Intracellular protein homeostasis
Yves le Dréan (MC)
Pascale le Goff (MC)
Denis Michel (PR)
Catherine Martin (AJT-EN-0.9)
Catherine Le Quement
- Original functions of chaperone proteins (BiP, Crt, Clusterin).
- Cellular responses to environmental stresses (Proteotoxic stresses; HSFs, endoplasmic reticulum stress; electromagnetic fields.
- Elementary principles of transcriptional regulation (cooperativity, combinatorial specificity, sigmoidicity, epigenetic gene occlusion).
- Deterministic vs non-deterministic gene expression. Random transcriptional responses lead to phenotypic heterogeneity in the cell population. This heterogeneity is physiologically useful for progenitor cells (development through selection/induction) but deleterious in post-mitotic tissues, where it is associated with the risk of cancer and aging. We are studying the sources of heterogeneous gene expression.
Studies since 1997
Zhadobov M, Augustine R, Sauleau R, Alekseev S, Di Paola A, Le Quément C, Mahamoud YS, Le Dréan Y (2011)
Complex permittivity of representative biological solutions in the 2-67 GHz range.
Bioelectromagnetics. in press
Nicol-Benoit F, Amon A, Vaillant C, le Goff P, le Dréan Y, Pakdel F, Flouriot G, Valotaire Y, Michel D (2011).
A dynamic model of transcriptional imprinting derived from the vitellogenesis memory effect.
Biophys J. 101:1557-68.
Michel D (2011).
Basic statistical recipes for the emergence of biochemical discernment.
Prog Biophys Mol Biol. 106:498-516
Michel D (2011).
Hierarchical cooperativity mediated by chromatin remodeling; the model of the MMTV transcription regulation.
J Theor Biol. 287:74-81
Le Quément C, Nicolas Nicolaz C, Zhadobov M, Desmots F, Sauleau R, Aubry M, Michel D, Le Dréan Y (2011).
Whole-genome expression analysis in primary human keratinocyte cell cultures exposed to 60 GHz radiation.
Bioelectromagnetics. in press
Zhadobov M, Sauleau R, Augustine R, Le Quément C, Le Dréan Y, Thouroude D (2011).
Near-field dosimetry for in vitro exposure of human cells at 60 GHz.
Bioelectromagnetics. in press
Sylvain Lecomte, Fabienne Desmots, F. Le Masson, Pascale Le Goff, Denis Michel, ES Christians, Yves Le Dréan (2010).
Roles of heat shock factor 1 and 2 in response to proteasome inhibition: consequence on p53 stability
Oncogene. In press
Denis Michel (2010).
How transcription factors can adjust the gene expression floodgates
Prog. Biophys. Mol. Biol. 102:16-37
The chain of events between gene promoter occupancy and RNA accumulation, mediating the specificity and dosage of gene expression.
Christophe Nicolas Nicolaz, Maxim Zhadobov, Fabienne Desmots, Ronan Sauleau, Daniel Thouroude, Denis Michel, Yves Le Drean (2009).
Absence of direct effect of low-power millimeter-wave radiation at 60.4 GHz on endoplasmic reticulum stress.
Cell. Biol. Toxicol. 25, 471-478
Aurélie Corduan, Sylvain Lecomte, Catherine Martin, Denis Michel and Fabienne Desmots (2009).
Sequential interplay between BAG6 and HSP70 upon heat shock
Cell. Mol. Life Sci. 66, 1998-2004.
Stabilization of the heat shock stress interactome through sequential permissive action and negative feed back.
Denis Michel (2009).
Fine tuning gene expression
Biochimie 91, 933-941
Shifting from stochastic to deterministic cellular behaviours through equating probability and reality.
Maxim Zhadobov, Christophe Nicolas Nicolaz, Ronan Sauleau, Fabienne Desmots, Daniel Thouroude, Denis Michel, and Yves Le Dréan (2009).
