Antonelli R.,International School for Advanced Studies |
Pizzarelli R.,International School for Advanced Studies |
Pedroni A.,International School for Advanced Studies |
Fritschy J.-M.,University of Zurich |
And 5 more authors.
The cell adhesion molecule Neuroligin2 (NL2) is localized selectively at GABAergic synapses, where it interacts with the scaffolding protein gephyrin in the post-synaptic density. However, the role of this interaction for formation and plasticity of GABAergic synapses is unclear. Here, we demonstrate that endogenous NL2 undergoes proline-directed phosphorylation at its unique S714-P consensus site, leading to the recruitment of the peptidyl-prolyl cis-trans isomerase Pin1. This signalling cascade negatively regulates NL2' s ability to interact with gephyrin at GABAergic post-synaptic sites. As a consequence, enhanced accumulation of NL2, gephyrin and GABA A receptors was detected at GABAergic synapses in the hippocampus of Pin1-knockout mice (Pin1â '/â ') associated with an increase in amplitude of spontaneous GABA A -mediated post-synaptic currents. Our results suggest that Pin1-dependent signalling represents a mechanism to modulate GABAergic transmission by regulating NL2/gephyrin interaction. © 2014 Macmillan Publishers Limited. All rights reserved. Source
Bublik D.R.,Laboratorio Nazionale Del Consorzio Interuniversitario per le Biotecnologie |
Scolz M.,Laboratorio Nazionale Del Consorzio Interuniversitario per le Biotecnologie |
Triolo G.,International Center for Genetic Engineering and Biotechnology |
Monte M.,International Center for Genetic Engineering and Biotechnology |
And 3 more authors.
Journal of Biological Chemistry
p21CIP1/WAF1 belongs to the CIP/KIP family of Cdk inhibitors, and its expression is tightly controlled during the cell cycle, mainly by transcriptional and post-translational mechanisms. Fine regulation of p21 CIP1/WAF1 levels is critical for cell cycle control and for cellular response to stress. In the present work, we describe a novel mechanism to modulate p21CIP1/WAF1 levels mediated by the human GTSE-1 (G 2 and S phase-expressed-1) protein. Our results provide evidence that hGTSE-1 protects p21CIP1/WAF1 from proteasome-dependent degradation as part of a functional complex containing the Hsp90-bindingTPR protein WISp39. We further show that the hGTSE-1 N-terminal portion is sufficient for p21 CIP1/WAF1 binding and stabilization. Finally, we demonstrate that hGTSE-1 mediated-p21CIP1/WAF1 stabilization is clearly involved in the ability of cells to counter-act cytotoxicity induced by the microtubule poison paclitaxel. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. Source
Peche L.Y.,Laboratorio Nazionale Del Consorzio Interuniversitario per le Biotecnologie |
Ladelfa M.F.,University of Buenos Aires |
Toledo M.F.,University of Buenos Aires |
Mano M.,International Center for Genetic Engineering and Biotechnology |
And 4 more authors.
Journal of Biological Chemistry
MageB2 belongs to the melanoma antigen gene (MAGE-I) family of tumor-specific antigens. Expression of this gene has been detected in human tumors of different origins. However, little is known about the protein function and how its expression affects tumor cell phenotypes. In this work, we found that human MageB2 protein promotes tumor cell proliferation in a p53-independent fashion, as observed both in cultured cells and growing tumors in mice. Gene expression analysis showed that MageB2 enhances the activity of E2F transcription factors. Mechanistically, the activation of E2Fs is related to the ability of MageB2 to interact with the E2F inhibitor HDAC1. Cellular distribution of MageB2 protein includes the nucleoli. Nevertheless, ribotoxic drugs rapidly promote its nucleolar exit.Weshow that MageB2 counter acts E2F inhibition by ribosomal proteins independently of Mdm2 expression. Importantly, MageB2 plays a critical role in impairing cell cycle arrest in response to Actinomycin D. The data presented here support a relevant function for human MageB2 in cancer cells both under cycling and stressed conditions, presenting a distinct functional feature with respect to other characterized MAGE-I proteins. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Source
Vermezovic J.,Istituto Fondazione Italiana per la Ricerca sul Cancro di Oncologia Molecolare |
Adamowicz M.,Istituto Fondazione Italiana per la Ricerca sul Cancro di Oncologia Molecolare |
Santarpia L.,Humanitas Clinical and Research Institute |
Rustighi A.,Laboratorio Nazionale Del Consorzio Interuniversitario per le Biotecnologie |
And 10 more authors.
Nature Structural and Molecular Biology
The DNA-damage response (DDR) ensures genome stability and proper inheritance of genetic information, both of which are essential to survival. It is presently unclear to what extent other signaling pathways modulate DDR function. Here we show that Notch receptor binds and inactivates ATM kinase and that this mechanism is evolutionarily conserved in Caenorhabditis elegans, Xenopus laevis and humans. In C. elegans, the Notch pathway impairs DDR signaling in gonad germ cells. In mammalian cells, activation of human Notch1 leads to reduced ATM signaling in a manner independent of Notch1 transcriptional activity. Notch1 binds directly to the regulatory FATC domain of ATM and inhibits ATM kinase activity. Notch1 and ATM activation are inversely correlated in human breast cancers, and inactivation of ATM by Notch1 contributes to the survival of Notch1-driven leukemia cells upon DNA damage. © 2015 Nature America, Inc. All rights reserved. Source
Giorgi C.,University of Ferrara |
Bonora M.,University of Ferrara |
Sorrentino G.,Laboratorio Nazionale Del Consorzio Interuniversitario per le Biotecnologie |
Missiroli S.,University of Ferrara |
And 11 more authors.
Proceedings of the National Academy of Sciences of the United States of America
The tumor suppressor p53 is a key protein in preventing cell transformation and tumor progression. Activated by a variety of stimuli, p53 regulates cell-cycle arrest and apoptosis. Along with its well-documented transcriptional control over cell-death programs within the nucleus, p53 exerts crucial although still poorly understood functions in the cytoplasm, directly modulating the apoptotic response at the mitochondrial level. Calcium (Ca(2+)) transfer between the endoplasmic reticulum (ER) and mitochondria represents a critical signal in the induction of apoptosis. However, the mechanism controlling this flux in response to stress stimuli remains largely unknown. Here we show that, in the cytoplasm, WT p53 localizes at the ER and at specialized contact domains between the ER and mitochondria (mitochondria-associated membranes). We demonstrate that, upon stress stimuli, WT p53 accumulates at these sites and modulates Ca(2+) homeostasis. Mechanistically, upon activation, WT p53 directly binds to the sarco/ER Ca(2+)-ATPase (SERCA) pump at the ER, changing its oxidative state and thus leading to an increased Ca(2+) load, followed by an enhanced transfer to mitochondria. The consequent mitochondrial Ca(2+) overload causes in turn alterations in the morphology of this organelle and induction of apoptosis. Pharmacological inactivation of WT p53 or naturally occurring p53 missense mutants inhibits SERCA pump activity at the ER, leading to a reduction of the Ca(2+) signaling from the ER to mitochondria. These findings define a critical nonnuclear function of p53 in regulating Ca(2+) signal-dependent apoptosis. Source