Publications by authors named "Jean-Claude Chambard"

15 Publications

  • Page 1 of 1

Induction of epithelial-mesenchymal transition (EMT) and Gli1 expression in head and neck squamous cell carcinoma (HNSCC) spheroid cultures.

Bosn J Basic Med Sci 2018 Nov 7;18(4):336-346. Epub 2018 Nov 7.

Research Institute on Signaling, Developmental Biology and Cancer, Centre A. Lacassagne, Nice, France Genetic, Immunology and Human Pathology Laboratory, Tunis Science Faculty, University El Manar, Tunis, Tunisia.

Tumor microenvironment provides a specialized niche in which a population of stem-like cells is enriched and contributes to cancer progression. Moreover, cancer stem cell (CSC) phenotype has been associated with epithelial-mesenchymal transition (EMT). Here we investigated the effect of tumor microenvironment on the phenotypic characteristics of head and neck cancer cells and expression of CSC markers using a three-dimensional (3D), spheroid, culture system of CAL33 cell line from human tongue squamous cell carcinoma. CAL33 cells derived from 2D monolayer cultures were grown in spheroid cultures containing serum-free medium (epidermal growth factor [EGF], fibroblast growth factor [FGF], and insulin). Adherent CAL33 cells from spheroids or standard control cultures were grown in the presence/absence of serum in combination with hypoxia/normoxia. Markers of EMT, CSC, and hypoxia were analyzed either by Western blotting, immunofluorescence, or reverse transcription quantitative PCR. Spheroid cultures showed hypoxic microenvironment (high carbonic anhydrase IX [CAIX] expression), mesenchymal-like characteristics (reduced E-cadherin and increased vimentin and N-cadherin expression, presence of larger colonies comprised of larger, spread cells with lower density), and increased expression of the CSC marker glioma-associated oncogene homolog 1 (Gli1). These effects were recapitulated in serum-free adherent CAL33 cells maintained for prolonged periods in hypoxia (1% O2) but, in contrast, were completely abolished by the presence of serum. Overall, we found that a combination of hypoxia, EGF and FGF was essential to induce the EMT in adherent CAL33 cell cultures. The addition of serum rapidly reverts the EMT of cells, affects CSC phenotype and, thus, prevents the detection of such cells in tumor cell lines.
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http://dx.doi.org/10.17305/bjbms.2018.3243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252098PMC
November 2018

Mitochondrial fission is associated with UCP1 activity in human brite/beige adipocytes.

Mol Metab 2018 01 22;7:35-44. Epub 2017 Nov 22.

Université Côte d'Azur, CNRS, Inserm, iBV, Nice, France. Electronic address:

Objective: Thermogenic adipocytes (i.e. brown or brite/beige adipocytes) are able to burn large amounts of lipids and carbohydrates as a result of highly active mitochondria and enhanced uncoupled respiration, due to UCP1 activity. Although mitochondria are the key organelles for this thermogenic function, limited human data are available.

Methods/results: We characterized changes in the mitochondrial function of human brite adipocytes, using hMADS cells as a model of white- to brite-adipocyte conversion. We found that profound molecular modifications were associated with morphological changes in mitochondria. The fission process was partly driven by the DRP1 protein, which also promoted mitochondrial uncoupling.

Conclusion: Our data demonstrate that white-to-brite conversion of human adipocytes relies on molecular, morphological and functional changes in mitochondria, which enable brite/beige cells to carry out thermogenesis.
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http://dx.doi.org/10.1016/j.molmet.2017.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784321PMC
January 2018

miR-125b affects mitochondrial biogenesis and impairs brite adipocyte formation and function.

Mol Metab 2016 Aug 15;5(8):615-625. Epub 2016 Jun 15.