Evaluation of the potential biological effects of the 60-GHz millimeter waves upon human cells
IEEE Trans. Antenn. Prop. 57, 2949-2956
Christophe Nicolas Nicolaz, Maxim Zhadobov, Fabienne Desmots, Armelle Ansart, Ronan Sauleau, Daniel Thouroude, Denis Michel, Yves Le Drean (2009).
Study of narrow band millimeter-wave potential interactions with endoplasmic reticulum stress sensor genes
Bioelecromagnetics 30, 365-373
Fabienne Desmots, Helen R. Russell, Denis Michel, and Peter J. McKinnon (2008).
Scythe regulates apoptosis inducing factor stability during endoplasmic reticulum stress induced apoptosis
J. Biol. Chem. 283, 3264-3271
Apoptosis regulation by Scythe/BAG6/BAT3 through molecular sequestration and nucleocytoplasmic shuttling activity
Maxim Zhadobov, Ronan Sauleau, Yves Le Dréan, S. I. Alekseev and M. C. Ziskin. (2008).
Numerical and experimental millimeter-wave dosimetry for in vitro experiments”.
IEEE Microwave Theory and Techniques, 56, 2998-3007.
Denis Michel (2008).
An alternative theoretical formula for hemoglobin oxygenation
Eur. Biophys. J. 37, 823-827
Experimental data suggest that sgmoidal equilibrium curves are generated through herarchical equilibration.
Philippe Nizard, Susanne Tetley, Yves Le Dréan, Tanguy Watrin, Pascale Le Goff, Mark R Wilson and Denis Michel (2007).
Stress-induced retro-translocation of clusterin/ApoJ into the cytosol
Traffic 8, 554-565.
Clusterin/ApoJ is an extracellular chaperone capable of reaching the cytosol is situations of stress. This atypical location explains different roles reported for this molecule (inhibition of mitochondria-mediated apoptosis, regulation of the NFkB pathway)
Maxim Zhadobov, Ronan Sauleau, Laurent Le Coq, Laure Debure, Daniel Thouroude, Denis Michel and Yves Le Dréan (2007).
Low-power millimeter wave radiations do not alter stress-sensitive gene expression of chaperone proteins.
Bioelectromagnetics 28, 188-196.
If care is taken to avoid thermal effects, exposure to millimetric waves do not alter the classical Hsp expression. To ensure the complete absence of thermal effects, the doses of irradiations used in this report were lower than the legal norms authorized for general population.
Denis Michel (2007).
Cooperative equilibrium curves generated by ordered ligand binding to multi-site molecules
Biophys. Chem. 129, 284-288 .
Fabien Loison, Laure Debure, Philippe Nizard, Pascale Le Goff, Denis Michel and Yves Le Dréan (2006)
Up-regulation of the clusterin gene after proteotoxic stress. Implication of HSF1/HSF2 heterocomplexes.
Biochem. J. 395, 223-231.
While heat shock induces HSF1 homotrimerisation, proteasome inhibition leads to the formation of HSF1/HSF2 heterotrimers, where HSF1 and HSF2 are activated by phosphorylation and stabilization respectively.
See the commentary of Johanna Ork and Lea Sistonen (2006) Clustering of heat-shock factors Biochem. J. 395, e5–e6.
Fabien Loison, Philippe Nizard, Tony Sourisseau, Pascale Le Goff, Laure Debure, Yves Le Drean and Denis Michel (2005).
A ubiquitin-based assay for the cytosolic uptake of protein transduction domains.
Mol. Ther. 11, 205-214.
A novel enzymatic system for intracellular protein delivery and MHC-I-based vaccination. See Alexander Varshavsky 2005. Ubiquitin fusion technique and related methods. Methods in Enzymology 399, 777-799.
Pascale Le Goff, Yves Le Drean, Christine Le Peron, Catherine Le Jossic-Corcos, Abdelkadder Ainouche and Denis Michel (2004).
