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Genève, Switzerland

Logette E.,University of Lausanne | Schuepbach-Mallepell S.,Geneva Medical Center | Mirjam J.E.,University of Lausanne | Leo X.H.,University of Lausanne | And 7 more authors.
Cell Death and Differentiation | Year: 2011

PIDD has been implicated in survival and apoptotic pathways in response to DNA damage, and a role for PIDD was recently identified in non-homologous end-joining (NHEJ) repair induced by γ-irradiation. Here, we present an interaction of PIDD with PCNA, first identified in a proteomics screen. PCNA has essential functions in DNA replication and repair following UV irradiation. Translesion synthesis (TLS) is a process that prevents UV irradiation-induced replication blockage and is characterized by PCNA monoubiquitination and interaction with the TLS polymerase eta (polη). Both of these processes are inhibited by p21. We report that PIDD modulates p21-PCNA dissociation, and promotes PCNA monoubiquitination and interaction with polη in response to UV irradiation. Furthermore, PIDD deficiency leads to a defect in TLS that is associated, both in vitro and in vivo, with cellular sensitization to UV-induced apoptosis. Thus, PIDD performs key functions upon UV irradiation, including TLS, NHEJ, NF-κB activation and cell death.Cell Death and Differentiation advance online publication, 18 March 2011; doi:10.1038/cdd.2011.19. Source

Ayyanan A.,Ecole Polytechnique Federale de Lausanne | Laribi O.,Ecole Polytechnique Federale de Lausanne | Laribi O.,EHESP School of Public Health | Schuepbach-Mallepell S.,Ecole Polytechnique Federale de Lausanne | And 10 more authors.
Molecular Endocrinology | Year: 2011

Bisphenol A [BPA, 2,2,-bis (hydroxyphenyl) propane] is one of the highest-volume chemicals produced worldwide. It is detected in body fluids of more than 90% of the human population. Originally synthesized as an estrogenic compound, it is currently utilized to manufacture food and beverage containers resulting in uptake with food and drinks. There is concern that exposure to low doses of BPA, defined as less than or equal to 5 mg/kg body weight /d, may have developmental effects on various hormone-responsive organs including the mammary gland. Here, we asked whether perinatal exposure to a range of low doses of BPA is sufficient to alter mammary gland hormone response later on in life, with a possible impact on breast cancer risk. To mimic human exposure, we added BPA to the drinking water of C57/Bl6 breeding pairs. Analysis of the mammary glands of their daughters at puberty showed that estrogen-dependent transcriptional events were perturbed and the number of terminal end buds, estrogen-induced proliferative structures, was altered in a dose-dependent fashion. Importantly, adult females showed an increase in mammary epithelial cell numbers comparable to that seen in females exposed to diethylbestrol, a compound exposure to which was previously linked to increased breast cancer risk. Molecularly, the mRNAs encoding Wnt-4 and receptor activator of nuclear factor kB ligand, two key mediators of hormone function implicated in control of mammary stem cell proliferation and carcinogenesis, showed increased induction by progesterone in the mammary tissue of exposed mice. Thus, perinatal exposure to environmentally relevant doses of BPA alters long-term hormone response that may increase the propensity to develop breast cancer. © 2011 by The Endocrine Society. Source

Antigny F.,Geneva Medical Center | Girardin N.,Geneva Medical Center | Frieden M.,Geneva Medical Center
Journal of Biological Chemistry | Year: 2012