Univ. Nice Sophia Antipolis, CNRS, Inserm, iBV, 06100 Nice, France. Electronic address:

Objective: In rodents and humans, besides brown adipose tissue (BAT), islands of thermogenic adipocytes, termed "brite" (brown-in-white) or beige adipocytes, emerge within white adipose tissue (WAT) after cold exposure or β3-adrenoceptor stimulation, which may protect from obesity and associated diseases. microRNAs are novel modulators of adipose tissue development and function. The purpose of this work was to characterize the role of microRNAs in the control of brite adipocyte formation.

Methods/results: Using human multipotent adipose derived stem cells, we identified miR-125b-5p as downregulated upon brite adipocyte formation. In humans and rodents, miR-125b-5p expression was lower in BAT than in WAT. In vitro, overexpression and knockdown of miR-125b-5p decreased and increased mitochondrial biogenesis, respectively. In vivo, miR-125b-5p levels were downregulated in subcutaneous WAT and interscapular BAT upon β3-adrenergic receptor stimulation. Injections of an miR-125b-5p mimic and LNA inhibitor directly into WAT inhibited and increased β3-adrenoceptor-mediated induction of UCP1, respectively, and mitochondrial brite adipocyte marker expression and mitochondriogenesis.

Conclusion: Collectively, our results demonstrate that miR-125b-5p plays an important role in the repression of brite adipocyte function by modulating oxygen consumption and mitochondrial gene expression.
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http://dx.doi.org/10.1016/j.molmet.2016.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021678PMC
August 2016

Visfatin expression analysis in association with recruitment and activation of human and rodent brown and brite adipocytes.

Adipocyte 2016 Apr-Jun;5(2):186-95. Epub 2015 Dec 9.

Univ. Nice-Sophia Antipolis, UFR Medecine, Nice, France; CNRS, iBV, UMR, 7277, Nice, France; INSERM, iBV, U1091, Nice, France.

Human brown adipocytes are able to burn fat and glucose and are now considered as a potential strategy to treat obesity, type 2 diabetes and metabolic disorders. Besides their thermogenic function, brown adipocytes are able to secrete adipokines. One of these is visfatin, a nicotinamide phosphoribosyltransferase involved in nicotinamide dinucleotide synthesis, which is known to participate in the synthesis of insulin by pancreatic β cells. In a therapeutic context, it is of interest to establish whether a potential correlation exists between brown adipocyte activation and/or brite adipocyte recruitment, and adipokine expression. We analyzed visfatin expression, as a pre-requisite to its secretion, in rodent and human biopsies and cell models of brown/brite adipocytes. We found that visfatin was preferentially expressed in mature adipocytes and that this expression was higher in brown adipose tissue of rodents compared to other fat depots. However, using various rodent models we were unable to find any correlation between visfatin expression and brown or brite adipocyte activation or recruitment. Interestingly, the situation is different in humans where visfatin expression was found to be equivalent between white and brown or brite adipocytes in vivo and in vitro. In conclusion, visfatin can be considered only as a rodent brown adipocyte biomarker, independently of tissue activation.
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http://dx.doi.org/10.1080/21623945.2015.1122854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916889PMC
July 2016

The K+ channel TASK1 modulates β-adrenergic response in brown adipose tissue through the mineralocorticoid receptor pathway.

FASEB J 2016 Feb 2;30(2):909-22. Epub 2015 Nov 2.

*University of Nice Sophia Antipolis, Nice, France; Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Valrose (iBV), Unité Mixte de Recherche (UMR) 7277, Nice, France; U1091, iBV, INSERM, Nice, France; UMR 7370 and Laboratories of Excellence, Ion Channel Science and Therapeutics, Laboratoire de PhysioMédecine Moléculaire (LP2M), CNRS, Nice, France; Laboratory of Metabolism, Department of Internal Medicine Specialties, Faculty of Medicine, University of Geneva, Geneva, Switzerland, UMR 7284 and **U1081, CNRS, Institute for Research in Cancer and Aging in Nice, INSERM, Nice, France; Anatomopathology Service, Pasteur Hospital, Centre Hospitalier Universitaire de Nice, Nice, France; Obesity Center, Department of Experimental and Clinical Medicine, Ancona, Italy; Warwick Medical School, University of Warwick, Coventry, United Kingdom