Intracellular trafficking of heat shock factor 2.
Exp. Cell. Res. 294, 480-493.
Activation and inactivation of transcription factors are tightly coupled phenomenons. Upon activation, many transcription factors are destructed through the ubiquitin-proteasome system. In the case of HSF2, we observed that activation treatments of HSF2 are followed by a passage of this transcription factor in subcellular structures containing insoluble proteins. This behaviour, conserved among vertebrates, suggests conformational inactivation and recycling mechanisms.
Laure Debure, Jean-Luc Vayssiere, Vincent Rincheval, Fabien Loison, Yves Le Drean and Denis Michel (2003).
Intracellular clusterin causes juxtanuclear aggregate formation and mitochondrial alteration.
J. Cell. Sci. 116, 3109-3120.
When accumulating at high concentration in the cytosolic compartment, clusterin is strongly cytotoxic.
Yves Le Dréan, Nathalie Mincheneau, Pascale Le Goff and Denis Michel (2002).
Potentiation of glucocorticoid receptor transcriptional activity by sumoylation.
Endocrinology 143, 3482-3489.
The influences of sumoylation on transcription factors functions are quite diverse. In the case of glucocorticoid receptor, we showed that symoylation induces changes in the sets of glucocorticoid-responsive genes, allowing differential gene regulation by a single transcription factor.
Tony Sourisseau, Christine Desbois, Laure Debure, David D. L. Bowtell, Andrew C. B. Cato, Jean Schneikert, Emmanuel Moyse and Denis Michel (2001).
Alteration of the stability of Bag-1 protein in the control of olfactory neuronal apoptosis.
J. Cell. Sci. 114, 1409-1416.
Cancers derived from olfactory neurons have long been shown rare, as compared with central neuroblastomas. This situation is intriguing, considering the continuous proliferation in the olfactory neuroepithelium and the exposure of this tissue to carcinogenic agents present in the environment. We propose that the resistance to cancer of this tissue may be related to the regulated instability of the anti-apoptotic co-chaperone Bag-1.
Raphaël Métivier, Yves le Dréan, Gilles Salbert and Farzad Packdel (2000).
Interplay between liganded and orphan nuclear receptors controls reproductive pathways.
Biochem. Cell. Biol. 78, 345-58.
Mazurais D, Porter M, Lethimonier C, Le Dréan G, Le Goff P, Randall C, Pakdel F, Bromage N, Kah O. (2000).
Effects of melatonin on liver estrogen receptor and vitellogenin expression in rainbow trout: an in vitro and in vivo study.
Gen Comp Endocrinol. 118, 344-353.
Françoise Adam, Tony Sourisseau, Raphaël Métivier, Yann Lepage, Christine Desbois, Denis Michel and Gilles Salbert (2000).
COUP-TFI (chicken ovalbumin upstream promoter-transcription factor I) regulates cell migration and axogenesis in differentiating P19 embryonalcarcinoma cells.
Mol. Endo. 14, 1918-1933.
Liu D, Chandy M, Lee SK, Le Dréan Y, Ando H, Xiong F, Woon Lee J, Hew CL. (2000).
A zebrafish ftz-F1 (Fushi tarazu factor 1) homologue requires multiple subdomains in the D and E regions for its transcriptional activity.
J Biol Chem. 275, 16758-16766.
Pascale Le Goff and Denis Michel (1999).
HSF1 activation occurs at different temperatures in somatic and male germ cells in the poïkilotherm rainbow trout.
Biochem. Biophys. Res. Commun. 259, 15-20
Hsp genes are upregulated at temperatures exceeding a given threshold, which depends on the considered organisms. Does the primary cellular thermostat correspond to the capacity of HSF1 from each species to be activated over a certain temperature? Using a poikilothem vertebrate (the fish rainbow trout), we presented data supporting that in fact the temperature sensor is not HSF1. Indeed, HSF1 is activated at different temperatures, depending on the thermosensitivity of each organ in the same animal.