In endothelial cells Ca2+ entry is an essential component of the Ca2+ signal that takes place during processes such as cell proliferation or angiogenesis. Ca2+ influx occurs via the storeoperated Ca2+ entry pathway, involving stromal interaction molecule-1 (STIM1) and Orai1, but also through channels gated by second messengers like the transient receptor potential canonical (TRPC) channels. The human umbilical vein-derived endothelial cell line EA.hy926 expressed STIM1 and Orai1 as well as several TRPC channels. By invalidating each of these molecules, we showed that TRPC3, TRPC4, and TRPC5 are essential for the formation of tubular structures observed after EA.hy926 cells were plated on Matrigel. On the contrary, the silencing of STIM1 or Orai1 did not prevent tubulogenesis. Soon after being plated on Matrigel, the cells displayed spontaneous Ca2+ oscillations that were strongly reduced by treatment with siRNA against TRPC3, TRPC4, or TRPC5, but not siRNA against STIM1 or Orai1. Furthermore, we showed that cell proliferation was reduced upon siRNA treatment against TRPC3, TRPC5, and Orai1 channels, whereas the knockdown of STIM1 had no effect. On primary human umbilical vein endothelial cells, TRPC1, TRPC4, and STIM1 are involved in tube formation, whereas Orai1 has no effect. These data showed that TRPC channels are essential for in vitro tubulogenesis, both on endothelial cell line and on primary endothelial cells. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Antigny F.,Geneva Medical Center | Konig S.,Geneva Medical Center | Bernheim L.,Geneva Medical Center | Frieden M.,Geneva Medical Center
Cell Calcium | Year: 2014

Cytosolic Ca2+ signals are fundamental for the early and late steps of myoblast differentiation and are, as in many cells, generated by Ca2+ release from internal stores as well as by plasma membrane Ca2+ entry. Our recent studies identified the store-operated Ca2+ channels, Orai1 and TRPC1&C4, as crucial for the early steps of human myogenesis and for the late fusion events. In the present work, we assessed the role of the inositol-1,4,5 tris-phosphate receptor (IP3R) type 1 during human myoblast differentiation. We demonstrated, using siRNA strategy that IP3R1 is required for the expression of muscle-specific transcription factors such as myogenin and MEF2 (myocyte enhancer factor 2), and for the formation of myotubes. The knockdown of IP3R1 strongly reduced endogenous spontaneous Ca2+ transients, and attenuated store-operated Ca2+ entry. As well, two Ca2+-dependent key enzymes of muscle differentiation, NFAT and CamKII are down-regulated upon siIP3R1 treatment. On the contrary, the overexpression of IP3R1 accelerated myoblasts differentiation. These findings identify Ca2+ release mediated by IP3R1 as an essential mechanism during the early steps of myoblast differentiation. © 2014 Elsevier Ltd. Source

Antigny F.,Geneva Medical Center | Koenig S.,Geneva Medical Center | Bernheim L.,Geneva Medical Center | Frieden M.,Geneva Medical Center
Journal of Cell Science | Year: 2013

Myogenesis involves expression of muscle-specific transcription factors such as myogenin and myocyte enhancer factor 2 (MEF2), and is essentially regulated by fluctuations of cytosolic Ca2+ concentration. Recently we demonstrated that molecular players of storeoperated Ca2+ entry (SOCE), stromal interacting molecule (STIM) and Orai, were fundamental in the differentiation process of postnatal human myoblasts. Besides STIM and Orai proteins, the family of transient receptor potential canonical (TRPC) channels was shown to be part of SOCE in several cellular systems. In the present study, we investigated the role of TRPC channels in the human myogenesis process. We demonstrate, using an siRNA strategy or dominant negative TRPC overexpression, that TRPC1 and TRPC4 participate in SOCE, are necessary for MEF2 expression, and allow the fusion process to generate myotubes of normal size. Conversely, the overexpression of STIM1 with TRPC4 or TRPC1 increased SOCE, accelerated myoblast fusion, and produced hypertrophic myotubes. Interestingly, in cells depleted of TRPC1 or TRPC4, the normalization of SOCE by increasing the extracellular calcium concentration or by overexpressing STIM1 or Orai1 was not sufficient to restore normal fusion process. A normal differentiation occurred only when TRPC channel was re-expressed. These findings indicate that Ca2+ entry mediated specifically by TRPC1 and TRPC4 allow the formation of normal-sized myotubes. ©2013. Published by The Company of Biologists Ltd. Source

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