Brown adipose tissue (BAT) is essential for adaptive thermogenesis and dissipation of caloric excess through the activity of uncoupling protein (UCP)-1. BAT in humans is of great interest for the treatment of obesity and related diseases. In this study, the expression of Twik-related acid-sensitive K(+) channel (TASK)-1 [a pH-sensitive potassium channel encoded by the potassium channel, 2-pore domain, subfamily K, member 3 (Kcnk3) gene] correlated highly with Ucp1 expression in obese and cold-exposed mice. In addition, Task1-null mice, compared with their controls, became overweight, mainly because of an increase in white adipose tissue mass and BAT whitening. Task1(-/-)-mouse-derived brown adipocytes, compared with wild-type mouse-derived brown adipocytes, displayed an impaired β3-adrenergic receptor response that was characterized by a decrease in oxygen consumption, Ucp1 expression, and lipolysis. This phenotype was thought to be caused by an exacerbation of mineralocorticoid receptor (MR) signaling, given that it was mimicked by corticoids and reversed by an MR inhibitor. We concluded that the K(+) channel TASK1 controls the thermogenic activity in brown adipocytes through modulation of β-adrenergic receptor signaling.
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http://dx.doi.org/10.1096/fj.15-277475DOI Listing
February 2016

Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis.

Nat Commun 2015 Apr 30;6:6993. Epub 2015 Apr 30.

1] INSERM, U1065, Microenvironnement, Signalisation et Cancer, Centre Méditerranéen de Médecine Moléculaire (C3M), 151 Route de Saint-Antoine de Ginestière, BP 23194, 06204 Nice, France [2] Université de Nice Sophia Antipolis, Faculté de Médecine, 06107 Nice, France.

Disruption of the endothelial barrier by tumour-derived secreted factors is a critical step in cancer cell extravasation and metastasis. Here, by comparative proteomic analysis of melanoma secretomes, we identify the matricellular protein SPARC as a novel tumour-derived vascular permeability factor. SPARC deficiency abrogates tumour-initiated permeability of lung capillaries and prevents extravasation, whereas SPARC overexpression enhances vascular leakiness, extravasation and lung metastasis. SPARC-induced paracellular permeability is dependent on the endothelial VCAM1 receptor and p38 MAPK signalling. Blocking VCAM1 impedes melanoma-induced endothelial permeability and extravasation. The clinical relevance of our findings is highlighted by high levels of SPARC detected in tumour from human pulmonary melanoma lesions. Our study establishes tumour-produced SPARC and VCAM1 as regulators of cancer extravasation, revealing a novel targetable interaction for prevention of metastasis.
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http://dx.doi.org/10.1038/ncomms7993DOI Listing
April 2015

The ω6-fatty acid, arachidonic acid, regulates the conversion of white to brite adipocyte through a prostaglandin/calcium mediated pathway.

Mol Metab 2014 Dec 16;3(9):834-47. Epub 2014 Sep 16.

Univ. Nice Sophia Antipolis, iBV, UMR 7277, 06100 Nice, France ; CNRS, iBV, UMR 7277, 06100 Nice, France ; Inserm, iBV, U1091, 06100 Nice, France.

Objective: Brite adipocytes are inducible energy-dissipating cells expressing UCP1 which appear within white adipose tissue of healthy adult individuals. Recruitment of these cells represents a potential strategy to fight obesity and associated diseases.

Methods/results: Using human Multipotent Adipose-Derived Stem cells, able to convert into brite adipocytes, we show that arachidonic acid strongly inhibits brite adipocyte formation via a cyclooxygenase pathway leading to secretion of PGE2 and PGF2α. Both prostaglandins induce an oscillatory Ca(++) signaling coupled to ERK pathway and trigger a decrease in UCP1 expression and in oxygen consumption without altering mitochondriogenesis. In mice fed a standard diet supplemented with ω6 arachidonic acid, PGF2α and PGE2 amounts are increased in subcutaneous white adipose tissue and associated with a decrease in the recruitment of brite adipocytes.