Catherine Jomary, Gilles Chatelain, Denis Michel, Ann Weston, Michael J. Neal and Stephen E. Jones (1999).
Effect of targeted expression of clusterin in photoreceptor cells on retinal development and differentiation.
J. Cell. Sci. 112, 1455-1464.
Considering the purported pro-apoptotic action of clusterin, we decided to construct transgenic mice overexpressing clusterin in a non-vital organ: retina. Surprisingly, retinas from these animals did not degenerate, but conversely presented a strongly decreased apoptosis rate. We believe now that the influence of clusterin on apoptosis is dependent on the form and location of the clusterin protein. In this work, it was the secreted protein.
Tony Sourisseau, Yves Le Dréan, Gilles Salbert, Frédéric Flamant and Denis Michel (1999).
A eukaryotic conditional expression system.
BioTechniques 27, 106-110.
Ando H, Ando J, Le Drean Y, Liu D, Xiong F, Hew CL. (1999).
Salmon gonadotropin IIbeta subunit promoter contains multiple DNA elements responsible for stimulation by gonadotropin-releasing hormone through protein kinase C-dependent and -independent pathways.
Mol Cell Endocrinol. 157, 143-152.
Claire Mauduit, Gilles Chatelain, Solange Magre, Gilbert Brun, Mohamed Benahmed and Denis Michel (1999).
Regulation by pH of the Alternative Splicing of the Stem Cell Factor Pre-mRNA in the Testis.
J. Biol. Chem. 274, 770-775.
The alternative splicing of "skipping exons" is generally believed to result from the existence of non consensual RNA sequences at the exon-intron boundaries. This is not the case for the internal skipping exon of SCF synthesized by Sertoli cells, dictating either soluble or membrane-anchored location of the final protein, with para- or juxtacrine actions respectively. Both soluble and membrane forms are necessary for normal embryonic and adult testicular functions respectively. Moreover, we showed that in this case, the type of SCF splicing is ultimately determined by intercellular contact.
Anglade Isabelle, David Mazurais, Véronique Douard, Catherine Le Jossic-Corcos, Evaristo Mananos, Denis Michel and Olivier Kah (1999).
Distribution of glutamic acid decarboxylase mRNA in the forebrain of the rainbow-trout as studied by in situ hybridization.
J. Comp. Neurol. 410, 277-289.
Mazurais David, Ian Brierley, Isabelle Anglade, Janice Drew, Clive Randall, Niall Bromage, Denis Michel, Olivier Kah and Linda M. Williams (1999).
Central malatonin receptors in the rainbow trout: comparative distribution of ligand binding and gene expression.
J. Comp. Neurol. 409, 313-324.
Catherine Le Jossic and Denis Michel (1998).
Striking evolutionary conservation of a cis-element related to nuclear receptor target sites and present in TR2 orphan receptor genes.
Biochem. Biophys. Res. Commun. 245, 64-69.
An amazingly conserved 19 bp-long DNA motif containing an IR-7 nuclear receptor element, in a non coding region: RGGTCACGAACTCTGACCY
Le Dréan Y, Liu D, Xiong F, Hew CL. (1997).
Presence of distinct cis-acting elements on gonadotropin gene promoters in diverse species dictates the selective recruitment of different transcription factors by steroidogenic factor-1.
Mol. Cell. Endocrinol. 135, 31-40.
Liu D, Le Drean Y, Ekker M, Xiong F, Hew CL. (1997).
Teleost FTZ-F1 homolog and its splicing variant determine the expression of the salmon gonadotropin IIbeta subunit gene.
Mol. Endocrinol. 11, 877-890.
Petit F, Le Goff P, Cravédi JP, Valotaire Y, Pakdel F. (1997).
Two complementary bioassays for screening the estrogenic potency of xenobiotics: recombinant yeast for trout estrogen receptor and trout hepatocyte cultures.
