal-regulated kinase arms of the unfolded protein response (UPR) become activated upon sorafenib treatment, whereas the ATF6 arm is inhibited.

First identification of small-molecule inhibitors of Pontin by combining virtual screening and enzymatic assay.

The human protein Pontin, which belongs to the AAA+ (ATPases associated with various cellular activities) family, is overexpressed in several cancers and its silencing in vitro leads to tumour cell growth arrest and apoptosis, making it a good target for cancer therapy. In particular, high levels of expression were found in hepatic tumours for which the therapeutic arsenal is rather limited. The three-dimensional structure of Pontin has been resolved previously, revealing a hexameric assembly with one ADP molecule co-crystallized in each subunit.

Rnd3/RhoE Is down-regulated in hepatocellular carcinoma and controls cellular invasion.

Unlabelled: We performed a review of public microarray data that revealed a significant down-regulation of Rnd3 expression in hepatocellular carcinoma (HCC), as compared to nontumor liver. Rnd3/RhoE is an atypical RhoGTPase family member because it is always under its active GTP-bound conformation and not sensitive to classical regulators. Rnd3 down-regulation was validated by quantitative real-time polymerase chain reaction in 120 independent tumors.

Physiological type I collagen organization induces the formation of a novel class of linear invadosomes.

Invadosomes are F-actin structures capable of degrading the matrix through the activation of matrix metalloproteases. As fibrillar type I collagen promotes pro-matrix metalloproteinase 2 activation by membrane type 1 matrix metalloproteinase, we aimed at investigating the functional relationships between collagen I organization and invadosome induction. We found that fibrillar collagen I induced linear F-actin structures, distributed along the fibrils, on endothelial cells, macrophages, fibroblasts, and tumor cells.

Molecular basis of differential target regulation by miR-96 and miR-182: the Glypican-3 as a model.

Besides the fact that miR-96 and miR-182 belong to the miR-182/183 cluster, their seed region (UUGGCA, nucleotides 2-7) is identical suggesting potential common properties in mRNA target recognition and cellular functions. Here, we used the mRNA encoding Glypican-3, a heparan-sulfate proteoglycan, as a model target as its short 3' untranslated region is predicted to contain one miR-96/182 site, and assessed whether it is post-transcriptionally regulated by these two microRNAs. We found that miR-96 downregulated GPC3 expression by targeting its mRNA 3'-untranslated region and interacting with the predicted site.

The multifaceted proteins Reptin and Pontin as major players in cancer.

Reptin and Pontin belong to the family of AAA+ ATPases (ATPases Associated with various cellular Activities). Several studies have reported their overexpression in cancer, including hepatocellular carcinoma and colorectal cancer. Functional studies have implicated them in many cellular processes highly relevant to cancer.