Conclusion: Our results suggest that dietary excess of ω6 polyunsaturated fatty acids present in Western diets, may also favor obesity by preventing the "browning" process to take place.
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http://dx.doi.org/10.1016/j.molmet.2014.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264041PMC
December 2014

Glucose uptake in brown fat cells is dependent on mTOR complex 2-promoted GLUT1 translocation.

J Cell Biol 2014 Nov;207(3):365-74

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE -0691 Stockholm, Sweden

Brown adipose tissue is the primary site for thermogenesis and can consume, in addition to free fatty acids, a very high amount of glucose from the blood, which can both acutely and chronically affect glucose homeostasis. Here, we show that mechanistic target of rapamycin (mTOR) complex 2 has a novel role in β3-adrenoceptor-stimulated glucose uptake in brown adipose tissue. We show that β3-adrenoceptors stimulate glucose uptake in brown adipose tissue via a signaling pathway that is comprised of two different parts: one part dependent on cAMP-mediated increases in GLUT1 transcription and de novo synthesis of GLUT1 and another part dependent on mTOR complex 2-stimulated translocation of newly synthesized GLUT1 to the plasma membrane, leading to increased glucose uptake. Both parts are essential for β3-adrenoceptor-stimulated glucose uptake. Importantly, the effect of β3-adrenoceptor on mTOR complex 2 is independent of the classical insulin-phosphoinositide 3-kinase-Akt pathway, highlighting a novel mechanism of mTOR complex 2 activation.
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http://dx.doi.org/10.1083/jcb.201403080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226734PMC
November 2014

Chondrogenic potential of stem cells derived from adipose tissue: a powerful pharmacological tool.

Biochem Biophys Res Commun 2013 Nov 14;440(4):786-91. Epub 2013 Oct 14.

University Nice Sophia Antipolis, iBV, UMR 7277, 06100 Nice, France; CNRS, iBV, UMR 7277, 06100 Nice, France; Inserm, iBV, U1091, 06100 Nice, France; Service de Rhumatologie, Hospital l'Archet 1 CHU, 06200 Nice, France.

Chondrogenesis has been widely investigated in vitro using bone marrow-derived mesenchymal stromal cells (BM-MSCs) or primary chondrocytes. However, their use raises some issues partially circumvented by the availability of Adipose tissue-derived MSCs. Herein; we characterized the chondrogenic potential of human Multipotent Adipose-Derived Stem (hMADS) cells, and their potential use as pharmacological tool. hMADS cells are able to synthesize matrix proteins including COMP, Aggrecan and type II Collagen. Furthermore, hMADS cells express BMP receptors in a similar manner to BM-MSC, and BMP6 treatment of differentiated cells prevents expression of the hypertrophic marker type X Collagen. We tested whether IL-1β and nicotine could impact chondrocyte differentiation. As expected, IL-1β induced ADAMTS-4 gene expression and modulated negatively chondrogenesis while these effects were reverted in the presence of the IL-1 receptor antagonist. Nicotine, at concentrations similar to those observed in blood of smokers, exhibited a dose dependent increase of Aggrecan expression, suggesting an unexpected protective effect of the drug under these conditions. Therefore, hMADS cells represent a valuable tool for the analysis of in vitro chondrocyte differentiation and to screen for potentially interesting pharmacological drugs.
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http://dx.doi.org/10.1016/j.bbrc.2013.10.012DOI Listing
November 2013

Raf-1 activation prevents caspase 9 processing downstream of apoptosome formation.

J Signal Transduct 2011 14;2011:834948. Epub 2010 Oct 14.

Institute of Developmental Biology and Cancer, CNRS UMR6543, A. Lacassagne Center, University of Nice Sophia-Antipolis, 33 Avenue Valombrose, 06189 Nice, France.