J. Mol. Endocrinol. 19, 321-335.
Denis Michel, Gilles Chatelain, Claire Mauduit, Mohamed Benhamed and Gilbert Brun (1997).
Recent evolutionary acquisition of alternative pre-mRNA splicing and 3' processing regulations, induced by B2 SINE insertion.
Nucl. Acids Res. 25, 3228-3234.
The Leukemia Inhibitory Factor (LIF)-receptor, can be synthesized in a soluble form, no longer capable of membrane anchoring. Its function was shown to be opposite of that of the normal full length LIFR, by sequestering the ligand in the medium. Circulating LIFR is massively upregulated in pregnant females, perhaps in relation with the anti-differentiation effect of LIF on embryonic cells (LIF should be added in the culture medium of ES cells). This situation is the consequence of the fortuitous insertion of a retroposon inside an intron of the LIFR gene, upstream of the transmembrane domain-coding exons and generating an alternative transcription termination site, in conjunction with intronic sequences. We have shown that this phenomenon occurred only in mice, but not in rat. This explains why attempts at identifying soluble LIFR in human had so far failed. This example reveals a striking property of molecular evolution: the rapid physiological exploitation of a fortuitous genome modification. Interestingly, a B2 retroposon also participated to the evolution of the retroviral restriction factor Fv1 gene at the level of the transcription termination site.
Denis Michel, Gilles Chatelain, Sophie North and Gilbert Brun (1997).
Stress-induced transcription of the Clusterin/ApoJ gene.
Biochem. J. 328, 45–50.
This work presented the first molecular criterion allowing to classify clusterin as a particular version of Hsp, which led to the concept of extracellular chaperones (see Wilson and Easterbrook-Smith 2000. Clusterin is a secreted mammalian chaperone. Trends Biochem. Sci. 25, 95-98).
Denis Michel, Alain Trembleau, Emmanuel Moyse and Gilbert Brun (1997).
Optimization of PCR/lambda exonuclease-mediated synthesis of sense and antisense DNA probes for in situ hybridization.
Histochem. J. 29, 685-693.
Denis Michel, Emmanuel Moyse, Alain Trembleau, François Jourdan and Gilbert Brun (1997).
Clusterin/ApoJ expression is associated with neuronal apoptosis in the olfactory mucosa of the adult mouse.
J. Cell. Sci. 110, 1635-1645.
The correlation between clusterin overexpression and apoptosis is obvious in many pathological or developmentally programmed cases of tissue regression. However the causal relationships between clusterin and cell death remain puzzling. Using the olfactory sensory system, a favorable model where glial and neuronal cells are anatomically well separated, we showed that the clusterin gene is expressed in surviving glial cells, while the clusterin protein accumulates in the involuting neuronal layer.
Maxim Zhadobov, Ronan Sauleau, Christophe Nicolas Nicolaz, Yves Le Dréan (2009).
Study of Narrow Band Millimeter-Wave Potential Interactions with Endoplasmic Reticulum Stress Sensor Genes
Bioelectromagnetics Newsletter 209 July/August 2009
Tony Sourisseau, Yves Le Drean, Gilles Salbert, Frédéric Flamant and Denis Michel (2001).
In Q. Lu and M.P. Weiner, GlaxoSmithKline (Eds.), Cloning and Expression Vectors for Gene Function Analysis. Section V: Special Purpose Vectors, pp163-167. Eaton Publishing, Natick.
Emmanuel Moyse and Denis Michel (1997).
Analyses of apoptosis-associated DNA fragmentation in vivo during neurodegeneration of the peripheral olfactory system in adult mammals.
Neuromethods 29, 133-159.
Marc Danik, Jean-Guy Chabot, Denis Michel and Remi Quirion (1999).
Clusterin and apolipoprotein E gene expression in the adult brain. In: Clusterin in normal brain functions and during neurodegeneration. Finch, C.B. (Ed) R.G. Landes Co. pp 17-34.