In many cell types, growth factor removal induces the release of cytochrome-c from mitochondria that leads to activation of caspase-9 in the apoptosome complex. Here, we show that sustained stimulation of the Raf-1/MAPK1,3 pathway prevents caspase-9 activation induced by serum depletion in CCL39/ΔRaf-1:ER fibroblasts. The protective effect mediated by Raf-1 is sensitive to MEK inhibition that is sufficient to induce caspase-9 cleavage in exponentially growing cells. Raf-1 activation does not inhibit the release of cytochrome-c from mitochondria while preventing caspase-9 activation. Gel filtration chromatography analysis of apoptosome formation in cells shows that Raf-1/MAPK1,3 activation does not interfere with APAF-1 oligomerization and recruitment of caspase 9. Raf-1-mediated caspase-9 inhibition is sensitive to emetine, indicating that the protective mechanism requires protein synthesis. However, the Raf/MAPK1,3 pathway does not regulate XIAP. Taken together, these results indicate that the Raf-1/MAPK1,3 pathway controls an apoptosis regulator that prevents caspase-9 activation in the apoptosome complex.
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http://dx.doi.org/10.1155/2011/834948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100593PMC
July 2011

ERK and cell death: mechanisms of ERK-induced cell death--apoptosis, autophagy and senescence.

FEBS J 2010 Jan 16;277(1):2-21. Epub 2009 Oct 16.

Department of Anatomy and Cellular Biology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Quebec, Canada.

The Ras/Raf/extracellular signal-regulated kinase (ERK) signaling pathway plays a crucial role in almost all cell functions and therefore requires exquisite control of its spatiotemporal activity. Depending on the cell type and stimulus, ERK activity will mediate different antiproliferative events, such as apoptosis, autophagy and senescence in vitro and in vivo. ERK activity can promote either intrinsic or extrinsic apoptotic pathways by induction of mitochondrial cytochrome c release or caspase-8 activation, permanent cell cycle arrest or autophagic vacuolization. These unusual effects require sustained ERK activity in specific subcellular compartments and could depend on the presence of reactive oxygen species. We will summarize the mechanisms involved in Ras/Raf/ERK antiproliferative functions.
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http://dx.doi.org/10.1111/j.1742-4658.2009.07366.xDOI Listing
January 2010

ERK implication in cell cycle regulation.

Biochim Biophys Acta 2007 Aug 17;1773(8):1299-310. Epub 2006 Nov 17.

Institute of Signaling Developmental Biology and Cancer, CNRS UMR 6543, Universite de Nice-Sofia Antipolis, Centre A. Lacassagne, 33 Avenue de Valombrose, 06189 Nice, France.

The Ras/Raf/MEK/ERK signaling cascade that integrates an extreme variety of extracellular stimuli into key biological responses controlling cell proliferation, differentiation or death is one of the most studied intracellular pathways. Here we present some evidences that have been accumulated over the last 15 years proving the requirement of ERK in the control of cell proliferation. In this review we focus (i) on the spatio-temporal control of ERK signaling, (ii) on the key cellular components linking extracellular signals to the induction and activation of cell cycle events controlling G1 to S-phase transition and (iii) on the role of ERK in the growth factor-independent G2/M phase of the cell cycle. As ERK pathway is often co-activated with the PI3 kinase signaling, we highlight some of the key points of convergence leading to a full activation of mTOR via ERK and AKT synergies. Finally, ERK and AKT targets being constitutively activated in so many human cancers, we briefly touched the cure issue of using more specific drugs in rationally selected cancer patients.
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http://dx.doi.org/10.1016/j.bbamcr.2006.11.010DOI Listing
August 2007

Low dose cadmium poisoning results in sustained ERK phosphorylation and caspase activation.

Biochem Biophys Res Commun 2006 Nov 2;350(3):803-7. Epub 2006 Oct 2.

Transcriptional Regulation and Differentiation, CNRS UMR 6548, Nice University, Parc Valrose, 06108 Nice cedex 2, France.

Cadmium poisoning has been known to result in a wide variety of cellular responses, including oxidative stress and kinase activation. It has been reported that ERK is activated following acute cadmium exposure, and this response is commonly seen as a classical ERK survival mechanism. Here, we analyzed different cell types for their responses to low concentrations of cadmium poisoning. We found that there is an association between cell susceptibility to cadmium toxicity and ERK activation. This activation is atypical, since it consists of a sustained ERK phosphorylation, that lasts up to 6 days post stimulation. This activation is associated with the appearance of cleaved caspases 8 and 3, processed PARP, and irreversible damage. Pharmacological inhibition of ERK phosphorylation results in the ability of cells to resist cadmium poisoning. Our data indicate that low cadmium concentrations result in an unconventional ERK sustained phosphorylation, which in turn leads to death signaling.
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http://dx.doi.org/10.1016/j.bbrc.2006.09.126DOI Listing
November 2006

Extracellular signal-regulated kinases phosphorylate mitogen-activated protein kinase phosphatase 3/DUSP6 at serines 159 and 197, two sites critical for its proteasomal degradation.

Mol Cell Biol 2005 Jan;25(2):854-64

Institute of Signaling, Developmental Biology and Cancer Research, CNRS UMR 6543, Centre Antoine Lacassagne, 33 Ave. de Valombrose, 06189 Nice, France.

Mitogen-activated protein (MAP) kinase phosphatases (MKPs) are dual-specificity phosphatases that dephosphorylate phosphothreonine and phosphotyrosine residues within MAP kinases. Here, we describe a novel posttranslational mechanism for regulating MKP-3/Pyst1/DUSP6, a member of the MKP family that is highly specific for extracellular signal-regulated kinase 1 and 2 (ERK1/2) inactivation. Using a fibroblast model in which the expression of either MKP-3 or a more stable MKP-3-green fluorescent protein (GFP) chimera was induced by tetracycline, we found that serum induces the phosphorylation of MKP-3 and its subsequent degradation by the proteasome in a MEK1 and MEK2 (MEK1/2)-ERK1/2-dependent manner. In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197. Tetracycline-inducible cell clones expressing either single or double serine mutants of MKP-3 or MKP-3-GFP confirmed that these two sites are targeted by the MEK1/2-ERK1/2 module in vivo. Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3. Hence, double mutation caused a threefold increase in the half-life of MKP-3. Finally, we show that the phosphorylation of MKP-3 has no effect on its catalytic activity. Thus, ERK1/2 exert a positive feedback loop on their own activity by promoting the degradation of MKP-3, one of their major inactivators in the cytosol, a situation opposite to that described for the nuclear phosphatase MKP-1.
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http://dx.doi.org/10.1128/MCB.25.2.854-864.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC543408PMC
January 2005

Adhesion-dependent control of Akt/protein kinase B occurs at multiple levels.

J Cell Physiol 2003 Jul;196(1):98-104

CNRS UMR 6543, Centre A. Lacassagne, Nice Cedex 2, France.

The protein kinase Akt, also known as Protein Kinase B, has been implicated in the survival of several cell types challenged with various apoptotic stimuli. In CCL39 lung fibroblasts, apoptosis is induced by anchorage and mitogen removal. Mitogen-induced activation of Akt is highly anchorage dependent in these cells and removal of adhesion is accompanied by a rapid loss in responsiveness to soluble agonists followed by a significant decrease in Akt abundance. Loss of the protein appears to be independent of kinase activation since the expression of a constitutively active form, gag-Akt, is also dependent upon cell adhesion. Although the disappearance of Akt is coincident with the induction of programmed cell death, it cannot be fully prevented by treatment of cells with the caspase inhibitor ZVAD or by sustained activation of the anti-apoptotic Raf/ERK pathway, in cells expressing an inducible DeltaRaf-1:ER construct. In addition, a previously unrecognized decrease in Akt mRNA levels following anchorage removal occurs suggesting that anchorage-dependent transcriptional and/or post-transcriptional mechanisms contribute to the adhesion-dependent regulation of Akt expression.
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http://dx.doi.org/10.1002/jcp.10276DOI Listing
July 2003
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